Methods of treating early breast cancer using rebosilil in combination with aromatase inhibitors

Abstract

The present disclosure relates to adjuvant treatment of HR + / HER2-phase II or III early breast cancer in adult patients. The methods comprise administering a rebosilil (CDK4 / 6 inhibitor) in combination with endocrine therapy.

Description

BACKGROUND

[0001] Breast cancer (BC) is the most commonly diagnosed cancer worldwide. It is estimated that there were approximately 1.7 million new cases of BC and 522,000 deaths attributed to the disease globally in 2012 (CA Cancer J Clin 65:87-108, 2015). BC incidence varies by ethnicity and region worldwide, from 27 per 100,000 in Central Africa and East Asia to 92 per 100,000 in North America (GLOBOCAN: Estimated Cancer Incidence, Mortality and Prevalence Worldwide 2012 [Internet] [cited 2018 Jun 26], https: / / publications.iarc.fr / Databases / Iarc-Cancerbases / GLOBOCAN-2012-Estimated-Cancer-Incidence-Mortality-And-Prevalence-Worldwide-In-2012-V1.0-2012). In the United States, BC is projected to be the most commonly diagnosed cancer in 2018, with an estimated 268,670 new cases and 41,400 deaths (CA Cancer J Clin 68:7-30, 2018). BC cases in European countries were estimated at 458,337 in 2012 (Eur J Cancer Oxf Engl 1990 49:1374-1403, 2013). Male BC is not common, representing about 1% of all BC cases, but its incidence is continuing to rise (Breast Cancer Res Treat 137:465-470, 2013).

[0002] The vast majority of newly diagnosed BC cases are early-stage breast cancer (EBC), confined to breast tissue and regional lymphatic vessels, and can be cured with localized treatments such as surgery and radiation therapy. According to data from the Surveillance, Epidemiology and End Results (SEER) program collected between 1975 and 2012, 93% of confirmed cases were EBC, with 62% confined to breast tissue and 31% located within breast tissue and regional lymph nodes (SEER Cancer Statistics Review, 1975-2015 [Internet]. Bethesda, MD, National Cancer Institute, 2018, https: / / seer.cancer.gov / csr / 1975_2015 / ).

[0003] In addition to primary surgical treatment, EBC treatment typically includes other anti-tumor therapies such as radiotherapy and adjuvant or neoadjuvant systemic therapy. While many EBC patients achieve disease-free survival through surgical resection and radiotherapy, micrometastases frequently lead to distant recurrence, a major cause of death in EBC patients (BMC Med 13:195, 2015). According to a meta-analysis of nearly 150,000 women in 200 randomized clinical trials conducted by the EBC Trialists' Collaborative Group (EBCTCG), approximately 36% and 20% of EBC patients without any adjuvant systemic therapy experienced recurrence and BC-related death, respectively, during a 5-year follow-up period (Lancet London 365:1687–1717, 2005). Furthermore, hormone receptor (HR)-positive EBC patients still experience recurrence and BC-related death 5 years post-surgery, with only 45% reporting recurrence-free status at 15-year follow-up.

[0004] Adjuvant systemic therapy for EBC patients includes cytotoxic therapy, biotherapy, and endocrine therapy, which can reduce local and distant recurrence, decrease BC-related mortality, and improve overall survival (OS) (Lancet London 365:1687–1717, 2005). The need for and selection of systemic adjuvant therapy depends on individual recurrence risk and may be influenced by several clinical, pathological, and genomic predictive and prognostic factors of the tumor and the patient, such as tumor stage, histopathological grade, tumor HR status, human epidermal growth factor receptor 2 (HER2) status, polygenic recurrence score, proliferative markers such as Ki67, menopausal status, comorbidities, and age. Using these factors, the postoperative recurrence risk of EBC can be categorized as low, intermediate, or high (BMC Med 13:195, 2015). While there is no consensus on the definitions of these risk groupings, generally speaking, patients with smaller tumors, no regional lymph node metastasis, low tumor grade, HR-positive and HER2-negative status, and low recurrence genomic score have a lower risk of recurrence (i.e., a 5-year recurrence rate of 5%-10%). These patients are usually considered for adjuvant endocrine therapy (ET) rather than chemotherapy, as the latter has relatively lower clinical benefit. On the other hand, patients with multiple regional lymph node metastases, high tumor grade, HER2-positive status, or high recurrence genomic score have a higher risk of recurrence. These patients are usually considered for adjuvant chemotherapy (while HER2-positive BC patients use HER2-targeted agents), and if the tumor expresses HR, adjuvant ET is also considered (usually after chemotherapy).

[0005] It is estimated that 75% of BCs express steroid hormone receptors (estrogen receptor [ER] and / or progesterone receptor [PgR]), therefore these patients may benefit from adjuvant ET using tamoxifen or aromatase inhibitors (AIs) (letrozole, anastrozole, or exemestane) (J Clin Oncol Off J Am Soc Clin Oncol [Journal of Clinical Oncology, Official Journal of the American Society of Clinical Oncology] 28:2784–2795, 2010). Unlike chemotherapy, ET can reduce the risk of recurrence and death in HR-positive EBCs (Lancet [The Lancet] London, UK 365:1687–1717, 2005).

[0006] Current clinical guidelines (see Ann Oncol Off J Eur Soc Med Oncol [Annals of Oncology, the Official Journal of the European Society for Medical Oncology] 26 Suppl 5:v8-30, 2015; and National Comprehensive Cancer Network. Breast Cancer (Version 1.2019) [Internet]. NCCN, 2019 [cited 2019 May 6], https: / / www.nccn.org / professionals / physician_gls / pdf / breast.pdf) recommend the following for adjuvant ET in HR-positive EBC: • For premenopausal women: 1.1. 5-10 years of tamoxifen therapy, with or without ovarian suppression, or 1.2. 5 years of AI therapy with ovarian suppression (see N Engl J Med [New England Journal of Medicine] 379:122-137, 2018) • For postmenopausal women: 1.3. Initial AI therapy for 5 years (or up to 10 years) based on the results of the MA.17R trial (see N Engl J Med [New England Journal of Medicine] 375:209-219, 2016), or 1.4. Initial tamoxifen therapy for 2-3 years followed by AI therapy (totaling up to 5 years of AI therapy, or up to 5 years of AI therapy), or 1.5. Tamoxifen therapy for about 5 years followed by 5 years of AI therapy, or 1.6. Tamoxifen therapy for up to 10 years (Ann Oncol Off J Eur Soc Med Oncol [Annals of Oncology, the Official Journal of the European Society for Medical Oncology] 26 Suppl 5:v8-30, 2015; National Comprehensive Cancer Network. Breast Cancer (Version 1.2019) [Internet]. NCCN, 2019 [cited 2019 May 6], https: / / www.nccn.org / professionals / physician_gls / pdf / breast.pdf) • For men: Limited data suggest that the combination of tamoxifen or an AI with a gonadotropin-releasing hormone (GnRH) agonist should be the preferred ET for HR-positive, HER2-negative EBC (Breast Cancer Res Treat 151 : 141-147, 2015).

[0007] WO 2015 / 022609 Al (incorporated herein by reference) discloses combination therapies for the treatment of cancer, including EBC. Some EBC patients can still relapse, especially those with poor clinical, pathological, and genomic features. In HR-positive, HER2-negative, EBC patients with multiple (> 4) regional lymph node metastases (roughly equivalent to anatomic stage III group in the AJCC 8th edition breast cancer staging), about 25-30% of patients will relapse within 5 years of ET using an AI-containing ET (Lancet Lond Engl 365: 1687-1717, 2005). Despite 5 years of ET, only 48% of these patients are free of distant recurrence within 20 years, and almost half of the patients die from BC within 20 years (N Engl J Med 377: 1836-1846, 2017). While patients with 1-3 regional lymph node metastases (typically corresponding to anatomic stage II group in the AJCC 8th edition breast cancer staging) can have a lower risk of relapse than patients with anatomic stage III group, despite receiving ET, 31% of these patients will still have a distant recurrence, and 28% of these patients will die from BC within 20 years (N Engl J Med 377: 1836-1846, 2017).

[0008] Adjuvant treatment options for HR+ HER2- EBC remain limited. While similar adjuvant treatments have been attempted for HR+ HER2- advanced or metastatic breast cancer patients, results from this approach have varied. In one example, the cdk4 / 6 inhibitor abemaciclib was initially approved for use in HR+ HER2- advanced or metastatic breast cancer patients (either alone or in combination with endocrine therapy), and subsequently shown to be effective in treating HR+ HER2- high-risk early breast cancer patients in the monarchE clinical trial (Johnston et al., 2023. Lancet 24(1), pp. 77-90). In contrast, the cdk4 / 6 inhibitor palbociclib, in combination with endocrine therapy, showed clinically relevant efficacy in HR+ HER2- metastatic breast cancer patients (PALOMA3 trial, described in Turner et al., 2015. N Engl J Med 2015; 373:209-219), but results were not confirmed in trials in HR+ HER2- early breast cancer patients (see PENELOPE-B trial, endocrine therapy plus palbociclib did not improve invasive disease-free survival (iDFS) compared to ET therapy plus placebo in patients with HR+ HER2- early breast cancer with residual invasive disease after completion of neoadjuvant chemotherapy (Loibl et al., 2021. Breast Cancer v39(14). Similarly, the PALLAS clinical trial in HR+ HER2- early breast cancer patients showed that palbociclib in combination with endocrine therapy did not improve iDFS compared to endocrine therapy alone (Mayer et al., 2021. Lancet, v22(2), pp. 212-222).

[0009] Thus, new treatment strategies can improve clinical outcomes for HR-positive, HER2-negative EBC patients. SUMMARY

[0010] Accordingly, disclosed herein are methods of treating early breast cancer using the CDK4 / 6 inhibitor Kisqali® (ribociclib) plus endocrine therapy (ET). The present disclosure provides methods of treating a patient having hormone receptor positive / human epidermal growth factor receptor 2 negative (HR+ / HER2-) early breast cancer (EBC). The present disclosure relies, inter alia, on the results of the NATALEE trial, a positive Phase III study of a CDK4 / 6 inhibitor to demonstrate consistent benefit of the inhibitor in a broad population of patients with HR+ / HER2- early breast cancer (EBC) at Stage II and III who are at risk of recurrence, including those patients with no nodal involvement. BRIEF DESCRIPTION OF DRAWINGS

[0011] Figure 1 A schematic of the study design of the NATALEE clinical trial is provided.

[0012] Figure 2 Simulated mean ANC curves for ribociclib 200 mg, 400 mg, and 600 mg QD 3 weeks on / 1 week off are shown; mean ANC curves were predicted by an ANC exposure-response model developed based on data from studies CLEE011X2101, CLEE011X1101, CLEE011X2107, CLEE011A2301, CLEE011E2301, and CLEE011F2301.

[0013] Figure 3 A schematic of the inclusion according to anatomic stage group in the NATALEE clinical trial is provided.

[0014] Figure 4 A schematic of ECGs and PK related to dosing (C1D15) is provided.

[0015] Figure 5 Questionnaires for, e.g., assessing quality of life and healthcare resource utilization (i.e., EORTC QLQ-C30) are illustrated.

[0016] Figure 6 Questionnaires for, e.g., assessing quality of life and healthcare resource utilization (i.e., EORTC QLQ-BR23) are illustrated.

[0017] Figure 7 Questionnaires for, e.g., assessing quality of life and healthcare resource utilization (i.e., EQ-5D-5L) are illustrated.

[0018] Figure 8 Questionnaires for, e.g., assessing quality of life and healthcare resource utilization (i.e., Hospital Anxiety and Depression Scale (HADS)) are illustrated.

[0019] Figure 9 Kaplan-Meier Plot (Full Analysis Set) showing overall survival analysis without primary invasive disease.

[0020] Figure 10 Forest plot (q) showing iDFS by stratification (per eCRF) (Full Analysis Set).

[0021] Figure 11A Forest plot showing iDFS - subgroup analysis.

[0022] Figure 11B Forest plot showing iDFS - subgroup analysis.

[0023] Figure 11C Forest plot showing iDFS - subgroup analysis.

[0024] Figure 11D Forest plot showing iDFS - subgroup analysis.

[0025] Figure 12 iDFS-Kaplan-Meier survival curves showing iDFS by II anatomical stage (eCRF strata) (Full Analysis Set).

[0026] Figure 13 iDFS-Kaplan-Meier survival curves showing iDFS by III anatomical stage (eCRF strata) (Full Analysis Set).

[0027] Figure 14 Kaplan-Meier curve showing RFS (Full Analysis Set).

[0028] Figure 15 Kaplan-Meier curve showing DDFS (Full Analysis Set).

[0029] Figure 16 Kaplan-Meier curve showing OS (Full Analysis Set). DETAILED DESCRIPTION

[0030] The present disclosure is described in more detail and exemplified below.

[0031] The present disclosure relates to methods of treating patients having breast cancer (BC). These methods are based, inter alia, on the surprising results of the NATALEE clinical trial, which demonstrated that CDK inhibitors in combination with endocrine therapy can provide a beneficial effect in early breast cancer (e.g., hormone receptor positive / human epidermal growth factor receptor 2 negative (HR+ / HER2-) early breast cancer) patients.

[0032] A. Treatment of early-stage breast cancer

[0033] One aspect of the disclosure relates to a method of treating breast cancer in an adult patient in need thereof, comprising administering to the patient a treatment comprising a cyclin-dependent kinase (CDK) inhibitor in combination with an endocrine therapy, wherein the breast cancer is early breast cancer (EBC).

[0034] EBC is characterized by localization of cancer cells in breast tissue and regional lymphatic vessels (e.g., formation of a tumor). In EBC, cancer cells are typically not detected outside of the breast or axillary lymph nodes. Early breast cancer can be a Stage 0, I, II, or III cancer (e.g., Stage 0, I, IIA, IIB, IIIA, IIIB, or IIIC). EBC can be distinguished from advanced breast cancer (also referred to as metastatic cancer), in which the cancer has spread to one or more sites of the body, such as bone, lung, liver, etc., based on its localization.

[0035] In some embodiments, the EBC is a carcinoma of the breast, e.g., adenocarcinoma. The EBC can be an invasive carcinoma. Invasive carcinoma, also known as infiltrating or invasive ductal carcinoma (IDC), is a type of breast cancer that begins in the milk ducts of the breast and moves into the surrounding tissue. Over time, IDC can spread (metastasize) to other parts of the body through lymph nodes or the bloodstream. The EBC can be a non-invasive carcinoma, such as ductal carcinoma in situ (DCIS). DCIS can spread along the milk ducts in the breast, but does not spread outside of the ductal system.

[0036] Signs and / or symptoms of early breast cancer can be one or more of the following: presence of a lump in the breast or armpit, thickening or swelling of part of the breast, irritation or dimpling of the breast skin (e.g., orange-peel dimpling), redness or scaly skin in the area of the nipple, a pulling sensation or pain in the nipple area, nipple discharge (other than breast milk, but including blood), any change in the size or shape of the breast, and / or pain in any part of the breast. Other signs and / or symptoms of early breast cancer can include: presence of one or more breast cancer cells; presence of a breast cancer tumor; or presence of a biochemical or genetic marker in the patient’s tissue or bodily fluid that indicates the presence of breast cancer (e.g., breast cancer biomarkers in a tissue biopsy or blood sample). The presence of breast cancer can be physical and can be detected using tests such as ultrasound, mammogram, magnetic resonance imaging, analysis of tissue samples (e.g., biopsy), and / or analysis of bodily fluid samples (e.g., blood samples). Any known detection can be used to detect signs and / or symptoms of cancer. The term “no evidence of disease” (NED or NEOD) can be used when there are no detectable signs and / or symptoms of cancer.

[0037] Breast cancer can be classified according to its histology. Histological grading (or “grading”) can refer to the degree to which cancer cells are not the same as normal cells, which can be distinguished, for example, by the degree of cell differentiation. Grade 1 refers to breast cancer cells that are similar to normal breast cells and generally grow slowly. Grade 2 refers to breast cancer cells that can not be similar to normal breast cells and grow rapidly. Grade 3 refers to breast cancer cells that are not similar to normal breast cells and generally grow rapidly. Grade 4 refers to breast cancer cells that are most dissimilar to normal breast cells and grow and spread faster than lower grade tumors.

[0038] Breast cancer can be classified according to a staging method. The staging method can be a pathologic staging method (e.g., based on a pathologist’s study of tumor tissue and any lymph nodes removed during surgery), or a clinical staging method (e.g., based on a clinician’s physical examination, tests, and / or imaging studies).

[0039] Generally, the staging method is used to classify breast cancer according to the size of the cancer (e.g., the primary tumor) and the extent to which the cancer has spread in the body.

[0040] One method for classifying breast cancer or a tumor according to its stage is the TNM classification or staging method. Using this method, a tumor can be classified as T0 when there is no evidence of a tumor, while classifications of T1, T2, T3, or T4 can be used to denote the size and invasion of the tumor. Tx can indicate that the tumor cannot be assessed. N (node) describes the extent to which the cancer has spread to nearby lymph nodes. Tumors can be classified as N0 when the tumor has not spread to local lymph nodes, while classifications of N1-N3 can be used to indicate lymph node spread.

[0041] M (metastasis) describes metastasis (e.g., spread of the cancer to other parts of the body). Tumors can be classified as M0 when there is no distant metastasis, and M1 when there is evidence of distant metastasis (Rosen and Sapra, TNM Classification, StatPearls Publishing; Treasure Island (FL), January 2023).

[0042] In breast cancer, Tl can be defined as a tumor that is 20 mm or less in diameter. Tla can be defined as a tumor that is more than 1 mm but not more than 5 mm in greatest dimension; Tlb can be defined as a tumor that is more than 5 mm but not more than 10 mm in greatest dimension; Tlc can be defined as a tumor that is more than 10 mm but not more than 20 mm in greatest dimension. T2 can be defined as a tumor that is more than 20 mm but not more than 50 mm in greatest dimension. T3 can be defined as a tumor that is more than 50 mm in greatest dimension. T4 can be defined as a tumor of any size that has directly invaded the chest wall and / or skin (e.g., an ulceration or a skin nodule). T4a can be invasion to the chest wall. T4b can be defined as edema or an ulceration of the breast skin, or a satellite nodule of the skin confined to the same breast. T4c can be defined as both T4a and T4b. T4d can be defined as inflammatory carcinoma, e.g., a carcinoma characterized by a diffuse erythema and edema involving about one-third or more of the breast skin.

[0043] The regional lymph nodes near the breast can include one or more of: (1) axillary lymph nodes, interpectoral lymph nodes (Rotter lymph nodes), and lymph nodes along the axillary vein and its tributaries. The axillary lymph nodes can be Grade I (lower axilla), Grade II (mid axilla), or Grade III (upper axilla); (2) internal mammary lymph nodes; (3) supraclavicular lymph nodes; and (4) intramammary lymph nodes.

[0044] For cancers that have or can have spread to lymph nodes, N0 indicates that the cancer has not spread to nearby lymph nodes; Nl indicates that the cancer has spread to 1-3 axillary lymph nodes, and / or a cancer is found in the internal mammary lymph nodes by a sentinel lymph node biopsy; N2 indicates that the cancer has spread to 4-9 axillary lymph nodes, or the internal mammary lymph nodes are enlarged; and N3 indicates that the cancer has spread to 10 or more axillary lymph nodes, with at least one cancer spread area greater than 2 mm, or to the supraclavicular lymph nodes, with at least one cancer spread area greater than 2 mm, or to at least one axillary lymph node, with at least one cancer spread area greater than 2 mm, and the internal mammary lymph nodes are enlarged, or to 4 or more axillary lymph nodes, with at least one cancer spread area greater than 2 mm, and to the internal mammary lymph nodes by a sentinel lymph node biopsy, or to the supraclavicular lymph nodes on the same side of the cancer, with at least one cancer spread area greater than 2 mm.

[0045] Lymph node classification can be clinical or pathological. Clinical classification can include cN1, defined as metastasis to ipsilateral grade I, II axillary lymph nodes; cN2a defined as metastasis to ipsilateral grade I, II axillary lymph nodes that are fixed to each other (matted); cN2b defined as metastasis to ipsilateral internal mammary lymph nodes detected clinically, and no clinically apparent metastasis to grade I, II axillary lymph nodes; cN3a defined as metastasis to ipsilateral infraclavicular (grade III axillary) lymph nodes, with or without involvement of grade I, II axillary lymph nodes; cN3b defined as metastasis to both ipsilateral internal mammary lymph nodes detected clinically and clinically apparent axillary lymph nodes; or cN3c defined as metastasis to ipsilateral supraclavicular lymph nodes, with or without involvement of axillary or internal mammary lymph nodes.

[0046] An additional item of the TMN classification system is the R classification system or residual tumor classification system, which can be used to indicate the status of a tumor after treatment. The R classification can indicate the effectiveness of treatment and can be used to predict prognosis. For example, a patient can be diagnosed with a tumor that is classified using the TMN classification system, then treated, and then any residual tumor can be classified according to the R classification system. Using this system, the extent of resection of a tumor can be classified as R0, Rl, or R2. In R0, there is no residual tumor after surgery, e.g., the surgical margins are free of residual tumor under a microscope. In Rl, there is no grossly visible residual tumor, but the microscopic margins still show the presence of tumor. In R2, there is still an apparent (grossly visible) tumor after surgery.

[0047] The TNM classification system predates many genetic and / or biochemical marker (or "biomarker") tests that are now routinely used to provide additional prognostic or predictive information about the type of cancer, and can be used in cancer classification along with these tests and / or other tests. For example, the TNM classification system can be used in combination with indicators such as tumor grade, estrogen receptor (ER) status, progesterone receptor (PR) status, and human epidermal growth factor receptor 2 (HER2) status. An example of such a combination is shown in Table 1 of Ann Surg Oncol. 2018 Jul; 25(7): 1783-1785. doi: 10.1245 / s10434-018-6486-6. Epub 2018 Apr 18.

[0048] One example of a biomarker used in breast cancer is the nuclear antigen Ki-67. Ki-67 levels in breast cancer cells can be measured using, for example, immunohistochemical staining. Anti-human Ki-67 antibody MIB1 can be used for immunohistochemistry. Ki-67 values are calculated as the percentage of positively labeled malignant cells out of the total number of malignant cells assessed (Breast Cancer Res Treat. 2013; 139(2): 539-552). Generally, Ki-67 expression correlates with high levels of cell proliferation (J Clin Oncol. 2005 Oct 1; 23(28):7212-20).

[0049] Gene tests, such as multi-gene or multi-parameter expression assays, can be used to evaluate the characteristics of breast cancer, metastatic risk, and / or risk of recurrence. One exemplary test is the Oncotype DX® test, in which a breast recurrence score of > 26 (range 0-100) indicates a risk of recurrence. In another exemplary test, the Prosigna® / PAM50 (Prediction Analysis of Microarray 50) test classifies tumors as low, intermediate, or high risk of metastasis based on the expression levels of 50 genes in the tumor. Other exemplary tests include, but are not limited to, the MammaPrint®, EndoPredict®, and Breast Cancer Index® tests, which can be used to determine a risk score for cancer recurrence.

[0050] Another method of tumor classification is the “stage grouping” classification system. This method, which can be used alone or with the TNM classification system and other tests, classifies breast cancer into anatomic stage groups (or “stages”). Thus, breast cancer can be classified according to a Stage 0, I, II, III, or IV stage group (or “anatomic stage group”). In particular, the stage group can be Stage 0, Ia, Ib, IIa, IIb, IIIa, IIIb, IIIC, or IV.

[0051] Stage 0: Stage zero (0) can describe disease that is only within the ducts of breast tissue and has not spread to the surrounding tissue of the breast. It is also referred to as non-invasive or ductal carcinoma in situ (Tis, N0, M0).

[0052] Stage Ia can refer to a tumor that is small, invasive, and has not spread to the lymph nodes (T1, N0, M0).

[0053] Stage Ib can refer to cancer that has spread to the lymph nodes, and the cancer in the lymph nodes is more than 0.2 mm but not more than 2 mm in size. There can be no evidence of a breast tumor, or the breast tumor is 20 mm or smaller (T0 or T1, N1mi (also referred to as “N1 micrometastasis”), M0).

[0054] Stage IIA can refer to cancer that meets either of the following: a. There is no evidence of a breast tumor, but the cancer has spread to 1-3 axillary lymph nodes. It has not spread to distant parts of the body (T0, N1, M0).

[0055] b. The tumor is 20 mm or smaller, and has spread to 1-3 axillary lymph nodes (T1, N1, M0).

[0056] c. The tumor is more than 20 mm but not more than 50 mm and has not spread to axillary lymph nodes (T2, N0, M0).

[0057] Stage IIB can refer to any of the following: a. The tumor is more than 20 mm but not more than 50 mm and has spread to 1-3 axillary lymph nodes (T2, N1, M0).

[0058] b. The tumor is more than 50 mm, but has not spread to axillary lymph nodes (T3, N0, M0).

[0059] Stage IIIA can refer to any size tumor that has spread to 4-9 axillary lymph nodes or internal mammary lymph nodes. It has not spread to other parts of the body (T0, T1, T2, or T3; N2; M0). Stage IIIA can also refer to a tumor that is more than 50 mm, which has spread to 1-3 axillary lymph nodes (T3, N1, M0).

[0060] Stage IIIB can refer to a tumor that has spread to the chest wall or is causing swelling or ulceration of the breast, or is diagnosed as inflammatory breast cancer. It can or can not have spread to up to 9 axillary or internal mammary lymph nodes. It has not spread to other parts of the body (T4; N0, N1, or N2; M0).

[0061] Stage IIIC can refer to any size tumor that has spread to 10 or more axillary lymph nodes, internal mammary lymph nodes, and / or infraclavicular lymph nodes. It has not spread to other parts of the body (any T, N3, M0).

[0062] Stage IV (metastatic) can refer to any size tumor that has spread to other organs, such as bone, lung, brain, liver, distant lymph nodes, or chest wall (any T, any N, M1). About 6% of metastatic cancer is found at the time of the first diagnosis of cancer. This can be referred to as de novo metastatic breast cancer. Most often, metastatic breast cancer is found after an early breast cancer has been diagnosed previously.

[0063] Recurrent cancer refers to cancer that has recurred after treatment, which can be described as local, regional, and / or distant (Breast Cancer: Stages, from Cancer.Net).

[0064] Recurrence can be evaluated by medical imaging and confirmed by histology (or cytology, where applicable). Recurrence can be classified as local, regional, or distant recurrence, or contralateral invasive breast cancer or second primary non-breast invasive cancer according to the following guidelines: - Local invasive breast cancer recurrence or ipsilateral invasive breast tumor recurrence: Invasive breast cancer involving the same breast as the primary tumor. Ductal and lobular carcinoma in situ, and tumors of the contralateral breast and / or contralateral lymph nodes are not considered local invasive recurrence. Can be confirmed by histology.

[0065] - Regional breast cancer recurrence: Ipsilateral axillary, regional lymph nodes (all stages), chest wall, or ipsilateral breast skin invasive breast cancer. Tumors of the contralateral breast are not considered regional recurrence. Can be confirmed by histology (preferred) or cytology.

[0066] - Distant recurrence: Distant metastasis of breast cancer (bone, distant lymph nodes, internal organs, CNS, bone marrow, etc.) or any non-local or regional site of invasive breast cancer recurrence. Distant recurrence can be confirmed by histology (preferred) or cytology.

[0067] o If bone metastasis is determined by bone scan, it can be confirmed by histology (preferred) or radiological imaging (CT, MRI, or FDG-PET-CT) if biopsy confirmation is not possible.

[0068] o Metastasis to the central nervous system can be confirmed by histology (preferred), cytology, or radiological imaging (CT or MRI with intravenous (IV) contrast) if biopsy confirmation is not possible.

[0069] o Metastasis to all other sites can be confirmed by histology (preferred) or cytology, unless the procedure presents an unacceptable risk to the patient.

[0070] - Contralateral invasive breast cancer: Any invasive breast cancer in the contralateral breast, with or without contralateral lymph node involvement. Contralateral invasive breast cancer must be confirmed by histology. In situ / non-invasive contralateral breast cancer is not included in contralateral invasive breast cancer.

[0071] - Second primary non-breast invasive cancer: Any second primary non-breast invasive cancer. Second primary non-breast invasive cancer must be confirmed by histology. In situ / non-invasive cancer and cutaneous basal or squamous cell carcinoma are not considered second primary non-breast invasive cancer.

[0072] Table B1 summarizes the AJCC 8th edition anatomic stage groups

[0073] Table B1

[0074] Note that T2, T3, and T4 tumors with nodal micrometastases (N1mi) can be staged using the N1 category.

[0075] Thus, in some embodiments, the adult patient treated using the methods described herein has EBC that is ductal carcinoma in situ, Stage I breast cancer, Stage II breast cancer (such as Stage IIA breast cancer or Stage IIB breast cancer), or Stage III breast cancer (such as Stage IIIA, Stage IIIB, or Stage IIIC breast cancer). In some embodiments, the patient has Stage II or Stage III early breast cancer. In some embodiments, the patient has Stage IIA cancer or Stage IIB cancer. In some embodiments, the patient has Stage IIIA cancer, Stage IIIB cancer, or Stage IIIC cancer. The patient can be lymph node positive (e.g., the cancer has spread to its lymph nodes) or lymph node negative (e.g., the cancer has not spread to its lymph nodes). In some embodiments, the treatment methods described herein are performed regardless of the lymph node status of the patient’s breast cancer.

[0076] In certain embodiments, the EBC is a hormone receptor positive (HR+) breast cancer, e.g., a breast cancer comprising cells that express one or more types of hormone receptors. Exemplary hormone receptors can be estrogen receptors (ER), e.g., ERa or ERb, and / or progesterone receptors (PR), e.g., PRA and PRB. The EBC can comprise breast cancer cells that express estrogen receptors (ER+) or progesterone receptors (PR+) or a combination of estrogen receptors and progesterone receptors (ER+ / PR+). In some embodiments, the EBC is ER+ / PR-, ER- / PR+, or ER+ / PR+.

[0077] In certain embodiments, the EBC is human epidermal growth factor receptor 2 (HER2) positive.

[0078] Certain embodiments relate to a method of preventing or alleviating a sign or symptom of early breast cancer, the method comprising administering to a patient a treatment comprising reloxaliid, a free base form thereof, or a pharmaceutically acceptable salt thereof, in combination with an aromatase inhibitor, preferably letrozole or anastrozole. In some embodiments, reloxaliid is in a free base form thereof or a pharmaceutically acceptable salt thereof, and is administered to the patient at a dose ranging from 150 mg / day to 450 mg / day on days 1-21 of a 28-day cycle. In some embodiments, the aromatase inhibitor is administered daily on a 28-day cycle.

[0079] B. CDK inhibitors and endocrine therapy

[0080] One aspect of the disclosure relates to a method of treating early stage breast cancer in an adult patient in need thereof comprising administering to the patient a treatment comprising a cyclin-dependent kinase (CDK) inhibitor in combination with an endocrine therapy (ET).

[0081] Cyclin-dependent kinases (CDKs) are serine / threonine protein kinases that form active complexes with cyclins in cells. In healthy cells, a variety of extracellular and intracellular signals tightly regulate the formation of CDK / cyclin complexes and control their phosphorylation of target proteins involved in the cell cycle, such as retinoblastoma (Rb) protein, lamin, histone H1, and components of the mitotic spindle. However, in cancer cells, CDKs can be overactivated, leading to uncontrolled tumor proliferation.

[0082] CDK4 and CDK6, which bind to D-cyclins, are exemplary CDKs that have been shown to promote the growth of certain breast cancer tumors. In these tumors, D-cyclins are overexpressed, leading to activation of CDK4 and CDK6, which subsequently leads to phosphorylation of Rb, release of the inhibition of E2F transcription factors by Rb, and rapid progression of tumor cells through the cell cycle (Shah et al., Oncology. 2018 May 15; 32(5): 216-222).

[0083] CDK inhibitors have been shown to block unregulated cell growth and division resulting from CDK over-activation and / or cyclin overexpression. For example, inhibitors of CDK / cyclin complexes, particularly CDK4 / 6, have been used to treat patients with certain types of cancer. The CDK4 / 6 inhibitors palbociclib, ribociclib, and abemaciclib have been approved by regulatory agencies for the treatment of hormone receptor-positive (HR+ or HR positive) and human epidermal growth factor receptor 2 negative (HER2-) advanced or metastatic breast cancer (Fassi et al., Science. January 14, 2022; 375(6577): eabc1495). To date, ribociclib has been approved by multiple regulatory agencies, including the U.S. Food and Drug Administration (FDA) and the European Commission. The FDA has approved it in combination with (1) an AI for the treatment of pre- / perimenopausal or postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer as initial endocrine-based therapy; or (2) fulvestrant for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer as initial endocrine-based therapy or after disease progression on ET. In Europe, ribociclib is indicated for the treatment of women with HR-positive, HER2-negative locally advanced or metastatic breast cancer in combination with an AI as initial endocrine-based therapy or for women who have received prior ET. For pre- or perimenopausal women, ET can be combined with a luteinizing hormone-releasing hormone agonist.

[0084] Thus, in some embodiments of the disclosure, the CDK inhibitor used in the methods disclosed herein can be a CDK4 / 6 inhibitor, e.g., an inhibitor of the CDK4 / 6 / cyclin complex. The cyclin can be a D cyclin, e.g., cyclin-D1 in the CDK4 / cyclin-D1 complex or cyclin-D3 in the CDK6 / cyclin-D3 complex.

[0085] In some embodiments, the CDK4 / 6 inhibitor can be a compound described by Formula A1, or a salt thereof.

[0086] (A1)

[0087] The compound of Formula A1 is known by the international nonproprietary name ribociclib. Thus, in some embodiments, the CDK4 / 6 inhibitor can be the compound having the international nonproprietary name ribociclib.

[0088] Ribociclib can be in the form of its free base or can be a pharmaceutically acceptable salt of ribociclib. The salts can exist either alone or in a mixture with the free compound (e.g. ribociclib), and are preferably pharmaceutically acceptable salts. Ribociclib salts are preferably formed from ribociclib compounds having a basic nitrogen atom with an organic or inorganic acid, for example as acid addition salts. Suitable inorganic acids are for example hydrohalic acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are for example succinic acid, carboxylic acids or sulfonic acids, such as fumaric acid or methanesulfonic acid. For the purposes of isolation or purification, it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates. For therapeutic use, only pharmaceutically acceptable salts or the free compounds are used (in cases where the use of a pharmaceutical formulation is appropriate), and these are therefore preferred.

[0089] In some embodiments, ribociclib can be in the form of racemates, diastereomers, enantiomers and tautomers, as well as the corresponding crystal modifications, if present, such as solvates, hydrates and polymorphs.

[0090] Ribociclib can be in the form of a pharmaceutically acceptable salt, for example a succinate salt, such as ribociclib succinate. The chemical name of ribociclib succinate is butanedioic acid—7-cyclopentyl- dimethyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7 N,N - pyrrolo[2,3-d]pyrimidine-6-carboxamide (1 : 1), corresponding to the molecular formula C H - pyrrolo[2,3-d]pyrimidine-6-carboxamide (1 : 1), corresponding to the molecular formula C 27 H 36 N8O5. Its relative molecular mass is 552.6 g / mol (EMA Assessment Report for Kisqali, Procedure No. EMEA / H / C / 004213 / 0000, dated 22 June 2017).

[0091] Oral tablet forms of ribociclib are known in the art (e.g., WO 2016 / 166703) and have been approved as the KISQALI® product. Various ribociclib salts have been described (e.g., see claim 85 of WO 2022 / 207788), and the approved KISQALI® product contains ribociclib succinate. The amount of any salt will be adjusted to provide the desired amount of ribociclib (e.g., 254.40 mg of ribociclib succinate is equivalent to 200 mg of ribociclib). Various polymorphic forms of ribociclib succinate are known (e.g., see WO 2019 / 040567, WO 2019 / 082143, WO 2019 / 150181, WO 2019 / 166987, WO 2020 / 225827, WO 2021 / 038590, etc.). The methods described herein can be carried out using the approved KISQALI® product, e.g., with an approved endocrine therapy.

[0092] As described herein, a CDK inhibitor (e.g., a CDK4 / 6 inhibitor, such as ribociclib or a pharmaceutically acceptable salt thereof, such as ribociclib succinate) can be administered with an endocrine therapy. In some embodiments of the disclosure, the endocrine therapy is an aromatase inhibitor.

[0093] Endocrine therapy (also known as hormone therapy or hormonal therapy) has been used to slow or stop the growth of hormone-sensitive cancers (also known as hormone-dependent cancers). Hormone-sensitive tumors express hormone (such as estrogen and / or progesterone) receptors, and hormones can promote the growth of the cancer. Thus, endocrine therapy refers to therapies that (1) interfere with the effects of hormones on cancer cells and / or (2) block the ability of the body to produce hormones.

[0094] An exemplary compound that interferes with the effects of hormones on breast cancer cells is a selective estrogen receptor modulator (SERM), which binds to the estrogen receptor and prevents estrogen from binding. SERMs can mimic the effects of estrogen. SERMs approved by the FDA for the treatment of breast cancer are tamoxifen (Nolvadex®) and toremifene (Fareston®). Other anti-estrogen drugs can bind to the estrogen receptor but do not mimic the effects of estrogen, and instead can target the estrogen receptor for destruction. An exemplary anti-estrogen compound is fulvestrant (Faslodex®).

[0095] Hormone production can be blocked by ablating the hormone-producing tissue or organ. For example, in premenopausal women, in which the ovaries are the primary source of estrogen, oophorectomy (also known as ovariectomy or ovariotomy) or radiation therapy can be performed to eliminate or reduce estrogen levels.

[0096] Alternatively, hormone production can be blocked by administering a compound that inhibits hormone synthesis and / or release. Chronic administration of gonadotropin-releasing hormone (GnRH) agonists can lead to desensitization, thereby suppressing gonadotropin secretion. In contrast, GnRH antagonists suppress GnRH signaling and gonadotropin secretion (Reprod Biomed Online. 2002;5 Suppl 1:1-7. doi: 10.1016 / s1472-6483(11)60210-1). Exemplary GnRH agonists are goserelin (Zoladex®) and leuprolide (Lupron®), which suppress the release of estrogen in the ovaries of women and the release of testosterone in the testes of men. In some embodiments, goserelin is used in the methods disclosed herein.

[0097] Another class of compounds that block estrogen production are specifically aromatase inhibitors. Aromatase inhibitors work by inhibiting the action of aromatase, which converts androgens to estrogens through a process called aromatization. Notably, in premenopausal women, the level of aromatase produced by the ovaries is so high that an aromatase inhibitor alone is not sufficient to block. For premenopausal women, an aromatase inhibitor can be used in combination with a compound that suppresses ovarian function (e.g., goserelin or leuprolide). In contrast, postmenopausal women primarily produce estrogen in peripheral tissues, not the ovaries, so an aromatase inhibitor can be sufficient to suppress estrogen production in these women.

[0098] There are two types of aromatase inhibitors: (1) steroidal inhibitors, such as exemestane (Aromasin®), which forms a permanent and inactive bond with aromatase; and (2) nonsteroidal inhibitors (NSAI), such as anastrozole (Arimidex®) or letrozole (Femara®).

[0099] Letrozole is a nonsteroidal competitive inhibitor of the aromatase system. Letrozole works by highly selectively inhibiting the conversion of androgens (primarily derived from the adrenal glands, the main source of estrogen in postmenopausal women) into estrogens. Treatment with daily doses of 0.1 to 5 mg of letrozole for two weeks induces a 75% to 95% decrease in estrogen levels without significant clinical or laboratory toxicity or changes in other hormone levels in the endocrine system (Lancet London 386:1341–1352, 2015; Cancer 75:2132–2138, 1995).

[0100] Like letrozole, anastrozole is a selective non-steroidal anti-inflammatory drug (NSAID). It significantly reduces serum estradiol levels and has no detectable effect on the formation of adrenocortical steroids or aldosterone.

[0101] In some embodiments, the endocrine therapy administered in conjunction with a CDK inhibitor (e.g., a CDK4 / 6 inhibitor, such as reboxil or a pharmaceutically acceptable salt thereof, such as reboxil succinate) is an aromatase inhibitor, such as anastrozole or letrozole. In some embodiments, the therapy further comprises a gonadotropin-releasing hormone agonist, such as goserelin.

[0102] Exemplary aromatase inhibitors are described in Breast Cancer Res Treat, October 2007; 105(Supplement 1):7-17.

[0103] Aromatase inhibitors can be nonsteroidal aromatase inhibitors or pharmaceutically acceptable salts thereof, as described by one of the following formulas.

[0104] Formula (B1) Formula (C1) Equation (D1) Equation (E1) In some embodiments, the aromatase inhibitor may be letrozole. The aromatase inhibitor may be a pharmaceutically acceptable salt of letrozole. The chemical name of letrozole is 4,4'-(1H-1,2,4-triazol-1-ylmethylene)dibenzonitrile. Letrozole is readily soluble in dichloromethane, slightly soluble in ethanol, and practically insoluble in water. Its molecular weight is 285.31 g / mol, and its empirical formula is C1. 17 H 11 N5, with a melting point range of 184°C to 185°C.

[0105] In some embodiments, letrozole can be in the form of a racemate, diastereomer, enantiomer, or tautomer, as well as the corresponding crystal modifications, if present, such as solvates, hydrates, and polymorphs.

[0106] In some embodiments, the aromatase inhibitor can be anastrozole or a pharmaceutically acceptable salt thereof. The chemical name of anastrozole is a,a,a',a'-tetramethyl-5-(1H-1,2,4-triazol-1-ylmethyl)-m- phenylenedinitrile. Anastrozole is freely soluble in methanol, acetone, ethanol, and tetrahydrofuran, and very slightly soluble in acetonitrile. Its molecular weight is 293.374 g / mol, empirical formula is C 17 H 19 N5, and melting point ranges from 80 °C to 86 °C. In some embodiments, anastrozole can be in the form of a solvate, hydrate, or polymorph.

[0107] In some embodiments, the endocrine therapy can comprise an aromatase inhibitor (e.g., letrozole or anastrozole) for postmenopausal women. For premenopausal women or men, the endocrine therapy can comprise an aromatase inhibitor (e.g., letrozole or anastrozole) and can further comprise a compound that suppresses gonadal function (e.g., a GnRH agonist, such as goserelin).

[0108] The GnRH agonist can be a compound according to the following formula: Formula (Fl) In some embodiments, the aromatase inhibitor can be goserelin or a pharmaceutically acceptable salt thereof. Goserelin is sold under the trade name Zoladex®. Its molecular weight is 1269.433 g / mol, empirical formula is C 59 H 84 N 18 O 14 In some embodiments, goserelin can be in the form of a solvate, hydrate, or polymorph.

[0109] C. Application - Dosage and Treatment Schedule

[0110] Further aspects of the present disclosure relate to a method of treating early breast cancer in an adult patient in need thereof, the method comprising administering to the patient a treatment comprising a cyclin-dependent kinase (CDK) inhibitor dose in combination with an endocrine therapy dose.

[0111] In some embodiments, the CDK inhibitor is a CDK4 / 6 inhibitor, e.g., ribociclib or a pharmaceutically acceptable salt thereof (such as ribociclib succinate), and the endocrine therapy is an aromatase inhibitor, e.g., letrozole. In some embodiments, the endocrine therapy is letrozole.

[0112] In a clinical trial in patients with advanced BC, a dose of 600 mg / day of ribociclib has been shown to be tolerable and effective when combined with ET, used on days 1-21 of a 28-day cycle (N Engl J Med 375: 1738-1748, 2016). However, since HR-positive, HER2-negative EBC can relapse later, with events that can occur one year after surgery and can continue for at least 15 years after diagnosis, longer treatment duration can also be beneficial for EBC. In some embodiments, ribociclib (in combination with ET) can be administered at a dose lower than 600 mg / day. For example, ribociclib (or a pharmaceutically acceptable salt thereof, e.g., ribociclib succinate) can be administered at a dose of about 400 mg / day. This exemplary dose can be administered as 2 x 200 mg / day.

[0113] In some embodiments, ribociclib (or a pharmaceutically acceptable salt thereof, e.g., ribociclib succinate) can be administered at a dose of about 400 mg / day. The dose of ribociclib or a pharmaceutically acceptable salt thereof (e.g., ribociclib succinate) can be administered once daily in the form of a tablet, e.g., as 2 x 200 mg tablets (it is understood that the two tablets can be taken simultaneously or sequentially in a single daily administration). The dose can be administered as an oral solution. The dose can be administered orally (by mouth). In some embodiments, the dose of ribociclib (or a pharmaceutically acceptable salt thereof, e.g., ribociclib succinate) is about 200 mg / day. This dose can be administered as a tablet (e.g., 1 x 200 mg tablet). The dose can be administered orally (by mouth). The dose can be a flat fixed dose, e.g., not calculated per body weight or body surface area.

[0114] For example, dose adjustments can be made to administer a dose of about 400 mg / day of ribociclib, or a pharmaceutically acceptable salt thereof (e.g., ribociclib succinate). For example, a dose of about 350 mg / day, about 300 mg / day, about 250 mg / day, about 200 mg / day, or about 150 mg / day of ribociclib, or a pharmaceutically acceptable salt thereof (e.g., ribociclib succinate) can be administered. In some embodiments, a dose of about 200 mg / day is administered after a prior dose of 400 mg / day has been administered. In some embodiments, the dose is administered in tablet form (e.g., 1 x 200 mg tablet). The dose of about 200 mg / day can be administered orally. Thus, a patient who has previously received a dose of about 400 mg of ribociclib, or a pharmaceutically acceptable salt thereof (e.g., ribociclib succinate) (e.g., 2 x 200 mg tablets orally) can be switched to a dose of about 200 mg / day (e.g., 1 x 200 mg tablet orally). The dose can be taken once daily (e.g., 1 x 200 mg tablet once daily, or 2 x 200 mg tablets once daily).

[0115] For patients who are intolerant to a dose of about 400 mg / day, dose adjustments can be made. For example, a patient who receives a dose of about 400 mg / day of ribociclib (or a pharmaceutically acceptable salt thereof, e.g., ribociclib succinate) and experiences one or more of thrombocytopenia, decreased absolute neutrophil count (ANC), febrile neutropenia, anemia, liver toxicity (e.g., as indicated by bilirubin levels and / or AST and ALT enzyme levels), drug-induced liver injury, cardiac abnormalities (e.g., as measured by QT interval), interstitial lung disease / pneumonitis, and / or other adverse events can receive an adjusted dose of ribociclib (or a pharmaceutically acceptable salt thereof, e.g., ribociclib succinate) of about 200 mg / day.

[0116] Thus, the dose of ribociclib (or a pharmaceutically acceptable salt thereof, e.g., ribociclib succinate) can range from about 150 mg / day to about 450 mg / day. The dose can be about 150 mg / day, about 200 mg / day, about 250 mg / day, about 300 mg / day, about 350 mg / day, or about 450 mg / day. The dose can be taken once daily.

[0117] In some embodiments, the dose of ribociclib (or a pharmaceutically acceptable salt thereof, e.g., ribociclib succinate) is not about 600 mg / day.

[0118] In some embodiments, the aromatase inhibitor is letrozole. The dosage of letrozole can be selected based on data indicative of disease-free survival of patients (e.g., clinical data; which can be combined with data regarding adverse effects such as impairment of renal function and / or impairment of liver function) to determine an effective dosage. The dosage can be selected by testing efficacy and tolerability in individual patients.

[0119] The dosage of letrozole can range from about 1 mg / day to about 4 mg / day. For example, the dosage of letrozole can be about 1 mg / day, about 1.25 mg / day, about 1.5 mg / day, about 1.75 mg / day, about 2 mg / day, about 2.25 mg / day, about 2.5 mg / day, about 2.75 mg / day, about 3 mg / day, about 3.25 mg / day, about 3.5 mg / day, about 3.75 mg / day, or about 4 mg / day. In some embodiments, the dosage of letrozole is about 2.5 mg / day. The dosage can be a flat fixed dose, e.g., not calculated by body weight or body surface area.

[0120] The dosage of letrozole can be administered orally (e.g., by mouth). Thus, any of the above dosages can be administered, such as a dosage of letrozole of about 2.5 mg / day. The dosage of letrozole can be administered orally. The dosage can be administered in tablet form. The dosage can be taken once daily.

[0121] In certain embodiments, the aromatase inhibitor is anastrozole. The dosage of anastrozole can be selected based on data indicative of disease-free survival of patients (e.g., clinical data; which can be combined with data regarding adverse effects such as impairment of renal function and / or impairment of liver function) to determine an effective dosage. The dosage can be selected by testing efficacy and tolerability in individual patients.

[0122] The dosage of anastrozole can range from about 0.5 mg / day to about 1.5 mg / day. For example, the dosage of anastrozole can be about 0.5 mg / day, about 0.75 mg / day, about 1 mg / day, about 1.25 mg / day, or about 1.50 mg / day. In some embodiments, the dosage of anastrozole is about 1 mg / day.

[0123] The dosage of anastrozole can be administered orally (e.g., by mouth). Thus, any of the above dosages can be administered, such as a dosage of anastrozole of about 1 mg / day. The dosage of anastrozole can be administered orally. The dosage can be administered in tablet form. The dosage can be taken once daily.

[0124] In addition to ribociclib (or a pharmaceutically acceptable salt thereof, e.g., ribociclib succinate) (e.g., about 400 mg / day or about 200 mg / day) and letrozole (about 2.5 mg / day) or anastrozole (about 1 mg / day), the patient can also receive a gonadotropin-releasing hormone agonist, e.g., goserelin. For example, premenopausal female patients and male patients can receive a dose of goserelin. The dose of goserelin can be selected based on data (e.g., clinical data) indicating efficacy in patients or by testing efficacy and tolerability in individual patients.

[0125] The dose of goserelin can range from about 2 mg to about 5 mg. The dose of goserelin can be about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, or about 5 mg. In some embodiments, the dose of goserelin is about 3.4 mg, 3.5 mg, 3.6 mg, or 3.7 mg. In some embodiments, the dose of goserelin is 3.6 mg. The dose can be a flat fixed dose, e.g., not calculated by body weight or body surface area.

[0126] The dose of goserelin can be administered subcutaneously. The dose can be administered subcutaneously at a time interval ranging from 2 weeks to 4 weeks.

[0127] In one embodiment, goserelin is administered subcutaneously at a dose of 3.6 mg.

[0128] The compounds can be administered separately, e.g., when the compounds are administered by different routes of administration and / or according to different treatment schedules. If administered separately, the compounds can be administered simultaneously or sequentially. In one illustrative example, two compounds are administered to a patient in two separate doses, but on the same day as each other. In this example, the two compounds can be administered simultaneously, or can be administered at different times. The compounds can be administered separately in two or more separate unit doses (e.g., where a unit dose is the amount of a compound administered to a patient in a single dose) and / or unit dosage forms.

[0129] The compounds can be administered in combination together. The compounds can be administered together in a single pharmaceutical composition, e.g., the compounds can be administered together in a single dose (e.g., unit dose). The unit dosage form can also be a fixed combination.

[0130] In some embodiments, the dose of ribociclib (or a pharmaceutically acceptable salt thereof, e.g., ribociclib succinate) (about 400 mg / day or about 200 mg / day) and the dose of the endocrine therapy (e.g., letrozole (dose about 2.5 mg / day) or anastrozole (dose about 1 mg / day)) are administered together. Typically, the doses can be administered at the same time each day (e.g., in the morning). The doses can be administered in the afternoon or evening. In some embodiments, the doses are not administered in the evening.

[0131] Further aspects of the disclosure relate to a method of treating early breast cancer in an adult patient in need thereof, the method comprising administering to the patient a treatment comprising a cyclin-dependent kinase (CDK) inhibitor dose in combination with an endocrine therapy dose according to a treatment schedule.

[0132] In some embodiments, the treatment schedule comprises a treatment cycle of about 28 days. During this cycle, the CDK inhibitor can be administered once daily on days 1-21 of the 28-day cycle, followed by a 7-day period in which the CDK inhibitor is discontinued, with the endocrine therapy being administered once daily continuously during the period of discontinuation. Thus, the endocrine therapy (e.g., letrozole or anastrozole) can be administered each day of the 28-day cycle.

[0133] Thus, in some embodiments, the CDK inhibitor is ribociclib (or a pharmaceutically acceptable salt thereof, e.g., ribociclib succinate) administered at a dose of about 400 mg / day (or about 200 mg / day) and the endocrine therapy is letrozole administered at a dose of about 2.5 mg / day or anastrozole administered at a dose of about 1 mg / day, wherein the ribociclib (or a pharmaceutically acceptable salt thereof, e.g., ribociclib succinate) is administered once daily on days 1-21 of the 28-day cycle, followed by a 7-day period (days 22-28 of the cycle) in which the ribociclib (or a pharmaceutically acceptable salt thereof, e.g., ribociclib succinate) is discontinued, and the letrozole or anastrozole is administered once daily continuously during the 28-day period (e.g., each day of the 28-day cycle). The ribociclib (or a pharmaceutically acceptable salt thereof, e.g., ribociclib succinate) can be administered orally, e.g., as a tablet. The letrozole or anastrozole can be administered orally, e.g., as a tablet.

[0134] For patients in whom treatment further comprises administration of goserelin (e.g., at a dose of about 3.6 mg), goserelin can be administered once during the 28-day cycle. Goserelin can be administered once every 2-4 weeks (e.g., every 4 weeks). In some embodiments, goserelin is administered on day 1 (± 3 days) of each 28-day cycle. Goserelin can be administered on day -3, day -2, day -1, day 1, day 2, or day 3 of the 28-day cycle.

[0135] Treatment can be administered for at least about 12 months. Treatment can be administered for at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, at least about 60 months, or longer. In some embodiments, the administration of ribociclib and letrozole is for at least about 48 months (about 4 years) or at least about 60 months (about 5 years). In some embodiments, treatment is administered for at least 36 months.

[0136] An exemplary dosage and treatment schedule is shown in Table B1.1.

[0137] Table B1.1. Exemplary Dosage and Treatment Schedule

[0138] In some embodiments, the patient has not received a loading dose prior to treatment. In some embodiments, the patient has received a loading dose prior to treatment. For example, the patient can have received a loading dose of ribociclib (e.g., KISQNIQ® or a ribociclib salt, such as ribociclib succinate) and / or an endocrine therapy (e.g., letrozole or anastrozole).

[0139] A loading dose can be an initial dose of a drug that can be given at or before the start of a course of treatment, and then decreased to a different, typically lower, dose (e.g., a treatment or maintenance dose). A loading dose can be a single dose or short-term regimen of a compound administered to a subject to rapidly increase the blood level of the drug. Suitably, a short-term regimen as used herein will be: 1 to 14 days; for example, 1 to 7 days; for example, 1 to 3 days; for example, three days; for example, two days; for example, one day. In some embodiments, a “loading dose” can increase the blood concentration of a drug to a therapeutically effective level. In some embodiments, a “loading dose” can increase the blood concentration of a drug to a therapeutically effective level in combination with a therapeutic dose of the drug. A “loading dose” can be administered once per day, or more than once per day (e.g., up to 4 times per day). In some embodiments, a loading dose can be used for a drug molecule that has a long half-life or is eliminated slowly in the body.

[0140] In some embodiments, treatment continues until the patient has no remaining signs and / or symptoms of breast cancer. In some embodiments, treatment continues until the patient has no detectable cancer and / or no signs of cancer recurrence (e.g., indications). In some embodiments, treatment is restarted if the patient exhibits one or more signs of cancer recurrence. In some embodiments, treatment continues until cancer recurrence. Signs and / or symptoms of cancer and cancer recurrence can be determined by monitoring the patient for months and years after treatment using tests such as physical examination, scanning and / or imaging of the cancer site (e.g., X-ray, computed tomography, mammography) and blood tests. In exemplary instances, different follow-up modalities may be mammography, clinical examination, whole-body or local MRI and / or CT scans. According to the National Cancer Information Network guidelines, breast cancer patients may (1) have a medical history and physical examination 1–4 times per year for 5 years, depending on clinical circumstances, (2) have a mammogram every 12 months, and (3) have no indication for laboratory or imaging examinations to screen for metastasis in the absence of clinical signs and symptoms suggestive of recurrent disease. When cancer is not detected, it can be assumed that the patient is awaiting treatment, but the recurrence of the disease must be monitored.

[0141] In some embodiments, the treatments disclosed herein may be administered to patients who no longer have detectable signs and / or symptoms of cancer but may still be at risk of cancer recurrence. Treatment for these patients may continue for a period of time, such as from at least about 3 months to at least about 10 years, for example, any time period of 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years. During this period, the patient may be monitored for cancer recurrence, for example, based on clinical examination, mammography, scans, imaging, sample collection (e.g., tissue biopsy), and / or blood tests. Patients who do not have detectable signs and / or symptoms of cancer during this time period may discontinue the treatment described herein. In some embodiments, patients may continue treatment for an additional period. In some embodiments, patients with cancer recurrence may discontinue treatment, for example, to try another treatment option.

[0142] D. patient

[0143] Another aspect of this disclosure relates to a method for treating early-stage breast cancer in adult patients in need, the method comprising administering a treatment to a patient comprising a combination of a cyclin-dependent kinase (CDK) inhibitor and an endocrine therapy, wherein the adult patient is selected or characterized according to one or more criteria.

[0144] The criteria can relate to patient demographics, characteristics of the patient's early breast cancer (e.g., type, stage, grade, hormone receptor status, etc.), prior treatment, and / or other criteria described herein.

[0145] I. age

[0146] In some embodiments, the patient is an adult, e.g., 18 years of age or older. In some embodiments, the patient is between about 18 years of age and about 45 years of age. In some embodiments, the patient is between about 45 years of age and about 54 years of age. In some embodiments, the patient is between about 55 years of age and about 64 years of age. In some embodiments, the patient is about 64 years of age or older. The patient can belong to an age category that is less than the median age of the given EBC patient population, or alternatively, the patient can belong to an age category that is greater than or equal to the median age of the EBC patient population.

[0147] II. Gender and menopausal status

[0148] In some embodiments, the patient is a female. In other embodiments, the patient is a male. For female patients, the patient can be premenopausal. Alternatively, the female patient can be postmenopausal.

[0149] A patient in a postmenopausal state can be defined as (1) a patient who has undergone bilateral oophorectomy; (2) a patient who is greater than or equal to 60 years of age; (3) a patient who is less than 60 years of age and amenorrheic for 12 months or longer (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) and has follicle-stimulating hormone (FSH) and plasma estradiol levels in the postmenopausal range according to the local normal range; or (4) a patient who is less than 60 years of age and on tamoxifen or toremifene and has FSH and plasma estradiol levels in the postmenopausal range.

[0150] For patients who do not meet the criteria for a postmenopausal state, a premenopausal state can be defined. For a female in a premenopausal state, amenorrhea can not be a reliable indicator of menopausal status, as ovarian function can still be intact or recoverable despite anovulation / amenorrhea. For these women with treatment-induced amenorrhea, FSH and / or estradiol can be measured serially according to local clinical guidelines to determine postmenopausal status.

[0151] III. Fertility

[0152] In some embodiments, the patient is a childbearing potential (CBP) female, defined as physiologically capable of becoming pregnant.

[0153] A woman can be considered to have CBP unless she has had 12 months or more of natural (spontaneous) amenorrhea and has an appropriate clinical profile (i.e., age appropriate, history of vasomotor symptoms) or has had surgical bilateral oophorectomy (with or without hysterectomy) or total hysterectomy or tubal ligation at least six weeks prior to randomization, confirmed by hormone level assessments. In the case of oophorectomy alone, a woman can be considered not to have CBP after confirmation by hormone level assessments.

[0154] In some embodiments, the patient is a non-pregnant woman with CBP.

[0155] In some embodiments, the patient is not a pregnant or lactating (breast-feeding) woman or a woman who plans to become pregnant or breast-feed during the treatment as described herein.

[0156] IV. Diagnosis of breast cancer

[0157] In some embodiments, the patient in need of treatment for early breast cancer is a patient who has been diagnosed with early breast cancer. The patient can not have received prior treatment for early breast cancer. The patient can have received prior treatment for early breast cancer, such as surgery, chemotherapy, radiation therapy, and / or hormone therapy, but can still be in need of treatment due to the early breast cancer not responding to the prior treatment. In some embodiments, the patient has received prior treatment for early breast cancer and the early breast cancer has recurred. In some embodiments, the patient has received prior treatment for a cancer that was diagnosed as early breast cancer. In some embodiments, the patient is at risk of developing early breast cancer and / or is at risk of recurrence of early breast cancer. The patient at risk can not have detectable signs or symptoms of early breast cancer, but can be at risk due to a prior diagnosis of cancer.

[0158] In some embodiments, the patient has received prior treatment for early breast cancer (e.g., HR+HER2- stage II or stage III early breast cancer) and does not have detectable signs or symptoms of early breast cancer, but is still at risk of recurrence of early breast cancer. Risk factors can be related to the early breast cancer the patient received treatment for, where a high tumor grade, large tumor size (e.g., greater than 2 mm), and axillary lymph node involvement can be associated with a higher risk of recurrence.

[0159] In some embodiments, the patient has breast cancer that has been diagnosed and / or confirmed (e.g., histologically confirmed) as breast cancer. The cancer can have been diagnosed within 18 months prior to the start of treatment. The cancer can be a unilaterally primary invasive adenocarcinoma. The cancer can be a multicentric and / or multifocal tumor.

[0160] V. Hormone receptor (HR) status and expression of human epidermal growth factor receptor 2 (HER2)

[0161] In some embodiments, the patient has a hormone receptor positive breast cancer. The breast cancer can be ER and / or PR positive. The breast cancer can be ER+ / PR-, ER- / PR+, or ER+ / PR+.

[0162] In some embodiments, the breast cancer the patient has is a HER2- breast cancer. For example, the breast cancer can be defined as a cancer with a negative in situ hybridization test result and / or an immunohistochemistry (IHC) status of 0+ or 1+. If the IHC of the breast cancer is 2+, a negative in situ hybridization (FISH, CISH, or SISH) can be used to confirm the HER2- status.

[0163] VI. Tumor characteristics

[0164] In some embodiments, the patient has a breast cancer comprising a tumor belonging to one of the following categories: • anatomic stage III group, or • anatomic stage IIB group, or • anatomic stage IIA group belonging to any of: • N1, or • N0, wherein: • grade 3, or • grade 2.

[0165] In some embodiments, for a patient having a tumor belonging to anatomic stage IIA group, N0, and grade 2, there can be additional indicators of classification of the breast cancer. For example, the tumor can have a Ki67 percentage of about 20% or greater than about 20%. In a multi-parameter test, the tumor can have a score indicating a risk of recurrence and / or spread of the cancer, for example, a Breast Cancer Index® breast recurrence score of > 26 (on a 0-100 scale) in the Oncotype DX® test, a high risk score in the Prosigna® / PAM50 (Prediction Analysis of Microarray 50) test, a high risk score in the MammaPrint® test, or a high risk score in the EndoPredict® EPclin test.

[0166] In some embodiments, the patient has a stage IIA tumor. In some embodiments, the patient has a stage IIB tumor. In some embodiments, the patient has a stage IIIA tumor. In some embodiments, the patient has a stage IIIB tumor. In some embodiments, the patient has a stage IIIC tumor.

[0167] In some embodiments, the patient does not have a stage IV tumor, for example, a breast cancer tumor with distant metastasis beyond the lymph nodes.

[0168] In some embodiments, the patient has a tumor with a lymph node status selected from NX, N0, N1, N2, or N3. For example, the patient can have a tumor with a N0 status. Alternatively, the patient can have a tumor with a N1, N2, or N3 status, or a tumor with any of N1, N2, or N3 status.

[0169] In some embodiments, the patient has a tumor with a T0 category, a Tis category, T1, T2, T3, or T4 category. In some embodiments, the patient has a tumor with a T0 category. The patient can have a tumor with a T1, T2, or T3 category status, or a tumor with any of T1, T2, or T3. In some embodiments, the patient has a tumor with a T4 category.

[0170] In some embodiments, the patient has a tumor with an M stage of M0.

[0171] In some embodiments, the patient has a tumor with a histological grade of GX, G1, G2, or G3 (e.g., Grade X, Grade 1, Grade 2, or Grade 3). The patient can have a tumor with a histological grade of Grade 1. The patient can have a tumor with a histological grade of Grade 2. The patient can have a tumor with a histological grade of Grade 3.

[0172] In certain embodiments, the patient has a tumor with a Ki67 status of less than or equal to 20%. The Ki67 category can be less than or equal to 14%, or the Ki67 category can be greater than 14%. Alternatively, the patient can have a tumor with a Ki67 status of more than 20%. Ki67 can be measured in an archival sample of the patient’s resected tumor. Ki67 is a proliferation marker in normal and human cell populations that can be used as a clinical marker for breast cancer and a predictive marker of success of endocrine therapy.

[0173] In some embodiments, the patient has a tumor that has been evaluated by a genomic test (e.g., one or more of Endopredict® test, Mammaprint® test, Oncotype DX® test, Prosigna / PAM50® test, and Breast Cancer Index® test). The patient can have one or more risk scores from the tests that indicate a high risk of cancer recurrence and / or metastasis.

[0174] In some embodiments, the tumor has an EndoPredict EPclin® risk score that indicates a high risk. In some embodiments, the tumor has a Mammaprint® test result that indicates a high risk. In some embodiments, the tumor has a Prosigna / PAM50® test result that indicates a high risk. In some embodiments, the tumor has an Oncotype DX Breast Recurrence Score that is greater than or equal to about 26.

[0175] Indicators (e.g., histopathological grade, T stage, N stage, M stage, and Ki67) can be determined at initial diagnosis or using a surgical specimen.

[0176] In some embodiments, the patient has a tumor of the ductal subtype. The patient can have a tumor of the lobular subtype. Alternatively, the patient can have a tumor that is neither of the ductal nor lobular subtype.

[0177] In some embodiments, the primary histology of the tumor is selected from invasive ductal carcinoma, not otherwise specified (NOS), invasive lobular carcinoma, medullary carcinoma, mucinous carcinoma, papillary carcinoma, tubular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

[0178] In some embodiments, the patient has a tumor comprising a HER2 ISH result comprising an IHC score of 0, 1+, 2+, or 3+. The HER2 ISH result can be obtained preoperatively or from a surgical specimen.

[0179] In some embodiments, the patient has a positive hormone receptor status. For example, a positive ER status and / or a positive PR status. The positive status can be obtained preoperatively or from a surgical specimen.

[0180] In certain embodiments, the patient has a tumor that is node negative (e.g., the patient is considered pN0). The patient can have a tumor that is node positive with micrometastases only (e.g., the patient is considered pN1mi). The patient can have a tumor that is T1-2, and preoperatively clinically node negative, not received neoadjuvant chemotherapy, has at least one macrometastasis in 1 or 2 sentinel lymph nodes, and / or has no fused growth lymph nodes or apparent extranodal disease at the time of sentinel cleanout (e.g., the patient is considered pN1).

[0181] In some embodiments, the breast cancer is staged by lymph node dissection (e.g., axillary lymph node dissection (ALND)). In some embodiments, the breast cancer is staged by sentinel lymph node (SLN) dissection.

[0182] In some embodiments, the tumor is located in the right breast only and not in the left breast. Alternatively, the tumor can be located in the left breast only and not in the right breast. In some embodiments, the tumor is bilateral, e.g., comprising cancer cells located in both the right breast and the left breast.

[0183] VII. Body Mass Index

[0184] In some embodiments, the patient has a body mass index (BMI) greater than 25 or equal to 25. In some embodiments, the patient has a BMI less than 25.

[0185] VIII. Previous treatments for cancer

[0186] In some embodiments, the patient has received a breast cancer treatment (also referred to as a therapy) prior to receiving the methods described herein.

[0187] The prior treatment can be an initial treatment (also referred to as an initial therapy, primary treatment or therapy, induction treatment or therapy, or first line treatment or therapy) of the breast cancer. In some embodiments, the patient has completed an initial treatment of the breast cancer prior to the treatment as described herein. Thus, the treatment described herein can be an adjuvant treatment following the prior treatment.

[0188] In some embodiments, the prior treatment is not an initial treatment, but is performed following the initial treatment or other treatment. In these instances, the treatment described herein can be an adjuvant treatment to the prior treatment, where the prior treatment itself is performed following one or more additional prior treatments of the breast cancer.

[0189] The prior treatment can itself be an adjuvant treatment to the initial treatment. The prior treatment can be a neoadjuvant treatment to the initial treatment. The prior treatment can be a neoadjuvant treatment to the treatment disclosed herein. In some embodiments, the patient has completed the prior treatment (e.g., the adjuvant and / or neoadjuvant treatment) prior to the treatment disclosed herein.

[0190] In further exemplary instances, the prior treatment is a neoadjuvant treatment to the initial treatment. For example, the prior treatment can be administered prior to the initial treatment to downsize the tumor. In some embodiments, both the prior treatment and the initial treatment of the neoadjuvant treatment are completed prior to the treatment described herein.

[0191] In some embodiments, the prior treatment is a neoadjuvant treatment to the treatment described herein.

[0192] The prior treatment can be radiotherapy (also referred to as “radiation therapy”), surgical treatment, or chemotherapy.

[0193] In some embodiments, the prior treatment is radiotherapy. The radiotherapy can be performed at one or more of the following locations: breast, chest wall, axillary lymph nodes, supraclavicular lymph nodes, and internal mammary lymph nodes.

[0194] In some embodiments, the patient has received surgical treatment. Thus, the prior treatment can be surgical resection of cancer cells (e.g., a tumor). For example, the patient can have undergone one or more of a mastectomy, a breast-conserving surgery, an axillary lymph node dissection, or a sentinel lymph node biopsy. In some embodiments, the patient has undergone a mastectomy. In some embodiments, the patient has undergone a lumpectomy. In some embodiments, the entire organ or even surrounding structures can be removed to achieve the necessary resection of the cancer (e.g., tumor). Surrounding normal, healthy tissue (referred to as the “surgical margin”) can be removed to improve the success of the surgery. Thus, in some embodiments, the prior treatment comprises complete tumor resection. The cancer can be completely removed with a final surgical specimen that is microscopically free of tumor.

[0195] In some embodiments, after surgical resection, the cancer can be R0 (e.g., the surgical margins are microscopically negative for residual tumor).

[0196] In some embodiments, after prior surgical treatment, the patient is administered a treatment as described herein as an adjuvant therapy. For example, a treatment described herein can be initiated after surgical resection, where the tumor is completely removed with a final surgical specimen that is microscopically free of tumor.

[0197] The prior treatment can be chemotherapy. In some embodiments, the patient has received prior treatment that is chemotherapy. The chemotherapy can be neoadjuvant chemotherapy. For example, the neoadjuvant chemotherapy can be administered prior to another treatment such as surgery, radiation therapy, or administration of another drug. The chemotherapy can be adjuvant chemotherapy. For example, the prior treatment can be chemotherapy administered after another treatment such as surgery, radiation therapy, or administration of another drug. The chemotherapy can be neoadjuvant / adjuvant chemotherapy. In these exemplary instances, the prior treatment (e.g., neoadjuvant chemotherapy and / or adjuvant chemotherapy) occurs prior to the treatment according to the methods described herein.

[0198] In some embodiments, the patient has received prior anti-neoplastic chemotherapy, e.g., an anthracycline or a taxane.

[0199] In some embodiments, the patient has received endocrine therapy (ET). The ET can be, for example, neoadjuvant and / or adjuvant ET. The patient can have received ET within 12 months prior to initiation of the methods of the disclosure. In some embodiments, the patient has received tamoxifen or toremifene as adjuvant ET, where the patient experienced a 5 half-life (e.g., 35 days) washout period prior to initiation of the methods of the disclosure. The patient can have received an aromatase inhibitor during the washout period.

[0200] In some embodiments, the patient has received endocrine therapy selected from an aromatase inhibitor, an anti-estrogen, a gonadotropin-releasing hormone analog, or a biological / targeted therapy.

[0201] In some embodiments, the patient has received prior treatment for the breast cancer, but the breast cancer did not respond to the treatment, e.g., due to resistance of the breast cancer cells to the drug. In some embodiments, the patient has received prior treatment for the breast cancer, but the breast cancer has relapsed (or “recurred”).

[0202] In some embodiments, the patient has received a treatment (also referred to as a therapy) for breast cancer prior to receiving the treatment described herein and is in remission. The patient can be in remission from early stage breast cancer, e.g., HR+ / HER2- early stage breast cancer. The HR+ / HER2- early stage breast cancer can be a stage II or stage III cancer.

[0203] The cancer can be in remission. The patient having the cancer can be in remission. In both cases, remission can refer to a reduction or disappearance of signs of the cancer in the patient after treatment for the cancer. Remission can be partial remission, in which the size of the cancer (e.g., cancer cells and / or tumors) or the extent of spread in the body has been reduced. For example, partial remission can reflect a 50% reduction in a measurable parameter of the cancer (e.g., growth, size, or spread of cancer cells and / or tumors). Remission can be complete remission, in which no signs of the cancer (e.g., cancer cells and / or tumors) are detected. When in complete remission, there can be no evidence of disease.

[0204] When in complete remission, there can be no detectable signs or symptoms of the cancer.

[0205] Remission can be associated with a period of time since the patient had detectable signs or symptoms of the cancer. For example, about 1 month after having no detectable signs or symptoms of the cancer, the patient can be described as being in remission. In some embodiments, the period of time is about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 24 months, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, about 36 months, or more. In some embodiments, the period of time is about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, or more.

[0206] Accordingly, the treatment as described herein can be administered to a patient in remission. In some embodiments, the patient is in complete remission. In some embodiments, the patient is in partial remission.

[0207] In some embodiments, at the start of the treatment described herein, the patient is in complete remission. For example, the patient can have no detectable cancer cells and / or tumors. The patient can have been diagnosed with early stage breast cancer at a prior time and can have received prior treatment, with the result that no cancer is detectable. Thus, a patient who has no symptoms of cancer can be administered the treatment described herein. In some embodiments, the patient can have been diagnosed with HR+ / HER2- early stage breast cancer and received surgical treatment to remove the cancer, and the HR+ / HER2- early stage breast cancer can no longer be detectable. In some embodiments, the patient can be at risk of developing HR+ / HER2- breast cancer based on the presence of a prior diagnosis of HR+ / HER2- breast cancer. For example, the patient can be at risk of recurrence of HR+ / HER2- breast cancer based on a prior diagnosis of HR+ / HER2- early stage breast cancer.

[0208] In some embodiments, the patient is in partial remission and exhibits detectable signs of cancer at the start of the treatment described herein. In some embodiments, the patient is diagnosed with HR+ / HER2- early stage breast cancer and has received prior treatment, but the cancer was not completely removed and / or the cancer has recurred. In some embodiments, the patient in partial remission can be at risk of regrowth and / or spread of HR+ / HER2- breast cancer based on a prior diagnosis of HR+ / HER2- early stage breast cancer.

[0209] In some embodiments, the treatment described herein prevents the growth of HR+ / HER2- breast cancer cells in a patient (e.g., a patient in remission (e.g., in complete remission or in partial remission)).

[0210] In some embodiments, the treatment described herein maintains remission (e.g., in complete remission or in partial remission) in a patient. The treatment can maintain remission for at least about 3 months, at least about 6 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, at least about 60 months, at least about 66 months, at least about 72 months, at least about 78 months, at least about 84 months, at least about 90 months, at least about 96 months, at least about 102 months, at least about 108 months, at least about 114 months, at least about 120 months, or more.

[0211] In some embodiments, the treatment reduces recurrence of breast cancer (e.g., early stage breast cancer, such as HR+ / HER2- early stage breast cancer). The treatment can reduce recurrence for at least about 3 months, at least about 6 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, at least about 60 months, at least about 66 months, at least about 72 months, at least about 78 months, at least about 84 months, at least about 90 months, at least about 96 months, at least about 102 months, at least about 108 months, at least about 114 months, at least about 120 months, or more.

[0212] Breast cancer recurrence can be ipsilateral breast tumor recurrence (IBTR), defined herein as the reappearance of a breast tumor in the same (i.e., ipsilateral) breast or chest wall. Breast cancer recurrence can be contralateral breast cancer, defined herein as primary breast cancer occurring at least three months after the first breast cancer in the opposite (i.e., contralateral) breast.

[0213] Accordingly, in some embodiments, the methods described herein comprise maintaining remission in an adult patient previously diagnosed with HR+ / HER2- stage II or stage III early stage breast cancer, the method comprising administering to the patient a treatment comprising a dose of ribociclib, the free base form thereof, or a pharmaceutically acceptable salt thereof, in combination with an aromatase inhibitor.

[0214] In some embodiments, the treatment described herein is an adjuvant therapy to prior treatment (also referred to as adjuvant treatment). The adjuvant therapy can be performed after any prior treatment, such as the prior treatments described herein. The adjuvant therapy can be performed after more than one prior treatment. For example, one prior treatment can be a neoadjuvant therapy performed prior to initial treatment (e.g., first line treatment) such as surgery and subsequent chemotherapy, radiotherapy, and / or endocrine therapy, after which the treatment described herein is administered as an adjuvant therapy.

[0215] Accordingly, in some embodiments, the methods described herein comprise preventing recurrence of breast cancer in an adult patient, the method comprising providing an adjuvant therapy to a patient who has received a prior treatment for HR+ / HER2- stage II or stage III early stage breast cancer, wherein the adjuvant therapy comprises administering 400 mg of ribociclib, or a pharmaceutically acceptable salt thereof, to the patient on days 1-21 of a 28-day cycle for at least 36 months, in combination with an aromatase inhibitor as defined herein administered daily on a 28-day cycle.

[0216] Thus, in some embodiments, the methods described herein comprise maintaining remission in an adult patient previously diagnosed with HR+ / HER2- Stage II or III early breast cancer, the method comprising providing adjuvant therapy to a patient who has received a prior treatment for HR+ / HER2- Stage II or III early breast cancer, wherein the adjuvant therapy comprises administering 400 mg of rebamipide, or a pharmaceutically acceptable salt thereof, to the patient on days 1-21 of a 28-day cycle for at least 36 months, in combination with an aromatase inhibitor as defined herein administered daily on a 28-day cycle.

[0217] In some embodiments, the adjuvant therapy does not comprise administration of a 600 mg / day dose of rebamipide.

[0218] Another aspect of the disclosure relates to a method of treating an adult patient who has been diagnosed with HR+ / HER2- Stage II or III early breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) rebamipide at a dose ranging from 150 mg / day to 450 mg / day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor daily on a 28-day cycle, wherein the method results in improvement in one or more of overall survival (OS), distant disease-free survival (DDFS), or relapse-free survival (RFS) in the patient.

[0219] In some embodiments, the early breast cancer can no longer be in Stage II or III when the treatment described herein begins. For example, the patient can have received at least one prior treatment for which the treatment described herein is adjuvant therapy.

[0220] Another aspect of the disclosure relates to a method for improving one or more of overall survival (OS), distant disease-free survival (DDFS), or relapse-free survival (RFS) in a patient who has been diagnosed with HR+ / HER2- Stage II or III early breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) rebamipide at a dose ranging from 150 mg / day to 450 mg / day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor daily on a 28-day cycle.

[0221] Further aspects of the disclosure relate to use of ribociclib for use in a method of improving one or more of overall survival (OS), distant disease-free survival (DDFS), or relapse-free survival (RFS) in an adult patient who has been diagnosed with HR+ / HER2- Stage II or III early stage breast cancer, wherein the method comprises administering to the patient an adjuvant therapy comprising (i) ribociclib at a dose ranging from 150 mg per day to 450 mg per day on Days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered every day of a 28-day cycle.

[0222] The methods described herein can prevent local and / or regional invasive recurrence of early stage breast cancer.

[0223] Accordingly, an aspect of the disclosure relates to a method for reducing the risk of local or regional invasive recurrence of early stage breast cancer in an adult patient who has been diagnosed with HR+ / HER2- Stage II or III early stage breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) ribociclib at a dose ranging from 150 mg per day to 450 mg per day on Days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered every day of a 28-day cycle.

[0224] An aspect of the disclosure relates to use of ribociclib for use in a method of reducing the risk of local or regional invasive recurrence of early stage breast cancer in an adult patient who has been diagnosed with HR+ / HER2- Stage II or III early stage breast cancer, wherein the method comprises administering to the patient an adjuvant therapy comprising (i) ribociclib at a dose ranging from 150 mg per day to 450 mg per day on Days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered every day of a 28-day cycle.

[0225] The methods described herein can prevent recurrence of cancer in tissues other than the breast, such as bone, liver, and lung or pleura.

[0226] Accordingly, a further aspect of the disclosure relates to a method for reducing the risk of invasive recurrence of early stage breast cancer in one or more of bone, liver, and lung or pleura in an adult patient who has been diagnosed with HR+ / HER2- Stage II or III early stage breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) ribociclib at a dose ranging from 150 mg per day to 450 mg per day on Days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered every day of a 28-day cycle.

[0227] Further aspects of the disclosure relate to use of ribociclib in a method of reducing the risk of invasive recurrence of early breast cancer in one or more of the bone, liver, and lung or pleura in an adult patient who has been diagnosed with HR+ / HER2- Stage II or Stage III early stage breast cancer, wherein the method comprises administering to the patient an adjuvant therapy comprising (i) ribociclib at a dose ranging from 150 mg per day to 450 mg per day on Days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor on every day of a 28-day cycle.

[0228] The administration of the therapy does not consider the lymph node status of the breast cancer.

[0229] Another aspect of the disclosure relates to a method for reducing the risk of recurrence of early breast cancer in an adult patient who has been diagnosed with HR+ / HER2- Stage II or Stage III early stage breast cancer, the method comprising administering an adjuvant therapy comprising (i) ribociclib at a dose ranging from 150 mg per day to 450 mg per day on Days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor on every day of a 28-day cycle, wherein the administration of the therapy does not consider the lymph node status of the breast cancer.

[0230] An aspect of the disclosure relates to use of ribociclib in a method of reducing the risk of recurrence of early breast cancer in an adult patient who has been diagnosed with HR+ / HER2- Stage II or Stage III early stage breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) ribociclib at a dose ranging from 150 mg per day to 450 mg per day on Days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor on every day of a 28-day cycle, wherein the administration of the therapy does not consider the lymph node status of the breast cancer.

[0231] For example, the breast cancer can have a lymph node status of N0, N1, N2, or N3. The breast cancer can have a lymph node status of N0.

[0232] In some embodiments, the early breast cancer is Stage II, e.g., Stage IIA. In some embodiments, the early breast cancer is Stage III, e.g., Stage IIIB or Stage IIIC.

[0233] In certain embodiments, the breast cancer is of the ductal subtype.

[0234] In some embodiments, the patient is Asian.

[0235] Patients can require adjuvant therapy after having received at least one prior treatment for breast cancer. In some embodiments, the methods described herein are adjuvant therapy because the patient has received at least one prior treatment for breast cancer selected from the group consisting of surgery, chemotherapy, and radiotherapy.

[0236] In some embodiments, the patient has not undergone a mastectomy.

[0237] In some embodiments, the dose of ribociclib is 400 mg per day. Ribociclib can be administered in the form of a salt, preferably ribociclib succinate.

[0238] In some embodiments, the aromatase inhibitor is letrozole or anastrozole. For example, the aromatase inhibitor can be letrozole, preferably administered at a dose of 2.5 mg per day. The aromatase inhibitor can be anastrozole, preferably administered at a dose of 1 mg per day.

[0239] In some embodiments, the dose of ribociclib is 400 mg per day, ribociclib is administered in the form of ribociclib succinate, and the aromatase inhibitor is letrozole or anastrozole, preferably 2.5 mg per day of letrozole or 1 mg per day of anastrozole.

[0240] In some embodiments, the patient achieves an improvement in OS, DDFS, and / or RFS of at least 36 months or a reduction in the risk of breast cancer recurrence.

[0241] In some embodiments, the patient has not previously received a CDK4 / 6 inhibitor.

[0242] In some embodiments, the patient has not received tamoxifen, raloxifene, or an aromatase inhibitor within 2 years prior to receiving the methods of the disclosure to reduce breast cancer risk (“chemoprevention”) and / or to treat osteoporosis.

[0243] In some embodiments, the patient has not received an anthracycline therapy with a cumulative dose of doxorubicin of 450 mg / m 2 or more, a cumulative dose of epirubicin of 900 mg / m 2 or more.

[0244] In some embodiments, the patient does not have a known hypersensitivity to any ribociclib and / or ET excipients (e.g., the patient does not have a genetic problem of rare galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption, or soybean hypersensitivity).

[0245] In some embodiments, the patient does not receive other anti-neoplastic therapy in addition to the adjuvant ET as described herein.

[0246] In some embodiments, the patient has not received major surgery, chemotherapy, or radiation therapy within 14 days of receiving the methods of the disclosure.

[0247] In some embodiments, the patient has not recovered from clinical and laboratory acute toxicities related to prior anticancer therapy to ≤ Grade 1 NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 4.03 at the day of randomization. Patients with alopecia of any grade, amenorrhea, Grade 2 neuropathy, or other toxicities not considered to pose a safety risk to the patient are excluded.

[0248] In some embodiments, the patient does not have a concurrent invasive malignancy or a prior invasive malignancy treated with curative intent within 2 years prior to randomization. The patient can have had adequate treatment of basal cell or squamous cell skin cancer or curative resection of carcinoma in situ of the cervix.

[0249] In some embodiments, the patient does not have a known history of human immunodeficiency virus (HIV) infection.

[0250] In some embodiments, the patient does not have a known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (testing is not mandatory unless required by local regulations).

[0251] In some embodiments, the patient does not have clinically significant, uncontrolled cardiac disease and / or cardiac repolarization abnormalities, including any of the following: • documented myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass surgery within 6 months prior to initiation of the methods of the disclosure.

[0252] • documented cardiomyopathy.

[0253] • left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO).

[0254] • long QT syndrome or a family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: • risk factors for Torsades de Pointes (TdP), including uncorrected hypocalcemia, hypokalemia, or hypomagnesemia, a history of heart failure, or a history of clinically significant / symptomatic bradyarrhythmia; • One or more concomitant medications with known risk of prolonging QT interval and / or known to cause TdP that cannot be discontinued or replaced by a safe alternative medication (e.g., within 5 half-lives or 7 days prior to initiation of the method of the disclosure); • QTcF interval cannot be determined.

[0255] • Clinically significant arrhythmia (e.g., ventricular tachycardia), complete left bundle branch block, and / or high-grade atrioventricular (AV) conduction abnormalities (e.g., bifascicular block, Mobitz type II, and third degree AV block).

[0256] • Uncontrolled arterial hypertension, systolic blood pressure > 160 mmHg.

[0257] In some embodiments, the patient has not received any of the following within 7 days prior to receiving the method of the disclosure: • Concomitant medications, herbal supplements, and / or fruits (e.g., grapefruit, pomelo, starfruit, Seville oranges) and juices thereof known as potent inhibitors or inducers of CYP3A4 / 5.

[0258] • Drugs with a narrow therapeutic window and primarily metabolized by CYP3A4 / 5.

[0259] In some embodiments, the patient does not consume grapefruit (or grapefruit juice). In some embodiments, the patient does not consume pomelo, starfruit, and Seville oranges (and juices thereof). In certain embodiments, the patient is not concomitantly using any of bosentan, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir, ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, and voriconazole.

[0260] In some embodiments, the patient is not currently receiving or has not received systemic corticosteroids within < 2 weeks prior to receiving the method of the disclosure, or has not fully recovered from the side effects of such treatment. In some embodiments, the patient can use corticosteroids in the following situations: short-term (< 5 days) systemic corticosteroids; topical application of any duration (e.g., for skin rash), inhaled sprays (e.g., for obstructive airway disease), eye drops, or local injections (e.g., intra-articular).

[0261] In some embodiments, the patient does not have a GI disease that impairs GI function or can significantly alter the absorption of the oral trial treatment (e.g., uncontrolled ulcerative disease, uncontrolled nausea, vomiting, or diarrhea, malabsorption syndrome, or small bowel resection).

[0262] In some embodiments, the patient does not have any other concurrent serious and / or uncontrolled medical disorder that can, in the Investigator’s opinion, pose unacceptable safety risk, prohibit the patient from treatment, or affect method compliance (e.g., chronic pancreatitis, chronic active hepatitis, cirrhosis or any other major liver disease, untreated or uncontrolled active fungal, bacterial or viral infection, active infection requiring systemic antibacterial therapy, etc.) or limit life expectancy to < 5 years.

[0263] In some embodiments, the patient has not participated in a treatment involving the study drug(s) within 30 days prior to receiving the method of the disclosure or within 5 half-lives of the study drug(s), whichever is longer.

[0264] IX. Other standards

[0265] In some embodiments, the patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

[0266] In some embodiments, the patient has bone marrow and organ function defined by the following values: • Absolute neutrophil count (ANC) > 1.5 x 10 9 / L.

[0267] • Platelets > 100 x 10 9 / L.

[0268] • Hemoglobin > 9.0 g / dL.

[0269] • Estimated glomerular filtration rate (eGFR) > 30 mL / min / 1.73 m 2 .

[0270] • Alanine aminotransferase (ALT) < 2.5 x upper limit of normal (ULN).

[0271] • Aspartate aminotransferase (AST) < 2.5 x ULN.

[0272] • Serum total bilirubin < ULN; or total bilirubin < 3.0 x ULN or direct bilirubin < 1.5 x ULN for patients with adequate documentation of Gilbert’s syndrome.

[0273] • International normalized ratio (INR) < 1.5 (unless the patient is receiving an anticoagulant, and the INR is within the therapeutic range for the intended use of the anticoagulant within 7 days prior to randomization).

[0274] • The following laboratory values are within the normal range or corrected to be within the normal range by supplementation (corrected local laboratory values should be documented within the normal range): • Potassium • Magnesium • Total calcium (corrected for serum albumin) In some embodiments, the patient has a QTcF interval (Fridericia-corrected QT interval) of < 450 msec on standard 12-lead ECG at screening and a resting heart rate of 50-90 beats per minute (determined from ECG).

[0275] X. Region and race / ethnicity

[0276] In some embodiments, the patient is located in North America. The patient can be located in Europe, for example Western Europe. The patient can be located in Oceania, for example Australia. In some embodiments, the patient is located in Asia. In some embodiments, the patient is located in Africa. In some embodiments, the patient is located in Latin America.

[0277] In some embodiments, the patient can be an American Indian. In some embodiments, the patient can be an Alaska Native. In some embodiments, the patient can be an Asian. In some embodiments, the patient can be Black or African American. In some embodiments, the patient can be a Native Hawaiian or other Pacific Islander. In some embodiments, the patient can also be White. In some embodiments, the patient can be of mixed race. In some embodiments, the patient can be non-Asian. In some embodiments, the patient can be Hispanic or Latino. In some embodiments, the patient is non-Hispanic or Latino.

[0278] E. Therapeutic effect readings

[0279] One aspect of the disclosure relates to a method of treating early breast cancer in an adult patient in need thereof, comprising administering to the patient a treatment comprising a cyclin-dependent kinase (CDK) inhibitor in combination with an endocrine therapy (ET), wherein the treatment is characterized by an improvement in the patient’s condition compared to a patient who does not receive the treatment or compared to the patient prior to treatment. In some embodiments, the treatment regimen is selected (e.g., the dose of ribociclib and / or aromatase inhibitor is selected) to achieve a certain degree of improvement in the patient’s condition compared to a patient who does not receive the treatment or compared to the patient prior to treatment.

[0280] In some embodiments, a patient who has not received a treatment described herein can include a patient who has not received ribociclib (or a pharmaceutically acceptable salt thereof, e.g., ribociclib succinate). In some embodiments, a patient who has not received a treatment described herein can include a patient who has not received ribociclib (or a pharmaceutically acceptable salt thereof, e.g., ribociclib succinate) in combination with endocrine therapy. For example, a patient can receive endocrine therapy alone without receiving ribociclib (or a pharmaceutically acceptable salt thereof, e.g., ribociclib succinate). A patient can receive letrozole alone without receiving ribociclib (or a pharmaceutically acceptable salt thereof, e.g., ribociclib succinate). A patient can receive anastrozole alone without receiving ribociclib (or a pharmaceutically acceptable salt thereof, e.g., ribociclib succinate). In some embodiments, a patient who has not received a treatment described herein can receive another cancer treatment, wherein the other cancer treatment is not a combination of ribociclib (or a pharmaceutically acceptable salt thereof, e.g., ribociclib succinate) and endocrine therapy. In some embodiments, a patient who has not received a treatment described herein can be a patient who has not received any cancer treatment.

[0281] Improvement in the patient's condition can be associated with a reduction in breast cancer signs and / or symptoms. For example, improvement can include a reduction in breast cancer progression and / or breast cancer recurrence. Improvement can include preventing breast cancer progression, early breast cancer recurrence, and / or breast cancer-caused death. Improvement can include reducing the risk of cancer progression, cancer recurrence, and / or the risk of cancer-caused death (or avoiding death).

[0282] In some embodiments, improvement in the patient's condition is maintenance of existing signs and / or symptoms of breast cancer. For example, after treatment, the breast cancer can have approximately the same characteristics as before treatment, but the breast cancer does not progress further or worsen in characteristics.

[0283] In some embodiments, improvement in the patient's condition is improved compared to a patient who has not received treatment. In some embodiments, the patient who has not received treatment receives another treatment for early breast cancer. In some embodiments, the patient who has not received treatment receives only endocrine therapy alone.

[0284] In some embodiments, improvement in the patient's condition can include one or more of a reduction in tumor size, prevention of tumor spread, prevention or reduction of breast cancer recurrence, prevention of a second primary malignancy, and increased survival rate.

[0285] For example, improvement in the patient's condition can include an absence (or reduction) of locoregional recurrence, distant recurrence, ipsilateral and contralateral invasive breast cancer, and a second primary non-breast invasive cancer.

[0286] In some embodiments, improvement in the patient's condition is related to measures such as disease-free survival (DFS), invasive disease-free survival (iDFS), overall survival (OS), distant disease-free survival (DDFS), recurrence-free survival (RFS), and local-regional recurrence-free survival (LRRFS).

[0287] Disease-free survival (DFS) can relate to the length of time patients are alive without local recurrence, contralateral recurrence, distant disease, secondary cancer, or new primary cancer. DFS can be defined as the time from the first date (e.g., the date of initiation of cancer treatment, or, alternatively, the date of completion of cancer treatment) to the date of recurrence of cancer or death of the patient.

[0288] Invasive disease-free survival (iDFS) can be defined as DFS, excluding ductal carcinoma in situ as a recurrence event.

[0289] Overall survival (OS) can relate to the length of time patients are alive, which can include death from any cause, regardless of whether breast cancer has recurred or spread. OS can be defined as the time from the first date (e.g., the date of initiation of cancer treatment, or, alternatively, the date of completion of cancer treatment) to the date of death from any cause.

[0290] Distant disease-free survival (DDFS) can relate to the length of time patients remain free of recurrence of cancer at distant sites (e.g., not in the original breast). DDFS can be defined as the time from the first date (e.g., the date of initiation of cancer treatment, or, alternatively, the date of completion of cancer treatment) to the date of first event of distant recurrence, death (any cause), or a second primary non-breast invasive cancer (excluding basal cell and squamous cell skin cancers).

[0291] Recurrence-free survival (RFS) can relate to any recurrence (local, regional, or distant) of the original breast cancer, but not including one or more new cancers. RFS can be defined as the time from the first date (e.g., the date of initiation of cancer treatment, or, alternatively, the date of completion of cancer treatment) to the date of first event of local invasive breast cancer recurrence, regional invasive recurrence, distant recurrence, or death (any cause).

[0292] Local-regional recurrence-free survival (LRRFS) can be defined as the time from the first date (e.g., the date of initiation of cancer treatment, or, alternatively, the date of completion of cancer treatment) to the date of first event of local (ipsilateral) invasive breast cancer recurrence, regional invasive recurrence, or death from any cause.

[0293] Accordingly, in some embodiments, the methods of the present disclosure improve one or more of DFS, iDFS, OS, DDFS, RFS, and LRRFS in a treated patient compared to an untreated patient. For example, the improvement in the patient’s condition can be an increase in the time period between a first date (e.g., the date on which cancer treatment began, or, alternatively, the date on which cancer treatment ended) and the date of occurrence of an event as defined by any of DFS, iDFS, OS, DDFS, RFS, and LRRFS.

[0294] In some embodiments, the improvement in the patient’s condition is a reduction in the incidence (or a reduction in the time until occurrence) of one or more of ipsilateral invasive breast tumor recurrence (IBTR), loco-regional invasive recurrence, distant recurrence (e.g., presence of metastasis), death from breast cancer, death from non-breast cancer causes, death from unknown causes, presence of invasive contralateral breast cancer, and presence of a second primary invasive cancer.

[0295] For example, the treatment can reduce the incidence (or reduce the time until occurrence) of death from breast cancer, death from non-breast cancer causes, and death from unknown causes.

[0296] In some embodiments, the improvement in the patient’s condition is a reduction in the incidence (or a reduction in the time until occurrence) of distant recurrence (e.g., presence of metastasis), death from breast cancer, death from non-breast cancer causes, death from unknown causes, and presence of a second primary invasive cancer.

[0297] In some embodiments, the improvement in the patient’s condition is a reduction in the incidence (or a reduction in the time until occurrence) of one or more of ipsilateral invasive breast tumor recurrence (IBTR), loco-regional invasive recurrence, distant recurrence (e.g., presence of metastasis), death from breast cancer, death from non-breast cancer causes, and death from unknown causes.

[0298] In some embodiments, the improvement in the patient’s condition is a reduction in the incidence (or a reduction in the time until occurrence) of one or more of ipsilateral invasive breast tumor recurrence (IBTR), loco-regional invasive recurrence, distant recurrence (e.g., presence of metastasis), death from breast cancer, death from non-breast cancer causes, and death from unknown causes.

[0299] If the improvement in the patient's condition is a reduction in the risk of invasive disease or other cancer-related event, different metrics can be used to determine the risk. In some embodiments, the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 1 when the risk is calculated relative to a patient who does not receive the treatment. For example, the hazard ratio can be less than about 0.9, about 0.8, about 0.7, about 0.6, about 0.5, about 0.4, about 0.3, about 0.2, or about 0.1. For example, the hazard ratio for iDFS can be calculated using a model (e.g., a Cox model unstratified and unadjusted for covariates or a Cox model stratified and adjusted for covariates) as described in Appendix A.

[0300] In some embodiments, the hazard ratio can be less than or equal to about 0.78. The hazard ratio can be less than or equal to about 0.72.

[0301] In some embodiments, the patient has HR+ / HER2- stage III early breast cancer and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to about 0.74 when the risk is calculated relative to a patient who does not receive the treatment. The hazard ratio can be less than or equal to about 0.76. In some embodiments, the treatment reduces the risk of invasive disease by at least 25% corresponding to a hazard ratio of 0.75 when the risk is calculated relative to a patient who does not receive the treatment.

[0302] In some embodiments, the treatment reduces the risk of invasive disease to a similar level for a subset of patients including patients with stage II early breast cancer, patients with stage III early breast cancer, premenopausal female or male patients, and postmenopausal female patients.

[0303] In some embodiments, the treatment as disclosed herein can achieve the following hazard ratios for a particular patient with HR+ / HER2- early breast cancer.

[0304] In some embodiments, the patient is a female and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.76 when the risk is calculated relative to a patient who does not receive the treatment.

[0305] In some embodiments, the patient is a premenopausal female or male and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.72 when the risk is calculated relative to a patient who does not receive the treatment.

[0306] In some embodiments, the patient is a postmenopausal female and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.78 when the risk is calculated relative to a patient who does not receive the treatment.

[0307] In some embodiments, the patient has received prior neoadjuvant / adjuvant chemotherapy, and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.73 when the risk is calculated relative to patients not receiving the treatment.

[0308] In some embodiments, the patient is located in North America, Western Europe, or Oceania, and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.76 when the risk is calculated relative to patients not receiving the treatment.

[0309] In some embodiments, the patient is not located in North America, Western Europe, or Oceania, and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.76 when the risk is calculated relative to patients not receiving the treatment.

[0310] In some embodiments, the patient has Stage II cancer, and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.76 when the risk is calculated relative to patients not receiving the treatment.

[0311] In some embodiments, the patient has Stage III cancer, and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.74 when the risk is calculated relative to patients not receiving the treatment.

[0312] In some embodiments, the patient has Stage IIA cancer, and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.5 when the risk is calculated relative to patients not receiving the treatment.

[0313] In some embodiments, the patient has Stage IIB cancer, and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.93 when the risk is calculated relative to patients not receiving the treatment.

[0314] In some embodiments, the patient has Stage IIIA cancer, and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.79 when the risk is calculated relative to patients not receiving the treatment.

[0315] In some embodiments, the patient has Stage IIIB cancer, and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.68 when the risk is calculated relative to patients not receiving the treatment.

[0316] In some embodiments, the patient has Stage IIIC cancer, and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.69 when the risk is calculated relative to patients not receiving the treatment.

[0317] In some embodiments, the patient has received prior adjuvant chemotherapy and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.67 when the risk is calculated relative to patients not receiving the treatment.

[0318] In some embodiments, the patient has not received prior adjuvant chemotherapy and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.81 when the risk is calculated relative to patients not receiving the treatment.

[0319] In some embodiments, the patient has received prior neoadjuvant chemotherapy and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.79 when the risk is calculated relative to patients not receiving the treatment.

[0320] In some embodiments, the patient has not received prior neoadjuvant chemotherapy and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.72 when the risk is calculated relative to patients not receiving the treatment.

[0321] In some embodiments, the patient has received prior radiation therapy and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.74 when the risk is calculated relative to patients not receiving the treatment.

[0322] In some embodiments, the patient has not received prior radiation therapy and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.98 when the risk is calculated relative to patients not receiving the treatment.

[0323] In some embodiments, the patient has received prior endocrine therapy and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.76 when the risk is calculated relative to patients not receiving the treatment.

[0324] In some embodiments, the patient has not received endocrine therapy and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.77 when the risk is calculated relative to patients not receiving the treatment.

[0325] In some embodiments, the patient has received prior mastectomy and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.85 when the risk is calculated relative to patients not receiving the treatment.

[0326] In some embodiments, the patient has not received prior mastectomy and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.55 when the risk is calculated relative to patients not receiving the treatment.

[0327] In some embodiments, the patient is Asian, and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.52 when the risk is calculated relative to a patient who does not receive the treatment.

[0328] In some embodiments, the patient is not Asian, and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.81 when the risk is calculated relative to a patient who does not receive the treatment.

[0329] In some embodiments, the patient is in Europe, and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.88 when the risk is calculated relative to a patient who does not receive the treatment.

[0330] In some embodiments, the patient is in North America or Australia, and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.70 when the risk is calculated relative to a patient who does not receive the treatment.

[0331] In some embodiments, the patient is in Asia, and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.34 when the risk is calculated relative to a patient who does not receive the treatment.

[0332] In some embodiments, the patient is in Latin America, and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.69 when the risk is calculated relative to a patient who does not receive the treatment.

[0333] In some embodiments, the patient is less than 45 years of age, and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.68 when the risk is calculated relative to a patient who does not receive the treatment.

[0334] In some embodiments, the patient is 45 to 54 years of age, and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.75 when the risk is calculated relative to a patient who does not receive the treatment.

[0335] In some embodiments, the patient is 55 to 64 years of age, and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.84 when the risk is calculated relative to a patient who does not receive the treatment.

[0336] In some embodiments, the patient is 65 years of age or older, and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.72 when the risk is calculated relative to a patient who does not receive the treatment.

[0337] In some embodiments, the patient receives letrozole, and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.79 when the risk is calculated relative to a patient who does not receive the treatment.

[0338] In some embodiments, the patient has an ER+ / PR+ cancer and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.73 when the risk is calculated relative to a patient not receiving the treatment.

[0339] In some embodiments, the patient has an ER+ / PR+ cancer and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.73 when the risk is calculated relative to a patient not receiving the treatment.

[0340] In some embodiments, the patient has an ER+ / PR- cancer and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.91 when the risk is calculated relative to a patient not receiving the treatment.

[0341] In some embodiments, the patient has a tumor with a lymph node status of 0 and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.63 when the risk is calculated relative to a patient not receiving the treatment.

[0342] In some embodiments, the patient has a tumor with a lymph node status of N1-N3 and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.77 when the risk is calculated relative to a patient not receiving the treatment.

[0343] In some embodiments, the patient has a tumor with a T1-T3 classification and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.74 when the risk is calculated relative to a patient not receiving the treatment.

[0344] In some embodiments, the patient has a tumor with a classification greater than T3 (e.g., T4) and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.83 when the risk is calculated relative to a patient not receiving the treatment.

[0345] In some embodiments, the patient has a tumor with a histologic grade of 1 and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.78 when the risk is calculated relative to a patient not receiving the treatment.

[0346] In some embodiments, the patient has a tumor with a histologic grade of 1 and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.78 when the risk is calculated relative to a patient not receiving the treatment.

[0347] In some embodiments, the patient has a tumor with a histologic grade of 2 and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.75 when the risk is calculated relative to a patient not receiving the treatment.

[0348] In some embodiments, the patient has a tumor with a histologic grade of 3, and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.78 when the risk is calculated relative to patients not receiving the treatment.

[0349] In some embodiments, the patient has a tumor with a Ki67 status of 20% or less, and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.80 when the risk is calculated relative to patients not receiving the treatment.

[0350] In some embodiments, the patient has a tumor with a Ki67 status greater than 20%, and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.75 when the risk is calculated relative to patients not receiving the treatment.

[0351] In some embodiments, the patient has a tumor of the ductal subtype, and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.68 when the risk is calculated relative to patients not receiving the treatment.

[0352] In some embodiments, the patient has a tumor of the non-ductal or lobular subtype, and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.89 when the risk is calculated relative to patients not receiving the treatment.

[0353] In some embodiments, the patient has a BMI of 25 or greater, and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.85 when the risk is calculated relative to patients not receiving the treatment.

[0354] In some embodiments, the patient has a BMI of less than 25, and the treatment can reduce the risk of invasive disease corresponding to a hazard ratio of less than about 0.64 when the risk is calculated relative to patients not receiving the treatment.

[0355] For overall survival, the treatment can not result in a reduction in overall survival corresponding to a hazard ratio of 0.76 when the risk is calculated relative to patients not receiving the treatment.

[0356] In some embodiments, the treatment does not cause or exacerbate an event, such as pneumonia, pulmonary embolism, dyspnea, alanine aminotransferase elevation, aspartate aminotransferase elevation, arthralgia, fatigue, neutropenia, decreased neutrophil count, and / or nausea.

[0357] In some embodiments, the treatment does not cause or exacerbate a condition associated with hepatobiliary toxicity, such as measured by an increase in alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, blood alkaline phosphatase, and / or blood bilirubin.

[0358] In some embodiments, the treatment does not cause or exacerbate a condition associated with myelosuppression (e.g., anemia and / or leukopenia). For example, the treatment does not cause or exacerbate leukopenia, or result in a decrease in white blood cell count, lymphopenia, or a decrease in lymphocyte count.

[0359] In some embodiments, the treatment does not cause or exacerbate a condition associated with myelosuppression (e.g., neutropenia, a decrease in neutrophil count, thrombocytopenia, a decrease in platelet count).

[0360] In some embodiments, the treatment does not prolong the QT interval in an electrocardiogram.

[0361] In some embodiments, the treatment does not cause or exacerbate a condition associated with nephrotoxicity (e.g., an increase in serum creatinine, a decrease in glomerular filtration rate, an increase in blood urea).

[0362] In some embodiments, the treatment does not cause or exacerbate a condition associated with reproductive toxicity, such as mastitis.

[0363] F. A treatment for HR+ / HER2- early breast cancer

[0364] One aspect of the disclosure relates to a method of treating HR+ / HER2- stage II or stage III early stage breast cancer in an adult patient in need thereof, comprising administering to the patient a treatment comprising a dose ranging from 150 mg / day to 450 mg / day of ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate) administered on days 1-21 of a 28-day cycle in combination with an endocrine therapy (such as an aromatase inhibitor, preferably letrozole or anastrozole) administered daily (e.g., days 1-28) of a 28-day cycle.

[0365] Another aspect of the disclosure relates to a method of preventing or reducing a sign or symptom of early stage breast cancer, comprising administering to the patient a treatment comprising a dose ranging from 150 mg / day to 450 mg / day of ribociclib, in its free base form or a pharmaceutically acceptable salt thereof, administered on days 1-21 of a 28-day cycle in combination with an aromatase inhibitor administered daily of a 28-day cycle, preferably letrozole or anastrozole.

[0366] Another aspect of the disclosure relates to a method of maintaining remission in an adult patient previously diagnosed with HR+ / HER2- Stage II or Stage III early breast cancer, the method comprising administering to the patient a treatment comprising a dose ranging from 150 mg / day to 450 mg / day of ribociclib, its free base form, or a pharmaceutically acceptable salt thereof, on Days 1-21 of a 28-day cycle, in combination with an aromatase inhibitor administered every day of a 28-day cycle, preferably letrozole or anastrozole.

[0367] In yet another aspect of the disclosure relates to a method of preventing recurrence of breast cancer in an adult patient, the method comprising providing an adjuvant therapy to a patient who has received a prior treatment for HR+ / HER2- Stage II or Stage III early breast cancer, wherein the adjuvant therapy comprises administering to the patient 400 mg of ribociclib, or a pharmaceutically acceptable salt thereof, on Days 1 to 21 of a 28-day cycle for at least 36 months, in combination with an aromatase inhibitor administered every day of a 28-day cycle as defined in any one of embodiments 23 to 28.

[0368] In some embodiments, the treatment comprises administering to the patient a treatment comprising a dose of about 400 mg / day (or a dose of about 200 mg / day) of ribociclib, or a pharmaceutically acceptable salt thereof (e.g., ribociclib succinate), administered on Days 1 to 21 of a 28-day cycle for 36 months in combination with an endocrine therapy comprising administration of a dose ranging from about 1 mg / day to about 4 mg / day of letrozole or a dose ranging from about 0.5 mg / day to about 1.5 mg / day of anastrozole every day (e.g., Days 1-28) of a 28-day cycle.

[0369] In some embodiments, the treatment comprises administering to the patient a treatment comprising a dose of about 400 mg / day (or a dose of about 200 mg / day) of ribociclib, or a pharmaceutically acceptable salt thereof (e.g., ribociclib succinate), administered on Days 1 to 21 of a 28-day cycle for 36 months in combination with an endocrine therapy comprising administration of a dose of about 2.5 mg / day of letrozole or a dose of about 1 mg / day of anastrozole on Days 1-28 of a 28-day cycle.

[0370] In some embodiments, the treatment reduces one or more of invasive ipsilateral breast tumor recurrence (IBTR), loco-regional invasive recurrence, distant recurrence (e.g., presence of metastasis), breast cancer cause of death, non-breast cancer cause of death, unknown cause of death, presence of invasive contralateral breast cancer, and presence of a second primary invasive cancer.

[0371] In some embodiments, the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 1 when the risk is calculated relative to patients who do not receive the treatment. For example, the hazard ratio for iDFS can be calculated using a model (e.g., Cox model unstratified and unadjusted for covariates or stratified and adjusted for covariates) as described in Appendix A.

[0372] In some embodiments, the hazard ratio can be less than or equal to about 0.78. The hazard ratio can be less than or equal to about 0.72.

[0373] In some embodiments, the patient has HR+ / HER2- stage III early breast cancer and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to about 0.74 when the risk is calculated relative to patients who do not receive the treatment. The hazard ratio can be less than or equal to about 0.76. In some embodiments, the treatment reduces the risk of invasive disease by at least 25% corresponding to a hazard ratio of 0.75 when the risk is calculated relative to patients who do not receive the treatment.

[0374] In some embodiments, the treatment reduces the risk of invasive disease to a similar level for a subset of patients including patients with stage II early breast cancer, patients with stage III early breast cancer, premenopausal female or male patients, and postmenopausal female patients.

[0375] For overall survival, the treatment can not result in a reduction in overall survival corresponding to a hazard ratio of 0.76 when the risk is calculated relative to patients who do not receive the treatment.

[0376] In some embodiments, the patient is a postmenopausal female. In some embodiments, the patient is a premenopausal female or male.

[0377] In some embodiments, the early breast cancer includes a stage II tumor. In some embodiments, the tumor can have a stage IIA anatomic stage. In some embodiments, the tumor can have a stage IIB anatomic stage. In some embodiments, the early breast cancer includes a stage III tumor. In some embodiments, the tumor can have a stage IIIA anatomic stage. In some embodiments, the tumor can have a stage IIIB anatomic stage. In some embodiments, the tumor can have a stage IIIC anatomic stage.

[0378] In some embodiments, the patient has received prior neoadjuvant chemotherapy. In some embodiments, the patient has received prior adjuvant chemotherapy.

[0379] In some embodiments, the patient has received prior radiation therapy.

[0380] In some embodiments, the patient has received a mastectomy. In some embodiments, the patient has not received a mastectomy.

[0381] In some embodiments, the patient is located in North America. In some embodiments, the patient is located in Europe, e.g., in Western Europe. In some embodiments, the patient is located in Oceania, e.g., in Australia. In some embodiments, the patient is located in Latin America. In some embodiments, the patient is located in Asia.

[0382] In some embodiments, the patient is Asian. In some embodiments, the patient is non-Asian.

[0383] In some embodiments, the patient can be American Indian. In some embodiments, the patient can be an Alaska Native. In some embodiments, the patient can be Black or African American. In some embodiments, the patient can be Native Hawaiian or other Pacific Islander. In some embodiments, the patient can also be White. In some embodiments, the patient can be of mixed race. In some embodiments, the patient can be non-Asian. In some embodiments, the patient can be Hispanic or Latino. In some embodiments, the patient is non-Hispanic or Latino.

[0384] In some embodiments, the patient is 18 years of age or older. The patient can be 18-44 years of age. The patient can be 45-54 years of age. The patient can be 55 to 64 years of age. The patient can be 65 years of age or older.

[0385] In some embodiments, the endocrine therapy is a non-steroidal aromatase inhibitor (NSAI). In some embodiments, the NSAI can be letrozole. In some embodiments, the NSAI can be anastrozole.

[0386] In some embodiments, the early stage breast cancer is selected from ER+ / PR+, ER- / PR+, and ER+ / PR- breast cancer.

[0387] In some embodiments, the administration of the treatment does not take into account the lymph node status of the breast cancer.

[0388] In some embodiments, the early stage breast cancer has a lymph node status of N0, N1, N2, or N3.

[0389] In some embodiments, the early stage breast cancer comprises a tumor of T0 category, T1, T2, T3, or T4 category.

[0390] In some embodiments, the early stage breast cancer has a histological grade of G1, G2, or G3 at the time of surgery.

[0391] In some embodiments, the early stage breast cancer has a Ki67 status of 20 or less (e.g., from an archival tumor). Alternatively, the early stage breast cancer can have a Ki67 status of greater than 20.

[0392] In some embodiments, the early breast cancer has a ductal histological subtype or a lobular histological subtype.

[0393] One aspect of the disclosure relates to a method of preventing breast cancer recurrence in an adult patient who has received prior treatment for HR+ / HER2- stage II or stage III early breast cancer, the method comprising administering to the patient (i) a dose of ribociclib, its free base form, or a pharmaceutically acceptable salt thereof, and (ii) a dose of an aromatase inhibitor, preferably letrozole or anastrozole.

[0394] Another aspect of the disclosure relates to a method of treating an adult patient in remission from HR+ / HER2- stage II or stage III early breast cancer, the method comprising administering to the patient (i) a dose of ribociclib, its free base form, or a pharmaceutically acceptable salt thereof, and (ii) a dose of an aromatase inhibitor, preferably letrozole or anastrozole.

[0395] Another aspect of the disclosure relates to a method of treating HR+ / HER2- stage II or stage III early breast cancer in an adult patient in need thereof, the method comprising administering to the patient (i) ribociclib, its free base form, or a pharmaceutically acceptable salt thereof, at a dose ranging from 150 mg / day to 450 mg / day, administered on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor, preferably letrozole or anastrozole, administered every day of a 28-day cycle.

[0396] One aspect of the disclosure relates to a method of treating breast cancer recurrence in an adult patient who has received at least one prior treatment for HR+ / HER2- stage II or stage III early breast cancer and has no detectable signs or symptoms of breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) a dose of ribociclib succinate administered on days 1 to 21 of a 28-day cycle, the total dose of ribociclib being 400 mg / day, and (ii) letrozole at a dose of 2.5 mg / day or anastrozole at a dose of 1 mg / day administered every day of a 28-day cycle.

[0397] Another aspect of the disclosure relates to a method of treating an adult patient in remission from HR+ / HER2- stage II or stage III early breast cancer and in need of adjuvant therapy, the method comprising administering to the patient an adjuvant therapy comprising (i) a dose of ribociclib succinate administered on days 1-21 of a 28-day cycle, the total dose of ribociclib being 400 mg / day, and (ii) letrozole at a dose of 2.5 mg / day or anastrozole at a dose of 1 mg / day administered every day of a 28-day cycle.

[0398] In some embodiments, the patient has a BMI of 25 or greater. In some embodiments, the patient has a BMI of less than 25.

[0399] Further aspects of the disclosure relate to a method of preventing or reducing signs or symptoms of early breast cancer, the method comprising administering to a patient a treatment comprising a combination of romosilast, the free base form thereof, or a pharmaceutically acceptable salt thereof, and an aromatase inhibitor (preferably letrozole or anastrozole). In some embodiments, romosilast is in the free base form thereof or a pharmaceutically acceptable salt thereof, and is administered to the patient at a dose ranging from 150 mg / day to 450 mg / day on days 1-21 of a 28-day cycle. In some embodiments, the aromatase inhibitor is administered daily on a 28-day cycle.

[0400] G. Patients in remission

[0401] An aspect of the disclosure relates to a method of treating HR+ / HER2- stage II or stage III early breast cancer in an adult patient in remission, the method comprising administering to the adult patient a combination of romosilast and an aromatase inhibitor, whereby the administration maintains the adult patient in remission for at least about 3 months.

[0402] Further aspects relate to a method of treating HR+ / HER2- stage II or stage III early breast cancer in an adult patient, the method comprising providing adjuvant therapy by administering a combination of romosilast and an aromatase inhibitor, wherein the patient is in complete remission at the start of the adjuvant therapy, and the administration of the combination of romosilast and an aromatase inhibitor maintains the adult patient in complete remission for at least about 3 months.

[0403] The administration of the combination of romosilast and an aromatase inhibitor can maintain the adult patient in remission (e.g., complete remission) for a period of at least about 3 months. In some embodiments, the administration maintains the adult patient in remission for at least about 6 months. In some embodiments, the administration maintains the adult patient in remission for at least about 9 months. In some embodiments, the administration maintains the adult patient in remission for at least about 12 months. In some embodiments, the administration maintains the adult patient in remission for at least about 15 months. In some embodiments, the administration maintains the adult patient in remission for at least about 18 months. In some embodiments, the administration maintains the adult patient in remission for at least about 21 months. In some embodiments, the administration maintains the adult patient in remission for at least about 24 months. In some embodiments, the administration maintains the adult patient in remission for at least about 27 months. In some embodiments, the administration maintains the adult patient in remission for at least about 30 months. In some embodiments, the administration maintains the adult patient in remission for at least about 33 months. In some embodiments, the administration maintains the adult patient in remission for at least about 36 months.

[0404] In certain embodiments, the administration of ribociclib and the aromatase inhibitor is for a treatment duration, and the administration maintains the adult patient in remission at least for the treatment duration.

[0405] For the methods described herein, the doses and treatment regimens of the combination of ribociclib and the aromatase inhibitor can follow the example embodiments as follows. In some embodiments, a 400 mg dose of ribociclib is administered orally once daily on days 1-21 of a 28-day cycle, and the aromatase inhibitor is administered once daily on each day of the 28-day cycle.

[0406] A 400 mg dose of ribociclib is administered orally once daily on days 1-21 of a 28-day cycle for a treatment duration of up to three years, and the aromatase inhibitor is administered once daily on each day of the 28-day cycle for up to three years. For example, a 400 mg dose of ribociclib can be administered orally once daily on days 1-21 of a 28-day cycle for a treatment duration of up to five years, and the aromatase inhibitor is administered once daily on each day of the 28-day cycle for up to five years.

[0407] In some embodiments, a pharmaceutically acceptable salt of ribociclib is administered orally in an amount equivalent to 400 mg of ribociclib. The pharmaceutically acceptable salt can be ribociclib succinate.

[0408] In some embodiments, the adult patient has never received treatment with a 600 mg dose of ribociclib.

[0409] In some embodiments, the adult patient has never been diagnosed with HR+ / HER2- advanced or metastatic breast cancer.

[0410] Ribociclib and the aromatase inhibitor can be administered as adjuvant therapy. In some embodiments, ribociclib is not administered at a dose of 600 mg / day.

[0411] The dose of ribociclib can be administered as a tablet. For example, two tablets can be administered orally once daily to an adult patient on days 1-21 of a 28-day cycle, repeated for a treatment duration, and each tablet contains an amount of a pharmaceutically acceptable salt of ribociclib equivalent to 200 mg of ribociclib. In some embodiments, the salt of ribociclib is ribociclib succinate. In some embodiments, the aromatase inhibitor is letrozole. In some embodiments, the aromatase inhibitor is anastrozole.

[0412] In some embodiments, the aromatase inhibitor is letrozole, and letrozole is administered at a dose ranging from 1 mg to 4 mg once daily. For example, the aromatase inhibitor can be letrozole, and letrozole can be administered at a dose of 2.5 mg / day once daily.

[0413] In some embodiments, the aromatase inhibitor is anastrozole, and the anastrozole is administered at a dose ranging from 0.5 mg once daily to 1.5 mg once daily. For example, the anastrozole can be administered at a dose of 1 mg once daily. The method of any one of embodiments 117 to 148, wherein the patient is a postmenopausal woman.

[0414] In some embodiments, the patient is a premenopausal woman or a man.

[0415] The patient can be a premenopausal woman or a man. Some embodiments (e.g., wherein the patient is a premenopausal woman or a man) further comprise administering to the adult patient a gonadotropin-releasing hormone agonist. In some embodiments, the gonadotropin-releasing hormone agonist is goserelin. In some embodiments, the goserelin is administered at a dose ranging from 2 mg to 5 mg. For example, the dose of goserelin can be 3.6 mg. In some embodiments, the goserelin is administered subcutaneously. In some embodiments, the goserelin is administered once every 4 weeks.

[0416] In some embodiments, the histological subtype of the breast cancer is a ductal subtype or its histological subtype is a lobular subtype.

[0417] In some embodiments, the breast cancer is a stage IIA cancer or a stage IIB cancer. For example, the breast cancer can be a stage IIA cancer. The breast cancer can be a stage IIB cancer.

[0418] In some embodiments, the breast cancer is a stage IIIA cancer, a stage IIIB cancer, or a stage IIIC cancer. For example, the breast cancer can be a stage IIIA cancer. The breast cancer can be a stage IIIB cancer. The breast cancer can be a stage IIIC cancer.

[0419] In some embodiments, the administration of the treatment does not take into account the lymph node status of the breast cancer. In some embodiments, the treatment with ribociclib and an aromatase inhibitor is not adjusted according to the lymph node status of the early stage breast cancer.

[0420] In some embodiments, the breast cancer has a lymph node status selected from the group consisting of NO, N1, N2, and N3. For example, the breast cancer can have a lymph node status of NO. The breast cancer can have a lymph node status of N1-N3. The breast cancer can have a lymph node status of N1. The breast cancer can have a lymph node status of N2. The breast cancer can have a lymph node status of N3.

[0421] In some embodiments, the breast cancer comprises one or more cells having a histological grade selected from the group consisting of G1, G2, or G3. For example, the breast cancer can comprise one or more cells having a histological grade of G1. The breast cancer can comprise one or more cells having a histological grade of G2. The breast cancer can comprise one or more cells having a histological grade of G3.

[0422] In some embodiments, the breast cancer comprises a tumor of T0, T1, T2, T3, or T4 category. For example, the breast cancer can comprise a tumor of T1, T2, or T3 category. The breast cancer can comprise a tumor of T0 category. The breast cancer can comprise a tumor of T1 category. The breast cancer can comprise a tumor of T2 category. The breast cancer can comprise a tumor of T3 category. The breast cancer can comprise a tumor of T4 category.

[0423] In some embodiments, the breast cancer has a Ki67 status of 20 or less. In some embodiments, the breast cancer has a Ki67 status of greater than 20.

[0424] In some embodiments, prior to administering rebimastat and an aromatase inhibitor to the adult patient, the patient underwent surgery for early stage breast cancer.

[0425] In some embodiments, prior to administering rebimastat and an aromatase inhibitor to the adult patient, the patient underwent (1) surgery for early stage breast cancer, followed by (2) chemotherapy.

[0426] In some embodiments, prior to administering rebimastat and an aromatase inhibitor to the adult patient, the patient underwent (1) surgery for early stage breast cancer, followed by (2) chemotherapy and / or endocrine therapy.

[0427] In some embodiments, the endocrine therapy is therapy with a prior aromatase inhibitor. The prior aromatase inhibitor can be letrozole or anastrozole.

[0428] In some embodiments, prior to administering rebimastat and an aromatase inhibitor to the adult patient, the patient underwent surgery for early stage breast cancer. In some embodiments, wherein the surgery comprises complete surgical resection of the cancer. In some embodiments, the surgery is a mastectomy.

[0429] In some embodiments, the patient received neoadjuvant therapy. For example, the neoadjuvant therapy can be chemotherapy.

[0430] In some embodiments, the adult patient is located in a geographic region selected from North America, Western Europe, or Oceania.

[0431] In some embodiments, the patient is Asian.

[0432] In some embodiments, the patient is 18 to 45 years of age. In some embodiments, the patient is 45 to 54 years of age. In some embodiments, the patient is 54 to 64 years of age. In some embodiments, the patient is greater than 64 years of age.

[0433] In some embodiments, the patient has a BMI of 25 or greater. In some embodiments, the patient has a BMI of less than 25.

[0434] In some embodiments, the treatment improves the patient's condition relative to a patient who has not received treatment and / or relative to the patient's condition prior to treatment.

[0435] In some embodiments, the treatment reduces the risk of invasive disease. For example, the treatment can reduce the risk of invasive disease in an adult patient corresponding to a hazard ratio of less than 1 when the risk is calculated relative to other patients who have received the same treatment as the adult patient except that they did not receive the ribociclib.

[0436] In some embodiments, the treatment reduces the risk of invasive disease in an adult patient corresponding to a hazard ratio of less than or equal to 0.78 when the risk is calculated relative to other patients who have received the same treatment as the adult patient except that they did not receive the ribociclib.

[0437] In some embodiments, the adult patient is a premenopausal woman or a man, and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.72 when the risk is calculated relative to other premenopausal women and men, respectively, who have received the same treatment as the premenopausal woman or man, respectively, except that they did not receive the ribociclib.

[0438] In some embodiments, the adult patient is diagnosed with HR+ / HER2- stage III early stage breast cancer, and the treatment reduces the risk of invasive disease in the adult patient corresponding to a hazard ratio of less than or equal to 0.74 when the risk is calculated relative to other patients who have received the same treatment as the adult patient except that they did not receive the ribociclib.

[0439] In some embodiments, the adult patient is diagnosed with HR+ / HER2- stage II early stage breast cancer, and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.76 when the risk is calculated relative to other patients who have received the same treatment as the adult patient except that they did not receive the ribociclib.

[0440] In some embodiments, the adult patient is diagnosed with HR+ / HER2- stage III early stage breast cancer, and the treatment reduces the risk of invasive disease by at least 25% corresponding to a hazard ratio of 0.75 when the risk is calculated relative to other patients who have received the same treatment as the adult patient except that they did not receive the ribociclib.

[0441] In some embodiments, the treatment reduces the risk of invasive disease to a similar level in a patient sub-group comprising patients with stage II early stage breast cancer, patients with stage III early stage breast cancer, premenopausal women or men, and postmenopausal women.

[0442] In some embodiments, the treatment does not result in a reduction in overall survival, corresponding to a hazard ratio of 0.76 when the risk is calculated relative to other patients who have received the same treatment as the adult patient except for not receiving the ribociclib.

[0443] In some embodiments, the treatment reduces and / or prevents one or more of a recurrence of the cancer, spread of the cancer, development and / or growth of additional cancers, and death caused by the cancer.

[0444] In some embodiments, the treatment reduces recurrence of the cancer, wherein the recurrence is one or more of an invasive ipsilateral breast tumor (IBTR) recurrence, a loco-regional invasive recurrence, and a distant recurrence.

[0445] In some embodiments, the treatment reduces spread of the cancer, wherein the spread of the cancer is an invasive contralateral breast cancer or an additional primary invasive cancer.

[0446] Another aspect of the disclosure relates to a use of ribociclib, or a pharmaceutically acceptable salt thereof, and an aromatase inhibitor in the manufacture of a medicament for treating HR+ / HER2- stage II or stage III early stage breast cancer in an adult patient, wherein the medicament is for administration by any of the methods described herein.

[0447] Another aspect of the disclosure relates to ribociclib, or a pharmaceutically acceptable salt thereof, and an aromatase inhibitor for use in treating HR+ / HER2- stage II or stage III early stage breast cancer in an adult patient, wherein the treatment is by any of the methods described herein.

[0448] Another aspect of the disclosure relates to a kit for performing a method of treating HR+ / HER2- stage II or stage III early stage breast cancer in an adult patient according to any of the methods described herein.

[0449] H. Purpose and Method of Using the Kit

[0450] An aspect of the disclosure provides a kit of parts for carrying out a method disclosed herein, e.g., a kit for performing a method of treating HR+ / HER2- stage II or stage III early stage breast cancer in an adult patient. The kit can be promoted, distributed, or sold as a unit for carrying out the methods of the disclosure.

[0451] In some embodiments, the kit comprises a dose of ribociclib, a free base form thereof, or a pharmaceutically acceptable salt thereof, and a dose of an aromatase inhibitor, e.g., letrozole or anastrozole. The kit can comprise directions and / or instructions, e.g., a schedule for administering the ribociclib and / or the aromatase inhibitor.

[0452] In some embodiments, the kit comprises a dose range of about 150 mg / day to 450 mg / day of ribociclib, and directions and / or instructions for administering ribociclib on days 1-21 of a 28-day cycle. The kit can further comprise a dose of an aromatase inhibitor, such as letrozole or anastrozole, for example, a dose of about 2.5 mg / day of letrozole or about 1 mg / day anastrozole, and can further comprise directions and / or instructions for administering the aromatase inhibitor every day of a 28-day cycle.

[0453] In some embodiments, the kit comprises a dose of ribociclib succinate (total dose of ribociclib 400 mg / day) and a dose of 2.5 mg / day of letrozole or 1 mg / day anastrozole. The kit can further comprise directions and / or instructions for administering the dose of ribociclib succinate on days 1-21 of a 28-day cycle and the dose of letrozole or anastrozole every day of a 28-day cycle.

[0454] Exemplary kits can comprise more than 1 daily dose, for example, a kit can comprise 21 doses of ribociclib or a free base form thereof or a pharmaceutically acceptable salt thereof, and 28 doses of an aromatase inhibitor (e.g., letrozole or anastrozole) for administration over an entire 28-day cycle. Other exemplary kits can comprise doses of ribociclib or a free base form thereof or a pharmaceutically acceptable salt thereof and an aromatase inhibitor (letrozole or anastrozole) for multiple 28-day cycles.

[0455] I. Exemplary Embodiment

[0456] Therapeutic methods and medical uses of the disclosure are provided in the following embodiments.

[0457] 1. A method of treating HR+ / HER2- stage II or stage III early stage breast cancer in an adult patient in need thereof, the method comprising administering to the patient a treatment comprising a dose range from 150 mg / day to 450 mg / day of ribociclib, a free base form thereof, or a pharmaceutically acceptable salt thereof, in combination with an aromatase inhibitor administered every day of a 28-day cycle, the aromatase inhibitor preferably being letrozole or anastrozole.

[0458] 2. A method of preventing or alleviating a sign or symptom of early stage breast cancer, the method comprising administering to a patient a treatment comprising ribociclib, a free base form thereof, or a pharmaceutically acceptable salt thereof, in combination with an aromatase inhibitor, the aromatase inhibitor preferably being letrozole or anastrozole.

[0459] 3. The method of embodiment 2, wherein the relacorilant, free base form thereof, or a pharmaceutically acceptable salt thereof is administered to the patient at a dose ranging from 150 mg / day to 450 mg / day on days 1-21 of a 28-day cycle.

[0460] 4. The method of embodiment 2 or 3, wherein the aromatase inhibitor is administered every day of a 28-day cycle.

[0461] 5. A method of preventing or reducing signs or symptoms of early stage breast cancer, the method comprising administering to a patient a treatment comprising relacorilant, free base form thereof, or a pharmaceutically acceptable salt thereof at a dose ranging from 150 mg / day to 450 mg / day on days 1-21 of a 28-day cycle in combination with an aromatase inhibitor administered every day of a 28-day cycle, the aromatase inhibitor preferably being letrozole or anastrozole.

[0462] 6. The method of any one of embodiments 1 to 5, wherein the patient is in remission from HR+ / HER2- stage II or stage III early stage breast cancer.

[0463] 7. A method of maintaining remission in an adult patient previously diagnosed with HR+ / HER2- stage II or stage III early stage breast cancer, the method comprising administering to the patient a treatment comprising a dose of relacorilant, free base form thereof, or a pharmaceutically acceptable salt thereof in combination with an aromatase inhibitor, the aromatase inhibitor preferably being letrozole or anastrozole.

[0464] 8. The method of embodiment 6 or embodiment 7, wherein the remission is complete remission.

[0465] 9. The method of embodiment 6 or embodiment 7, wherein the remission is partial remission.

[0466] 10. The method of any one of embodiments 1 to 9, wherein the treatment reduces recurrence of HR+ / HER2- stage II or stage III early stage breast cancer.

[0467] 11. The method of embodiment 10, wherein the treatment prevents recurrence for at least 3 months.

[0468] 12. The method of embodiment 11, wherein the treatment prevents recurrence for at least 6 months.

[0469] 13. The method of embodiment 12, wherein the treatment prevents recurrence for at least 1 year.

[0470] 14. The method of any one of embodiments 1 to 13, wherein the patient has no signs or symptoms of cancer prior to receiving the treatment.

[0471] 15. The method of any one of embodiments 1 to 14, wherein the treatment prevents growth of HR+ / HER2- breast cancer cells.

[0472] 16. The method of any one of embodiments 1 to 15, wherein the treatment is adjuvant therapy.

[0473] 17. The method of any one of embodiments 1 to 16, wherein the romosilast is a pharmaceutically acceptable salt of romosilast.

[0474] 18. The method of embodiment 17, wherein the romosilast salt is romosilast succinate.

[0475] 19. The method of any one of embodiments 1 to 18, wherein the dose of romosilast is 200 mg / day or 400 mg / day.

[0476] 20. The method of any one of embodiments 1 to 18, wherein the romosilast is not administered at a dose of 600 mg / day.

[0477] 21. The method of any one of embodiments 1 to 19, wherein the romosilast is administered as romosilast succinate and the total dose of romosilast is 200 mg / day.

[0478] 22. The method of any one of embodiments 1 to 19, wherein the romosilast is administered as romosilast succinate and the total dose of romosilast is 400 mg / day.

[0479] 23. The method of any one of embodiments 1 to 19, wherein the romosilast is administered at a dose of 400 mg / day for a period of time followed by administration of romosilast at a dose of 200 mg / day.

[0480] 24. The method of any one of embodiments 1 to 23, wherein the dose of romosilast is administered orally.

[0481] 25. The method of any one of embodiments 1 to 24, wherein the dose of romosilast is administered as a tablet.

[0482] 26. The method of any one of embodiments 1 to 24, wherein the aromatase inhibitor is letrozole or anastrozole.

[0483] 27. The method of any one of embodiments 1 to 26, wherein the aromatase inhibitor is administered orally.

[0484] 28. The method of embodiment 26 or 27, wherein the letrozole is administered at a dose ranging from 1 mg / day to 4 mg / day.

[0485] 29. The method of embodiment 28, wherein the letrozole is administered at a dose of 2.5 mg / day.

[0486] 30. The method of embodiment 26 or 27, wherein the anastrozole is administered at a dose ranging from 0.5 mg / day to 1.5 mg / day.

[0487] 31. The method of embodiment 30, wherein the anastrozole is administered at a dose of 1 mg / day.

[0488] 32. The method of any one of embodiments 1 to 31, wherein the treatment comprises a gonadotropin-releasing hormone agonist.

[0489] 33. The method of embodiment 32, wherein the gonadotropin-releasing hormone agonist is goserelin.

[0490] 34. The method of embodiment 33, wherein the goserelin is administered at a dose ranging from 2 mg to 5 mg.

[0491] 35. The method of embodiment 34, wherein the dose of goserelin is 3.6 mg.

[0492] 36. The method of any one of embodiments 33 to 35, wherein the goserelin is administered subcutaneously.

[0493] 37. The method of any one of embodiments 33 to 36, wherein the goserelin is administered once every 4 weeks.

[0494] 38. The method of any one of embodiments 1 to 31, wherein the patient is a postmenopausal woman.

[0495] 39. The method of any one of embodiments 1 to 37, wherein the patient is a premenopausal woman or a man.

[0496] 40. The method of any one of embodiments 1 to 39, wherein the patient is administered the treatment for at least 12 months.

[0497] 41. The method of embodiment 40, wherein the patient is administered the treatment for at least 24 months.

[0498] 42. The method of embodiment 40 or embodiment 41, wherein the patient is administered the treatment for at least 36 months.

[0499] 43. The method of any one of embodiments 40 to 41, wherein the patient is administered the treatment for at least 48 months.

[0500] 44. The method of any one of embodiments 40-41, wherein the treatment is administered to the patient for at least 60 months.

[0501] 45. The method of any one of embodiments 1-44, wherein the treatment continues until the patient is free of detectable cancer.

[0502] 46. The method of any one of embodiments 1-45, wherein the breast cancer is ER+ and PR+.

[0503] 47. The method of any one of embodiments 1-45, wherein the breast cancer is ER- and PR+.

[0504] 48. The method of any one of embodiments 1-45, wherein the breast cancer is ER+ and PR-.

[0505] 49. The method of any one of embodiments 1-48, wherein the histological subtype of the breast cancer is a ductal subtype or its histological subtype is a lobular subtype.

[0506] 50. The method of any one of embodiments 1-49, wherein the breast cancer is a stage IIA cancer or a stage IIB cancer.

[0507] 51. The method of embodiment 50, wherein the breast cancer is a stage IIA cancer.

[0508] 52. The method of embodiment 50, wherein the breast cancer is a stage IIB cancer.

[0509] 53. The method of any one of embodiments 1-49, wherein the breast cancer is a stage IIIA cancer, a stage IIIB cancer, or a stage IIIC cancer.

[0510] 54. The method of embodiment 53, wherein the breast cancer is a stage IIIA cancer.

[0511] 55. The method of embodiment 53, wherein the breast cancer is a stage IIIB cancer.

[0512] 56. The method of embodiment 53, wherein the breast cancer is a stage IIIC cancer.

[0513] 57. The method of any one of embodiments 1-56, wherein the administration of the treatment does not take into account the lymph node status of the breast cancer.

[0514] 58. The method of any one of embodiments 1-57, wherein the breast cancer has a lymph node status selected from the group consisting of NO, Nl, N2, and N3.

[0515] 59. The method of embodiment 57 or 58, wherein the breast cancer has a lymph node status of NO.

[0516] 60. The method of embodiment 57 or 58, wherein the breast cancer has a lymph node status of N1 to N3.

[0517] 61. The method of embodiment 57 or 58, wherein the breast cancer has a lymph node status of N1.

[0518] 62. The method of embodiment 57 or 58, wherein the breast cancer has a lymph node status of N2.

[0519] 63. The method of embodiment 57 or 58, wherein the breast cancer has a lymph node status of N3.

[0520] 64. The method of any one of embodiments 1 to 63, wherein the breast cancer comprises one or more cells having a histologic grade selected from G1, G2, or G3.

[0521] 65. The method of embodiment 64, wherein the breast cancer comprises one or more cells having a histologic grade of G1.

[0522] 66. The method of embodiment 64, wherein the breast cancer comprises one or more cells having a histologic grade of G2.

[0523] 67. The method of embodiment 64, wherein the breast cancer comprises one or more cells having a histologic grade of G3.

[0524] 68. The method of any one of embodiments 1 to 67, wherein the breast cancer comprises a tumor of T0, T1, T2, T3, or T4 category.

[0525] 69. The method of embodiment 68, wherein the breast cancer comprises a tumor of T1, T2, or T3 category.

[0526] 70. The method of embodiment 68, wherein the breast cancer comprises a tumor of T0 category.

[0527] 71. The method of embodiment 68 or 69, wherein the breast cancer comprises a tumor of T1 category.

[0528] 72. The method of embodiment 68 or 69, wherein the breast cancer comprises a tumor of T2 category.

[0529] 73. The method of embodiment 68 or 69, wherein the breast cancer comprises a tumor of T3 category.

[0530] 74. The method of embodiment 68, wherein the breast cancer comprises a tumor of T4 category.

[0531] 75. The method of any one of embodiments 1 to 74, wherein the breast cancer has a Ki67 status of 20 or less.

[0532] 76. The method of any one of embodiments 1 to 74, wherein the breast cancer has a Ki67 status of more than 20.

[0533] 77. The method of any one of embodiments 1 to 76, wherein the patient received a loading dose of (i) ribociclib and / or (ii) endocrine therapy prior to the administration.

[0534] 78. The method of any one of embodiments 1 to 77, wherein the patient received at least one prior treatment for cancer.

[0535] 79. The method of embodiment 78, wherein the prior treatment is an adjuvant treatment following another prior treatment.

[0536] 80. The method of embodiment 78 or 79, wherein the prior treatment is surgery.

[0537] 81. The method of embodiment 80, wherein the surgery comprises complete surgical resection of the cancer.

[0538] 82. The method of embodiment 80 or 81, wherein the surgery is a mastectomy.

[0539] 83. The method of embodiment 80 or 81, wherein the prior treatment is chemotherapy.

[0540] 84. The method of embodiment 83, wherein the prior treatment is adjuvant chemotherapy.

[0541] 85. The method of embodiment 83, wherein the prior treatment is neoadjuvant chemotherapy.

[0542] 86. The method of embodiment 78 or 79, wherein the prior treatment is endocrine therapy.

[0543] 87. The method of embodiment 78 or 79, wherein the prior treatment is radiation therapy.

[0544] 88. The method of any one of embodiments 78 to 87, wherein the patient did not respond to the prior treatment.

[0545] 89. The method of any one of embodiments 1 to 88, wherein the patient is located in a geographic region selected from North America, Western Europe, or Oceania.

[0546] 90. The method of any one of embodiments 1 to 89, wherein the patient is of Asian descent.

[0547] 91. The method of any one of embodiments 1 to 90, wherein the patient is 18 to 45 years of age.

[0548] 92. The method of any one of embodiments 1 to 90, wherein the patient is 45 to 54 years of age.

[0549] 93. The method of any one of embodiments 1 to 90, wherein the patient is 54 to 64 years of age.

[0550] 94. The method of any one of embodiments 1 to 90, wherein the patient is greater than 64 years of age.

[0551] 95. The method of any one of embodiments 1 to 94, wherein the patient has a BMI of 25 or greater.

[0552] 96. The method of any one of embodiments 1 to 94, wherein the patient has a BMI of less than 25.

[0553] 97. The method of any one of embodiments 1 to 96, wherein the treatment improves the patient’s condition relative to a patient who does not receive the treatment and / or relative to the patient’s condition prior to treatment.

[0554] 98. The method of any one of embodiments 1 to 97, wherein the treatment reduces the risk of invasive disease.

[0555] 99. The method of embodiment 98, wherein the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than 1 when the risk is calculated relative to a patient who does not receive the treatment.

[0556] 100. The method of embodiment 99, wherein the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.78 when the risk is calculated relative to a patient who does not receive the treatment.

[0557] 101. The method of any one of embodiments 1 to 37 and 39 to 100, wherein the patient is a premenopausal woman or man and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.72 when the risk is calculated relative to a patient who does not receive the treatment.

[0558] 102. The method of any one of embodiments 98 to 100, wherein the patient has HR+ / HER2- stage III early stage breast cancer and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.74 when the risk is calculated relative to a patient who does not receive the treatment.

[0559] 103. The method of any one of embodiments 98-100, wherein the patient has HR+ / HER2- stage II early stage breast cancer, and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.76 when the risk is calculated relative to a patient who does not receive the treatment.

[0560] 104. The method of any one of embodiments 98-100, wherein the patient has HR+ / HER2- stage III early stage breast cancer, and the treatment reduces the risk of invasive disease by at least 25% corresponding to a hazard ratio of 0.75 when the risk is calculated relative to a patient who does not receive the treatment.

[0561] 105. The method of any one of embodiments 1-104, wherein the treatment reduces the risk of invasive disease to a similar level for a patient subset comprising a stage II early stage breast cancer patient, a stage III early stage breast cancer patient, a premenopausal female or male patient, and a postmenopausal female patient.

[0562] 106. The method of any one of embodiments 1-105, wherein the treatment does not result in a reduction in overall survival corresponding to a hazard ratio of 0.76 when the risk is calculated relative to a patient who does not receive the treatment.

[0563] 107. The method of any one of embodiments 1-106, wherein the treatment reduces and / or prevents one or more of recurrence of cancer, spread of cancer, development and / or growth of additional cancer, and death caused by cancer.

[0564] 108. The method of embodiment 107, wherein the treatment reduces recurrence of cancer, wherein the recurrence is one or more of invasive ipsilateral breast tumor (IBTR) recurrence, loco-regional invasive recurrence, and distant recurrence.

[0565] 109. The method of embodiment 107 or embodiment 108, wherein the treatment reduces spread of cancer, wherein the spread of cancer is invasive contralateral breast cancer or additional primary invasive cancer.

[0566] 110. The method of any one of embodiments 1-109, wherein the treatment prevents death caused by cancer.

[0567] 111. A method of maintaining remission in an adult patient previously diagnosed with HR+ / HER2- stage II or stage III early breast cancer, the method comprising administering to the patient a treatment comprising a dose ranging from 150 mg per day to 450 mg per day of ribociclib, the free base form thereof, or a pharmaceutically acceptable salt thereof, on days 1-21 of a 28-day cycle in combination with an aromatase inhibitor administered every day of a 28-day cycle, preferably letrozole or anastrozole.

[0568] 112. A method of preventing recurrence of breast cancer in an adult patient, the method comprising providing adjuvant therapy to a patient who has received a prior treatment for HR+ / HER2- stage II or stage III early breast cancer, wherein the adjuvant therapy comprises administering to the patient 400 mg of ribociclib, or a pharmaceutically acceptable salt thereof, on days 1 to 21 of a 28-day cycle for at least 36 months in combination with an aromatase inhibitor administered every day of a 28-day cycle as defined in any one of embodiments 26 to 31.

[0569] 113. The method of embodiment 112, wherein the prior treatment is surgical resection of the cancer.

[0570] 114. Ribociclib, or a pharmaceutically acceptable salt thereof, and an aromatase inhibitor for use in a method of treating HR+ / HER2- stage II or stage III early breast cancer in an adult patient, wherein the method is a method of any one of embodiments 1 to 112.

[0571] 115. Use of ribociclib, or a pharmaceutically acceptable salt thereof, and an aromatase inhibitor in the manufacture of a medicament for treating HR+ / HER2- stage II or stage III early breast cancer in an adult patient, wherein the medicament is for administration by a method of any one of embodiments 1 to 112.

[0572] 116. A kit for performing a method of treating HR+ / HER2- stage II or stage III early breast cancer in an adult patient according to any one of embodiments 1 to 112.

[0573] 117. A method of treating HR+ / HER2- stage II or stage III early breast cancer in an adult patient in remission, the method comprising administering to the adult patient a combination of ribociclib and an aromatase inhibitor, whereby the administration maintains the adult patient in remission for at least 3 months.

[0574] 118. A method of treating HR+ / HER2- stage II or stage III early stage breast cancer in an adult patient, the method comprising providing adjuvant therapy by administering a combination of romosiyli and an aromatase inhibitor, wherein the patient is in complete remission at the start of the adjuvant therapy, and the administration of the combination of romosiyli and an aromatase inhibitor maintains the adult patient in complete remission for at least 3 months.

[0575] 119. The method of embodiment 117 or 118, wherein the administration maintains the adult patient in remission (e.g., complete remission) for at least 6 months.

[0576] 120. The method of embodiment 117 or 118, wherein the administration maintains the adult patient in remission (e.g., complete remission) for at least 9 months.

[0577] 121. The method of embodiment 117 or 118, wherein the administration maintains the adult patient in remission (e.g., complete remission) for at least 12 months.

[0578] 122. The method of embodiment 117 or 118, wherein the administration maintains the adult patient in remission (e.g., complete remission) for at least 15 months.

[0579] 123. The method of embodiment 117 or 118, wherein the administration maintains the adult patient in remission (e.g., complete remission) for at least 18 months.

[0580] 124. The method of embodiment 117 or 118, wherein the administration maintains the adult patient in remission (e.g., complete remission) for at least 21 months.

[0581] 125. The method of embodiment 117 or 118, wherein the administration maintains the adult patient in remission (e.g., complete remission) for at least 24 months.

[0582] 126. The method of embodiment 117 or 118, wherein the administration maintains the adult patient in remission (e.g., complete remission) for at least 27 months.

[0583] 127. The method of embodiment 117 or 118, wherein the administration maintains the adult patient in remission (e.g., complete remission) for at least 30 months.

[0584] 128. The method of embodiment 117 or 118, wherein the administration maintains the adult patient in remission (e.g., complete remission) for at least 33 months.

[0585] 129. The method of embodiment 117 or 118, wherein the administration maintains the adult patient in remission (e.g., complete remission) for at least 36 months.

[0586] 130. The method of any one of embodiments 117 to 129, wherein the ribociclib and the aromatase inhibitor are administered for a treatment duration, and the administration maintains the adult patient in remission (e.g., complete remission) at least for the treatment duration.

[0587] 131. The method of any one of embodiments 117 to 129, wherein the 400 mg dose of ribociclib is administered orally once daily on days 1-21 of a 28-day cycle, and the aromatase inhibitor is administered once daily on each day of a 28-day cycle.

[0588] 132. The method of any one of embodiments 117 to 129, wherein the 400 mg dose of ribociclib is administered orally once daily on days 1-21 of a 28-day cycle, the treatment duration is up to three years, and the aromatase inhibitor is administered once daily on each day of a 28-day cycle for up to three years.

[0589] 133. The method of any one of embodiments 117 to 129, wherein the 400 mg dose of ribociclib is administered orally once daily on days 1-21 of a 28-day cycle, the treatment duration is up to five years, and the aromatase inhibitor is administered once daily on each day of a 28-day cycle for up to three years.

[0590] 134. The method of any one of embodiments 117 to 133, wherein a pharmaceutically acceptable salt of ribociclib is administered orally in an amount equivalent to 400 mg of ribociclib.

[0591] 135. The method of embodiment 134, wherein the pharmaceutically acceptable salt is ribociclib succinate.

[0592] 136. The method of any one of embodiments 117 to 135, wherein the adult patient has never received treatment with a 600 mg dose of ribociclib.

[0593] 137. The method of any one of embodiments 117 to 136, wherein the adult patient has never been diagnosed with HR+ / HER2- advanced or metastatic breast cancer.

[0594] 138. The method of any one of embodiments 117 to 137, wherein the ribociclib and the aromatase inhibitor are administered as adjuvant therapy.

[0595] 139. The method of any one of embodiments 117 to 138, wherein the ribociclib is not administered at a dose of 600 mg / day.

[0596] 140. The method of any one of embodiments 117 to 139, wherein the dose of roserixib is administered as a tablet.

[0597] 141. The method of any one of embodiments 117 to 139, wherein two tablets are administered orally once daily to the adult patient on days 1-21 of a 28-day cycle, repeated for the duration of treatment, and each tablet contains an amount of a pharmaceutically acceptable salt of roserixib equivalent to 200 mg of roserixib.

[0598] 142. The method of embodiment 141, wherein the salt of roserixib is roserixib succinate.

[0599] 143. The method of any one of embodiments 117 to 142, wherein the aromatase inhibitor is letrozole.

[0600] 144. The method of any one of embodiments 117 to 142, wherein the aromatase inhibitor is anastrozole.

[0601] 145. The method of any one of embodiments 117 to 144, wherein the aromatase inhibitor is letrozole, and the letrozole is administered at a dose ranging from 1 mg to 4 mg once daily.

[0602] 146. The method of any one of embodiments 117 to 144, wherein the aromatase inhibitor is letrozole, and the letrozole is administered at a dose of 2.5 mg once daily.

[0603] 147. The method of any one of embodiments 117 to 144, wherein the aromatase inhibitor is anastrozole, and the anastrozole is administered at a dose ranging from 0.5 mg once daily to 1.5 mg once daily.

[0604] 148. The method of any one of embodiments 117 to 144, wherein the aromatase inhibitor is anastrozole, and the anastrozole is administered at a dose of 1 mg once daily.

[0605] 149. The method of any one of embodiments 114 to 148, further comprising administering a gonadotropin-releasing hormone agonist to the adult patient.

[0606] 150. The method of embodiment 149, wherein the gonadotropin-releasing hormone agonist is goserelin.

[0607] 151. The method of embodiment 150, wherein the goserelin is administered at a dose ranging from 2 mg to 5 mg.

[0608] 152. The method of embodiment 151, wherein the dose of goserelin is 3.6 mg.

[0609] 153. The method of any one of embodiments 150-152, wherein the goserelin is administered subcutaneously.

[0610] 154. The method of any one of embodiments 150-153, wherein the goserelin is administered once every 4 weeks.

[0611] 155. The method of any one of embodiments 117-148, wherein the patient is a postmenopausal woman.

[0612] 156. The method of any one of embodiments 117-154, wherein the patient is a premenopausal woman or a man.

[0613] 157. The method of any one of embodiments 117-156, wherein the histological subtype of the breast cancer is a ductal subtype or its histological subtype is a lobular subtype.

[0614] 158. The method of any one of embodiments 117-156, wherein the breast cancer is a stage IIA cancer or a stage IIB cancer.

[0615] 159. The method of any one of embodiments 117-156, wherein the breast cancer is a stage IIA cancer.

[0616] 160. The method of any one of embodiments 117-156, wherein the breast cancer is a stage IIB cancer.

[0617] 161. The method of any one of embodiments 117-156, wherein the breast cancer is a stage IIIA cancer, a stage IIIB cancer, or a stage IIIC cancer.

[0618] 162. The method of any one of embodiments 117-156, wherein the breast cancer is a stage IIIA cancer.

[0619] 163. The method of any one of embodiments 117-156, wherein the breast cancer is a stage IIIB cancer.

[0620] 164. The method of any one of embodiments 117-156, wherein the breast cancer is a stage IIIC cancer.

[0621] 165. The method of any one of embodiments 117-156, wherein the administration of the treatment is irrespective of the lymph node status of the breast cancer.

[0622] 166. The method of any one of embodiments 117 to 156, wherein the treatment with ribociclib and an aromatase inhibitor is not adjusted according to the lymph node status of the early breast cancer.

[0623] 167. The method of any one of embodiments 117 to 156, wherein the breast cancer has a lymph node status selected from N0, N1, N2, and N3.

[0624] 168. The method of any one of embodiments 117 to 156, wherein the breast cancer has a lymph node status of N0.

[0625] 169. The method of any one of embodiments 117 to 156, wherein the breast cancer has a lymph node status of N1-N3.

[0626] 170. The method of any one of embodiments 117 to 156, wherein the breast cancer has a lymph node status of N1.

[0627] 171. The method of any one of embodiments 117 to 156, wherein the breast cancer has a lymph node status of N2.

[0628] 172. The method of any one of embodiments 117 to 156, wherein the breast cancer has a lymph node status of N3.

[0629] 173. The method of any one of embodiments 117 to 156, wherein the breast cancer comprises one or more cells having a histologic grade selected from G1, G2, or G3.

[0630] 174. The method of any one of embodiments 117 to 156, wherein the breast cancer comprises one or more cells having a histologic grade of G1.

[0631] 175. The method of any one of embodiments 117 to 156, wherein the breast cancer comprises one or more cells having a histologic grade of G2.

[0632] 176. The method of any one of embodiments 117 to 156, wherein the breast cancer comprises one or more cells having a histologic grade of G3.

[0633] 177. The method of any one of embodiments 117 to 156, wherein the breast cancer comprises a tumor of T0, T1, T2, T3, or T4 category.

[0634] 178. The method of any one of embodiments 117 to 156, wherein the breast cancer comprises a tumor of T1, T2, or T3 category.

[0635] 179. The method of any one of embodiments 117-156, wherein the breast cancer comprises a tumor of T0 category.

[0636] 180. The method of any one of embodiments 117-156, wherein the breast cancer comprises a tumor of T1 category.

[0637] 181. The method of any one of embodiments 117-156, wherein the breast cancer comprises a tumor of T2 category.

[0638] 182. The method of any one of embodiments 117-156, wherein the breast cancer comprises a tumor of T3 category.

[0639] 183. The method of any one of embodiments 117-156, wherein the breast cancer comprises a tumor of T4 category.

[0640] 184. The method of any one of embodiments 117-156, wherein the breast cancer has a Ki67 status of 20 or less.

[0641] 185. The method of any one of embodiments 117-156, wherein the breast cancer has a Ki67 status of more than 20.

[0642] 186. The method of any one of embodiments 117-185, wherein prior to administering to the adult patient rebimastat and an aromatase inhibitor, the patient underwent surgery for early stage breast cancer.

[0643] 187. The method of any one of embodiments 117-185, wherein prior to administering to the adult patient rebimastat and an aromatase inhibitor, the patient underwent (1) surgery for early stage breast cancer, followed by (2) chemotherapy.

[0644] 188. The method of any one of embodiments 117-185, wherein prior to administering to the adult patient rebimastat and an aromatase inhibitor, the patient underwent (1) surgery for early stage breast cancer, followed by (2) chemotherapy and / or endocrine therapy.

[0645] 189. The method of embodiment 188, wherein the endocrine therapy is therapy with a prior aromatase inhibitor.

[0646] 190. The method of embodiment 188, wherein the prior aromatase inhibitor is letrozole or anastrozole.

[0647] 191. The method of any one of embodiments 117 to 185, wherein the patient has undergone surgery for early stage breast cancer prior to administration of the rebimastat and aromatase inhibitor to the adult patient.

[0648] 192. The method of any one of embodiments 186 to 191, wherein the surgery comprises complete surgical removal of the cancer.

[0649] 193. The method of any one of embodiments 186 to 191, wherein the surgery is mastectomy.

[0650] 194. The method of any one of embodiments 186 to 191, wherein the patient has received neoadjuvant therapy.

[0651] 195. The method of embodiment 194, wherein the neoadjuvant therapy is chemotherapy.

[0652] 196. The method of any one of embodiments 117 to 195, wherein the adult patient is located in a geographic region selected from North America, Western Europe, or Oceania.

[0653] 197. The method of any one of embodiments 117 to 195, wherein the patient is of Asian descent.

[0654] 198. The method of any one of embodiments 117 to 195, wherein the patient is between 18 and 45 years of age.

[0655] 199. The method of any one of embodiments 117 to 195, wherein the patient is between 45 and 54 years of age.

[0656] 200. The method of any one of embodiments 117 to 195, wherein the patient is between 54 and 64 years of age.

[0657] 201. The method of any one of embodiments 117 to 195, wherein the patient is greater than 64 years of age.

[0658] 202. The method of any one of embodiments 117 to 195, wherein the patient has a BMI of 25 or greater.

[0659] 203. The method of any one of embodiments 117 to 195, wherein the patient has a BMI of less than 25.

[0660] 204. The method of any one of embodiments 117 to 203, wherein the treatment improves the patient’s condition relative to a patient who does not receive the treatment and / or relative to the patient’s condition prior to treatment.

[0661] 205. The method of any one of embodiments 117 to 203, wherein the treatment reduces the risk of invasive disease.

[0662] 206. The method of any one of embodiments 117 to 203, wherein the treatment reduces the risk of invasive disease in the adult patient, corresponding to a hazard ratio of less than 1 when the risk is calculated relative to other patients who have received the same treatment as the adult patient except for not receiving the roxadustat.

[0663] 207. The method of any one of embodiments 117 to 203, wherein the treatment reduces the risk of invasive disease in the adult patient, corresponding to a hazard ratio of less than or equal to 0.78 when the risk is calculated relative to other patients who have received the same treatment as the adult patient except for not receiving the roxadustat.

[0664] 208. The method of any one of embodiments 117 to 203, wherein the adult patient is a premenopausal woman or a man, and the treatment reduces the risk of invasive disease, corresponding to a hazard ratio of less than or equal to 0.72 when the risk is calculated relative to other premenopausal women and men, respectively, who have received the same treatment as the premenopausal woman or man, respectively, except for not receiving roxadustat.

[0665] 209. The method of any one of embodiments 117 to 203, wherein the adult patient is diagnosed with HR+ / HER2- stage III early stage breast cancer, and the treatment reduces the risk of invasive disease in the adult patient, corresponding to a hazard ratio of less than or equal to 0.74 when the risk is calculated relative to other patients who have received the same treatment as the adult patient except for not receiving the roxadustat.

[0666] 210. The method of any one of embodiments 117 to 203, wherein the adult patient is diagnosed with HR+ / HER2- stage II early stage breast cancer, and the treatment reduces the risk of invasive disease, corresponding to a hazard ratio of less than or equal to 0.76 when the risk is calculated relative to other patients who have received the same treatment as the adult patient except for not receiving the roxadustat.

[0667] 211. The method of any one of embodiments 117 to 203, wherein the adult patient is diagnosed with HR+ / HER2- stage III early stage breast cancer, and the treatment reduces the risk of invasive disease by at least 25%, corresponding to a hazard ratio of 0.75 when the risk is calculated relative to other patients who have received the same treatment as the adult patient except for not receiving the roxadustat.

[0668] 212. The method of any one of embodiments 117 to 203, wherein the treatment reduces the risk of invasive disease to a similar level in a patient subpopulation comprising a patient who is a stage II early breast cancer patient, a stage III early breast cancer patient, a premenopausal female or male patient, and a postmenopausal female patient.

[0669] 213. The method of any one of embodiments 117 to 203, wherein the treatment does not result in a reduction in overall survival, corresponding to a hazard ratio of 0.76 when the risk is calculated relative to other patients who have received the same treatment as the adult patient except for not receiving the romosiylin.

[0670] 214. The method of any one of embodiments 117 to 203, wherein the treatment reduces and / or prevents one or more of recurrence of cancer, spread of cancer, occurrence and / or growth of additional cancer, and death caused by cancer.

[0671] 215. The method of any one of embodiments 117 to 203, wherein the treatment reduces recurrence of cancer, wherein the recurrence is one or more of invasive ipsilateral breast tumor recurrence (IBTR), loco-regional invasive recurrence, and distant recurrence.

[0672] 216. The method of any one of embodiments 117 to 203, wherein the treatment reduces spread of cancer, wherein the spread of cancer is invasive contralateral breast cancer or additional primary invasive cancer.

[0673] 217. Romosiylin, or a pharmaceutically acceptable salt thereof, and an aromatase inhibitor for use in a method of treating HR+ / HER2- stage II or stage III early breast cancer in an adult patient, wherein the method is a method of any one of embodiments 117 to 216.

[0674] 218. Use of romosiylin, or a pharmaceutically acceptable salt thereof, and an aromatase inhibitor in the manufacture of a medicament for treating HR+ / HER2- stage II or stage III early breast cancer in an adult patient, wherein the medicament is to be administered by a method of any one of embodiments 117 to 216.

[0675] 219. A kit for performing a method of treating HR+ / HER2- stage II or stage III early breast cancer in an adult patient according to any one of embodiments 117 to 216.

[0676] 220. A method of treating an adult patient who has been diagnosed with HR+ / HER2- Stage II or Stage III early stage breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) administering repoxilil at a dose ranging from 150 mg / day to 450 mg / day on Days 1-21 of a 28-day cycle, and (ii) administering an aromatase inhibitor on each day of a 28-day cycle, wherein the method results in one or more of an improvement in overall survival (OS), distant disease-free survival (DDFS), or relapse-free survival (RFS) in the patient.

[0677] 221. A method for improving one or more of overall survival (OS), distant disease-free survival (DDFS), or relapse-free survival (RFS) in a patient who has been diagnosed with HR+ / HER2- Stage II or Stage III early stage breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) administering repoxilil at a dose ranging from 150 mg / day to 450 mg / day on Days 1-21 of a 28-day cycle, and (ii) administering an aromatase inhibitor on each day of a 28-day cycle.

[0678] 222. A method for reducing the risk of local or regional invasive recurrence of early stage breast cancer in an adult patient who has been diagnosed with HR+ / HER2- Stage II or Stage III early stage breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) administering repoxilil at a dose ranging from 150 mg / day to 450 mg / day on Days 1-21 of a 28-day cycle, and (ii) administering an aromatase inhibitor on each day of a 28-day cycle.

[0679] 223. A method for reducing the risk of invasive recurrence of early stage breast cancer in one or more of bone, liver, and lung or pleura in an adult patient who has been diagnosed with HR+ / HER2- Stage II or Stage III early stage breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) administering repoxilil at a dose ranging from 150 mg / day to 450 mg / day on Days 1-21 of a 28-day cycle, and (ii) administering an aromatase inhibitor on each day of a 28-day cycle.

[0680] 224. The method of any one of embodiments 220 to 223, wherein the administration of the treatment does not take into account the lymph node status of the breast cancer.

[0681] 225. A method for reducing the risk of early breast cancer recurrence in an adult patient who has been diagnosed with HR+ / HER2- Stage II or Stage III early stage breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) administering repoxilumab at a dose ranging from 150 mg / day to 450 mg / day on Days 1-21 of a 28-day cycle, and (ii) administering an aromatase inhibitor every day of a 28-day cycle, wherein the administration of the therapy is independent of the lymph node status of the breast cancer.

[0682] 226. The method of any one of embodiments 220 to 225, wherein the breast cancer has a lymph node status of NO, N1, N2, or N3.

[0683] 227. The method of embodiment 226, wherein the breast cancer has a lymph node status of NO.

[0684] 228. The method of any one of embodiments 220 to 227, wherein the early stage breast cancer is Stage II, e.g., Stage IIA.

[0685] 229. The method of any one of embodiments 220 to 227, wherein the early stage breast cancer is Stage III, e.g., Stage IIIB or Stage IIIC.

[0686] 230. The method of any one of embodiments 220 to 229, wherein the breast cancer is of the ductal subtype.

[0687] 231. The method of any one of embodiments 220 to 230, wherein the patient is of Asian descent.

[0688] 232. The method of any one of embodiments 220 to 231, wherein the method is adjuvant therapy because the patient has received at least one prior treatment for breast cancer selected from the group consisting of surgery, chemotherapy, and radiotherapy.

[0689] 233. The method of embodiment 232, wherein the patient has not undergone a mastectomy.

[0690] 234. The method of any one of embodiments 220 to 233, wherein the dose of repoxilumab is 400 mg / day.

[0691] 235. The method of any one of embodiments 220 to 234, wherein the repoxilumab is administered in the form of a salt, preferably repoxilumab succinate.

[0692] 236. The method of any one of embodiments 220 to 235, wherein the aromatase inhibitor is letrozole or anastrozole.

[0693] 237. The method of embodiment 236, wherein the aromatase inhibitor is letrozole, preferably administered at a dose of 2.5 mg / day.

[0694] 238. The method of embodiment 236, wherein the aromatase inhibitor is anastrozole, preferably administered at a dose of 1 mg / day.

[0695] 239. The method of any one of embodiments 220-238, wherein the dose of ribociclib is 400 mg / day, the ribociclib is administered as ribociclib succinate, and the aromatase inhibitor is letrozole or anastrozole, preferably 2.5 mg / day of letrozole or 1 mg / day of anastrozole.

[0696] 240. The method of any one of embodiments 220-239, wherein the patient achieves an improvement in OS, DDFS, and / or RFS, or a reduction in the risk of breast cancer recurrence for at least 36 months.

[0697] 241. Ribociclib for use in a method of improving one or more of overall survival (OS), distant disease-free survival (DDFS), or recurrence-free survival (RFS) in an adult patient who has been diagnosed with HR+ / HER2- Stage II or Stage III early stage breast cancer, wherein the method comprises administering to the patient an adjuvant therapy comprising (i) administering ribociclib at a dose ranging from 150 mg / day to 450 mg / day on Days 1-21 of a 28-day cycle, and (ii) administering an aromatase inhibitor every day of a 28-day cycle.

[0698] 242. Ribociclib for use in a method of reducing the risk of local or regional invasive recurrence of early stage breast cancer in an adult patient who has been diagnosed with HR+ / HER2- Stage II or Stage III early stage breast cancer, wherein the method comprises administering to the patient an adjuvant therapy comprising (i) administering ribociclib at a dose ranging from 150 mg / day to 450 mg / day on Days 1-21 of a 28-day cycle, and (ii) administering an aromatase inhibitor every day of a 28-day cycle.

[0699] 243. Ribociclib for use in a method of reducing the risk of invasive recurrence of early breast cancer in one or more of the bone, liver, and lung or pleura in an adult patient who has been diagnosed with HR+ / HER2- stage II or stage III early stage breast cancer, wherein the method comprises administering to the patient an adjuvant therapy comprising (i) ribociclib at a dose ranging from 150 mg per day to 450 mg per day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor every day on a 28-day cycle.

[0700] 244. Ribociclib for use according to any one of embodiments 241 to 243, wherein the administration of the treatment is irrespective of the nodal status of the breast cancer.

[0701] 245. Ribociclib for use in a method of reducing the risk of recurrence of early breast cancer in an adult patient who has been diagnosed with HR+ / HER2- stage II or stage III early stage breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) ribociclib at a dose ranging from 150 mg per day to 450 mg per day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor every day on a 28-day cycle, wherein the administration of the treatment is irrespective of the nodal status of the breast cancer.

[0702] 246. Ribociclib for use according to any one of embodiments 241 to 245, wherein the breast cancer has a nodal status of NO, N1, N2 or N3.

[0703] 247. Ribociclib for use according to embodiment 246, wherein the breast cancer has a nodal status of NO.

[0704] 248. Ribociclib for use according to any one of embodiments 241 to 247, wherein the early breast cancer is stage II, e.g. stage IIA.

[0705] 249. Ribociclib for use according to any one of embodiments 241 to 247, wherein the early breast cancer is stage III, e.g. stage IIIB or stage IIIC.

[0706] 250. Ribociclib for use according to any one of embodiments 241 to 249, wherein the breast cancer is of ductal subtype.

[0707] 251. Ribociclib for use according to any one of embodiments 241 to 250, wherein the patient is of Asian ethnicity.

[0708] 252. Reparixin for use according to any one of embodiments 241 to 251, wherein the method is adjuvant therapy because the patient has received at least one prior treatment for breast cancer selected from the group consisting of surgery, chemotherapy and radiotherapy.

[0709] 253. Reparixin for use according to embodiment 252, wherein the patient has not undergone mastectomy.

[0710] 254. Reparixin for use according to any one of embodiments 241 to 253, wherein the dose of reparixin is 400 mg / day.

[0711] 255. Reparixin for use according to any one of embodiments 241 to 254, wherein the reparixin is administered in the form of a salt, preferably of reparixin succinate.

[0712] 256. Reparixin for use according to any one of embodiments 241 to 255, wherein the aromatase inhibitor is letrozole or anastrozole.

[0713] 257. Reparixin for use according to embodiment 256, wherein the aromatase inhibitor is letrozole, preferably administered at a dose of 2.5 mg / day.

[0714] 258. Reparixin for use according to embodiment 256, wherein the aromatase inhibitor is anastrozole, preferably administered at a dose of 1 mg / day.

[0715] 259. Reparixin for use according to any one of embodiments 241 to 258, wherein the dose of reparixin is 400 mg / day, the reparixin is administered in the form of reparixin succinate and the aromatase inhibitor is letrozole or anastrozole, preferably 2.5 mg / day of letrozole or 1 mg / day of anastrozole.

[0716] 260. Reparixin for use according to any one of embodiments 241 to 259, wherein the patient achieves an improvement in OS, DDFS and / or RFS of at least 36 months or a reduction in the risk of breast cancer recurrence.

[0717] 261. Rovletuxizumab for use in a method of treating HR+ / HER2- Stage II or III early breast cancer in an adult patient who has received at least one prior treatment for early breast cancer and who has no signs or symptoms of cancer, wherein the method comprises administering to the patient adjuvant therapy comprising (i) administering a dose of rovletuxizumab for 1 to 21 days of a 28-day cycle, the total dose of rovletuxizumab being 400 mg / day, and (ii) administering letrozole at a dose of 2.5 mg / day or anastrozole at a dose of 1 mg / day every day of a 28-day cycle.

[0718] 262. Rovletuxizumab for use as described in embodiment 261, wherein the adjuvant therapy comprises letrozole at a dose of 2.5 mg / day.

[0719] 263. Rovletuxizumab for use as described in embodiment 261, wherein the adjuvant therapy comprises anastrozole at a dose of 1 mg / day.

[0720] 264. Rovletuxizumab for use as described in any one of embodiments 261 to 263, wherein the breast cancer has a lymph node status of NO, N1, N2 or N3.

[0721] 265. Rovletuxizumab for use as described in embodiment 264, wherein the breast cancer has a lymph node status of NO.

[0722] 266. Rovletuxizumab for use as described in any one of embodiments 261 to 265, wherein the early breast cancer is Stage II, for example, Stage IIA.

[0723] 267. Rovletuxizumab for use as described in any one of embodiments 261 to 265, wherein the early breast cancer is Stage III, for example, Stage IIIB.

[0724] 268. Rovletuxizumab for use as described in any one of embodiments 261 to 265, wherein the early breast cancer is Stage III, for example, Stage IIIC.

[0725] 269. Rovletuxizumab for use as described in any one of embodiments 261 to 268, wherein the breast cancer is of ductal subtype.

[0726] 270. Rovletuxizumab for use as described in any one of embodiments 261 to 269, wherein the patient is of Asian descent.

[0727] 271. Use of roseroxytb succinate as described in any one of embodiments 261 to 270, wherein the method is adjuvant therapy because the patient has received at least one prior treatment for breast cancer selected from the group consisting of surgery, chemotherapy, endocrine therapy, and radiation therapy.

[0728] 272. Use of roseroxytb succinate as described in embodiment 271, wherein the patient has not undergone mastectomy.

[0729] 273. Use of roseroxytb succinate as described in any one of embodiments 261 to 272, wherein the method improves overall survival (OS), distant disease-free survival (DDFS), and / or relapse-free survival (RFS) of the breast cancer in the patient by at least 36 months; or the method reduces the risk of recurrence of the breast cancer in the patient by at least 36 months.

[0730] 274. A method of preventing recurrence of breast cancer in an adult patient who has received prior treatment for HR+ / HER2- Stage II or III early stage breast cancer, the method comprising administering to the patient (i) a dose of roseroxytb, a free base form thereof, or a pharmaceutically acceptable salt thereof, and (ii) a dose of an aromatase inhibitor, preferably letrozole or anastrozole.

[0731] 275. A method of treating an adult patient in remission from HR+ / HER2- Stage II or III early stage breast cancer, the method comprising administering to the patient (i) a dose of roseroxytb, a free base form thereof, or a pharmaceutically acceptable salt thereof, and (ii) a dose of an aromatase inhibitor, preferably letrozole or anastrozole.

[0732] 276. A method of treating HR+ / HER2- Stage II or III early stage breast cancer in an adult patient in need thereof, the method comprising administering to the patient (i) roseroxytb, a free base form thereof, or a pharmaceutically acceptable salt thereof, at a dose ranging from 150 mg per day to 450 mg per day, administered on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor, preferably letrozole or anastrozole, administered every day of a 28-day cycle.

[0733] 277. The method of any one of embodiments 274 to 276, wherein the roseroxytb is a pharmaceutically acceptable salt of roseroxytb.

[0734] 278. The method of embodiment 277, wherein the salt of roseroxytb is roseroxytb succinate.

[0735] 279. The method of any one of embodiments 274, 275, 277, and 278, wherein the dose of rosercimib is not 600 mg / day.

[0736] 280. The method of any one of embodiments 274 to 278, wherein the dose of rosercimib is 200 mg / day or 400 mg / day.

[0737] 281. The method of embodiment 280, wherein rosercimib is administered as rosercimib succinate and the total dose of rosercimib is 200 mg / day.

[0738] 282. The method of embodiment 280, wherein rosercimib is administered as rosercimib succinate and the total dose of rosercimib is 400 mg / day.

[0739] 283. The method of embodiment 280, wherein the rosercimib is administered at a dose of 400 mg / day for a period of time followed by administration of rosercimib at a dose of 200 mg / day.

[0740] 284. The method of any one of embodiments 274 to 283, wherein the dose of rosercimib is administered orally.

[0741] 285. The method of any one of embodiments 274 to 284, wherein the dose of rosercimib is administered as a tablet.

[0742] 286. The method of any one of embodiments 274 to 285, wherein the aromatase inhibitor is letrozole or anastrozole.

[0743] 287. The method of any one of embodiments 274 to 286, wherein the aromatase inhibitor is administered orally.

[0744] 288. The method of embodiment 286 or 287, wherein the letrozole is administered at a dose ranging from 1 mg / day to 4 mg / day.

[0745] 289. The method of embodiment 288, wherein the letrozole is administered at a dose of 2.5 mg / day.

[0746] 290. The method of embodiment 286 or 287, wherein the anastrozole is administered at a dose ranging from 0.5 mg / day to 1.5 mg / day.

[0747] 291. The method of embodiment 290, wherein the anastrozole is administered at a dose of 1 mg / day.

[0748] 292. A method of treating breast cancer recurrence in an adult patient who has received at least one prior therapy for HR+ / HER2- Stage II or III early stage breast cancer and has no detectable signs or symptoms of breast cancer, comprising administering to the patient an adjuvant therapy comprising (i) a dose of roseroxytbine succinate on Days 1-21 of a 28-day cycle, the total dose of roseroxytbine being 400 mg / day, and (ii) a dose of 2.5 mg / day of letrozole or 1 mg / day of anastrozole on each day of a 28-day cycle.

[0749] 293. A method of treating an adult patient in remission from HR+ / HER2- Stage II or III early stage breast cancer and in need of adjuvant therapy, comprising administering to the patient an adjuvant therapy comprising (i) a dose of roseroxytbine succinate on Days 1-21 of a 28-day cycle, the total dose of roseroxytbine being 400 mg / day, and (ii) a dose of 2.5 mg / day of letrozole or 1 mg / day of anastrozole on each day of a 28-day cycle.

[0750] 294. The method of any one of embodiments 274-293, wherein the treatment further comprises administering a gonadotropin-releasing hormone agonist.

[0751] 295. The method of embodiment 294, wherein the gonadotropin-releasing hormone agonist is goserelin.

[0752] 296. The method of embodiment 295, wherein the goserelin is administered at a dose ranging from 2 mg to 5 mg.

[0753] 297. The method of embodiment 296, wherein the dose of goserelin is 3.6 mg.

[0754] 298. The method of any one of embodiments 294-297, wherein the goserelin is administered subcutaneously.

[0755] 299. The method of any one of embodiments 294-298, wherein the goserelin is administered once every 4 weeks.

[0756] 300. The method of any one of embodiments 274-299, wherein the patient is a postmenopausal woman.

[0757] 301. The method of any one of embodiments 274-293, wherein the patient is a premenopausal woman or a man.

[0758] 302. The method of any one of embodiments 274 to 301, wherein the treatment is administered to the patient for at least 12 months.

[0759] 303. The method of embodiment 302, wherein the treatment is administered to the patient for at least 24 months.

[0760] 304. The method of embodiment 302 or 303, wherein the treatment is administered to the patient for at least 36 months.

[0761] 305. The method of any one of embodiments 302 to 304, wherein the treatment is administered to the patient for at least 48 months.

[0762] 306. The method of any one of embodiments 302 to 305, wherein the treatment is administered to the patient for at least 60 months.

[0763] 307. The method of any one of embodiments 274 to 306, wherein the breast cancer is ER+ and PR+.

[0764] 308. The method of any one of embodiments 274 to 306, wherein the breast cancer is ER- and PR+.

[0765] 309. The method of any one of embodiments 274 to 306, wherein the breast cancer is ER+ and PR-.

[0766] 310. The method of any one of embodiments 274 to 309, wherein the histological subtype of the breast cancer is a ductal subtype.

[0767] 311. The method of any one of embodiments 274 to 310, wherein the histological subtype of the breast cancer is a lobular subtype.

[0768] 312. The method of any one of embodiments 274 to 311, wherein the breast cancer is a stage IIA cancer or a stage IIB cancer.

[0769] 313. The method of embodiment 312, wherein the breast cancer is a stage IIA cancer.

[0770] 314. The method of embodiment 312, wherein the breast cancer is a stage IIB cancer.

[0771] 315. The method of any one of embodiments 274 to 311, wherein the breast cancer is a stage IIIA cancer, a stage IIIB cancer, or a stage IIIC cancer.

[0772] 316. The method of embodiment 315, wherein the breast cancer is a stage IIIA cancer.

[0773] 317. The method of embodiment 315, wherein the breast cancer is a stage IIIB cancer.

[0774] 318. The method of embodiment 315, wherein the breast cancer is a stage IIIC cancer.

[0775] 319. The method of any one of embodiments 274-318, wherein the administration of the treatment is irrespective of the lymph node status of the breast cancer.

[0776] 320. The method of any one of embodiments 274-319, wherein the breast cancer has a lymph node status selected from the group consisting of NO, Nl, N2, and N3.

[0777] 321. The method of embodiment 319 or 320, wherein the breast cancer has a lymph node status of NO.

[0778] 322. The method of embodiment 319 or 320, wherein the breast cancer has a lymph node status of Nl to N3.

[0779] 323. The method of embodiment 319 or 320, wherein the breast cancer has a lymph node status of Nl.

[0780] 324. The method of embodiment 319 or 320, wherein the breast cancer has a lymph node status of N2.

[0781] 325. The method of embodiment 319 or 320, wherein the breast cancer has a lymph node status of N3.

[0782] 326. The method of any one of embodiments 274-325, wherein the breast cancer comprises one or more cells having a histological grade selected from the group consisting of Gl, G2, or G3.

[0783] 327. The method of embodiment 326, wherein the breast cancer comprises one or more cells having a histological grade of Gl.

[0784] 328. The method of embodiment 326, wherein the breast cancer comprises one or more cells having a histological grade of G2.

[0785] 329. The method of embodiment 326, wherein the breast cancer comprises one or more cells having a histological grade of G3.

[0786] 330. The method of any one of embodiments 274-329, wherein the breast cancer comprises a tumor of the T0, Tl, T2, T3, or T4 classification.

[0787] 331. The method of embodiment 330, wherein the breast cancer comprises a tumor of T1, T2, or T3 category.

[0788] 332. The method of embodiment 330, wherein the breast cancer comprises a tumor of TO category.

[0789] 333. The method of embodiment 330 or embodiment 331, wherein the breast cancer comprises a tumor of T1 category.

[0790] 334. The method of embodiment 330 or embodiment 331, wherein the breast cancer comprises a tumor of T2 category.

[0791] 335. The method of embodiment 330 or embodiment 331, wherein the breast cancer comprises a tumor of T3 category.

[0792] 336. The method of embodiment 330, wherein the breast cancer comprises a tumor of T4 category.

[0793] 337. The method of any one of embodiments 274-336, wherein the breast cancer has a Ki67 status of 20 or less.

[0794] 338. The method of any one of embodiments 274-336, wherein the breast cancer has a Ki67 status of more than 20.

[0795] 339. The method of any one of embodiments 274-338, wherein the patient received a loading dose of (i) ribociclib and / or (ii) endocrine therapy prior to the administration.

[0796] 340. The method of any one of embodiments 274-291 and 293-339, wherein the patient received at least one prior treatment for cancer.

[0797] 341. The method of embodiment 292 or embodiment 340, wherein the prior treatment is an adjuvant therapy following another prior treatment.

[0798] 342. The method of embodiment 340 or 341, wherein the prior treatment is surgery.

[0799] 343. The method of embodiment 342, wherein the surgery comprises complete surgical resection of the cancer.

[0800] 344. The method of embodiment 342 or embodiment 343, wherein the surgery is a mastectomy.

[0801] 345. The method of embodiment 340 or embodiment 341, wherein the prior treatment is chemotherapy.

[0802] 346. The method of embodiment 345, wherein the prior treatment is adjuvant chemotherapy.

[0803] 347. The method of embodiment 345, wherein the prior treatment is neoadjuvant chemotherapy.

[0804] 348. The method of embodiment 340 or embodiment 341, wherein the prior treatment is endocrine therapy.

[0805] 349. The method of embodiment 340 or embodiment 341, wherein the prior treatment is radiation therapy.

[0806] 350. The method of any one of embodiments 292 and 340-349, wherein the patient is unresponsive to a prior treatment.

[0807] 351. The method of any one of embodiments 274-350, wherein the patient is located in a geographic region selected from North America, Western Europe, or Oceania.

[0808] 352. The method of any one of embodiments 274-351, wherein the patient is of Asian descent.

[0809] 353. The method of any one of embodiments 274-352, wherein the patient is 18 to 45 years of age.

[0810] 354. The method of any one of embodiments 274-352, wherein the patient is 45 to 54 years of age.

[0811] 355. The method of any one of embodiments 274-352, wherein the patient is 54 to 64 years of age.

[0812] 356. The method of any one of embodiments 274-352, wherein the patient is greater than 64 years of age.

[0813] 357. The method of any one of embodiments 274-357, wherein the patient has a BMI of 25 or greater.

[0814] 358. The method of any one of embodiments 274-357, wherein the patient has a BMI of less than 25.

[0815] 359. The method of any one of embodiments 274-358, wherein the treatment improves the patient’s condition relative to a patient who does not receive the treatment and / or relative to the patient’s condition prior to treatment.

[0816] 360. The method of any one of embodiments 274 to 359, wherein the treatment reduces the risk of invasive disease.

[0817] 361. The method of embodiment 360, wherein the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than 1 when the risk is calculated relative to a patient who does not receive the treatment.

[0818] 362. The method of embodiment 361, wherein the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.78 when the risk is calculated relative to a patient who does not receive the treatment.

[0819] 363. The method of any one of embodiments 274 to 299 and 301 to 362, wherein the patient is a premenopausal woman or man and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.72 when the risk is calculated relative to a patient who does not receive the treatment.

[0820] 364. The method of any one of embodiments 360 to 362, wherein the cancer is HR+ / HER2- stage III early stage breast cancer and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.74 when the risk is calculated relative to a patient who does not receive the treatment.

[0821] 365. The method of any one of embodiments 360 to 362, wherein the cancer is HR+ / HER2- stage II early stage breast cancer and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.76 when the risk is calculated relative to a patient who does not receive the treatment.

[0822] 366. The method of any one of embodiments 360 to 362, wherein the cancer is HR+ / HER2- stage III early stage breast cancer and the treatment reduces the risk of invasive disease by at least 25% corresponding to a hazard ratio of 0.75 when the risk is calculated relative to a patient who does not receive the treatment.

[0823] 367. The method of any one of embodiments 360 to 366, wherein the treatment reduces the risk of invasive disease to a similar level for a patient subset comprising a patient with stage II early stage breast cancer, a patient with stage III early stage breast cancer, a premenopausal woman or man patient, and a postmenopausal woman patient.

[0824] 368. The method of any one of embodiments 274 to 367, wherein the treatment does not result in a reduction in overall survival corresponding to a hazard ratio of 0.76 when the risk is calculated relative to a patient who does not receive the treatment.

[0825] 369. The method of any one of embodiments 274 to 368, wherein the treatment reduces and / or prevents one or more of recurrence of cancer, spread of cancer, occurrence and / or growth of additional cancer, and risk of death from cancer.

[0826] 370. The method of embodiment 369, wherein the treatment reduces recurrence of cancer, wherein the recurrence is one or more of invasive ipsilateral breast tumor recurrence (IBTR), loco-regional invasive recurrence, and distant recurrence.

[0827] 371. The method of embodiment 369, wherein the treatment reduces spread of cancer, wherein the spread of cancer is invasive contralateral breast cancer or additional primary invasive cancer.

[0828] 372. The method of any one of embodiments 274 to 371, wherein the treatment prevents death from cancer.

[0829] J. Further Exemplary Embodiments

[0830] Further methods of treatment and uses of ribociclib are provided in the following embodiments.

[0831] 1. A method of treating an adult patient who has been diagnosed with HR+ / HER2- Stage II or Stage III early stage breast cancer, the method comprising administering to the patient adjuvant therapy comprising (i) ribociclib at a dose ranging from 150 mg per day to 450 mg per day on Days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor on every day of a 28-day cycle, wherein the method results in one or more of improvement in overall survival (OS), distant disease-free survival (DDFS), or recurrence-free survival (RFS) of the patient.

[0832] 2. A method for improving one or more of overall survival (OS), distant disease-free survival (DDFS), or recurrence-free survival (RFS) of a patient who has been diagnosed with HR+ / HER2- Stage II or Stage III early stage breast cancer, the method comprising administering to the patient adjuvant therapy comprising (i) ribociclib at a dose ranging from 150 mg per day to 450 mg per day on Days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor on every day of a 28-day cycle.

[0833] 3. A method for reducing the risk of local or regional invasive recurrence of early breast cancer in an adult patient who has been diagnosed with HR+ / HER2- Stage II or Stage III early breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) administering repoxilumab at a dose ranging from 150 mg / day to 450 mg / day on Days 1-21 of a 28-day cycle, and (ii) administering an aromatase inhibitor every day of a 28-day cycle.

[0834] 4. A method for reducing the risk of invasive recurrence of early breast cancer in one or more of the bone, liver, and lung or pleura in an adult patient who has been diagnosed with HR+ / HER2- Stage II or Stage III early breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) administering repoxilumab at a dose ranging from 150 mg / day to 450 mg / day on Days 1-21 of a 28-day cycle, and (ii) administering an aromatase inhibitor every day of a 28-day cycle.

[0835] 5. The method of any one of claims 1 to 4, wherein the administration of the treatment is irrespective of the lymph node status of the breast cancer.

[0836] 6. A method for reducing the risk of recurrence of early breast cancer in an adult patient who has been diagnosed with HR+ / HER2- Stage II or Stage III early breast cancer, the method comprising administering an adjuvant therapy comprising (i) administering repoxilumab at a dose ranging from 150 mg / day to 450 mg / day on Days 1-21 of a 28-day cycle, and (ii) administering an aromatase inhibitor every day of a 28-day cycle, wherein the administration of the treatment is irrespective of the lymph node status of the breast cancer.

[0837] 7. The method of any one of claims 1 to 6, wherein the breast cancer has a lymph node status of NO, N1, N2, or N3.

[0838] 8. The method of claim 7, wherein the breast cancer has a lymph node status of NO.

[0839] 9. The method of any one of claims 1 to 8, wherein the early breast cancer is Stage II, e.g., Stage IIA.

[0840] 10. The method of any one of claims 1 to 8, wherein the early breast cancer is Stage III, e.g., Stage IIIB or Stage IIIC.

[0841] 11. The method of any one of claims 1 to 10, wherein the breast cancer is of the ductal subtype.

[0842] 12. The method of any one of claims 1 to 11, wherein the patient is of Asian descent.

[0843] 13. The method of any one of claims 1 to 12, wherein the method is adjuvant therapy because the patient has received at least one prior treatment for breast cancer selected from the group consisting of surgery, chemotherapy, and radiotherapy.

[0844] 14. The method of claim 13, wherein the patient has not undergone mastectomy.

[0845] 15. The method of any one of claims 1 to 14, wherein the dose of ribociclib is 400 mg per day.

[0846] 16. The method of any one of claims 1 to 15, wherein the ribociclib is administered as a salt, preferably ribociclib succinate.

[0847] 17. The method of any one of claims 1 to 16, wherein the aromatase inhibitor is letrozole or anastrozole.

[0848] 18. The method of claim 17, wherein the aromatase inhibitor is letrozole, preferably administered at a dose of 2.5 mg per day.

[0849] 19. The method of claim 17, wherein the aromatase inhibitor is anastrozole, preferably administered at a dose of 1 mg per day.

[0850] 20. The method of any one of claims 1 to 19, wherein the dose of ribociclib is 400 mg per day, the ribociclib is administered as ribociclib succinate, and the aromatase inhibitor is letrozole or anastrozole, preferably 2.5 mg per day of letrozole or 1 mg per day of anastrozole.

[0851] 21. The method of any one of claims 1 to 20, wherein the patient achieves an improvement in OS, DDFS, and / or RFS or a reduction in the risk of breast cancer recurrence for at least 36 months.

[0852] 22. Ribociclib for use in a method of improving one or more of overall survival (OS), disease-free survival (DDFS), or relapse-free survival (RFS) in an adult patient who has been diagnosed with HR+ / HER2- stage II or stage III early stage breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) ribociclib at a dose ranging from 150 mg per day to 450 mg per day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered every day of a 28-day cycle.

[0853] 23. Ribociclib for use in a method of reducing the risk of local or regional invasive recurrence of early breast cancer in an adult patient who has been diagnosed with HR+ / HER2- Stage II or Stage III early breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) ribociclib at a dose ranging from 150 mg per day to 450 mg per day on Days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor every day of a 28-day cycle.

[0854] 24. Ribociclib for use in a method of reducing the risk of invasive recurrence of early breast cancer in one or more of bone, liver, and lung or pleura in an adult patient who has been diagnosed with HR+ / HER2- Stage II or Stage III early breast cancer, and the method is an adjuvant therapy, the method comprising administering to the patient an adjuvant therapy comprising (i) ribociclib at a dose ranging from 150 mg per day to 450 mg per day on Days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor every day of a 28-day cycle.

[0855] 25. Ribociclib for use according to any one of claims 22 to 24, wherein the administration of the treatment is irrespective of the nodal status of the breast cancer.

[0856] 26. Ribociclib for use in a method of reducing the risk of recurrence of early breast cancer in an adult patient who has been diagnosed with HR+ / HER2- Stage II or Stage III early breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) ribociclib at a dose ranging from 150 mg per day to 450 mg per day on Days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor every day of a 28-day cycle, wherein the administration of the treatment is irrespective of the nodal status of the breast cancer.

[0857] 27. Ribociclib for use according to any one of claims 22 to 26, wherein the breast cancer has a nodal status of NO, N1, N2, or N3.

[0858] 28. Ribociclib for use according to claim 27, wherein the breast cancer has a nodal status of NO.

[0859] 29. Ribociclib for use according to any one of claims 22 to 28, wherein the early breast cancer is Stage II, for example, Stage IIA.

[0860] 30. Ribociclib for use according to any one of claims 22 to 28, wherein the early breast cancer is Stage III, for example, Stage IIIB or Stage IIIC.

[0861] 31. Reparixin for use according to any one of claims 22 to 30, wherein the breast cancer is of ductal subtype.

[0862] 32. Reparixin for use according to any one of claims 22 to 31, wherein the patient is of Asian ethnicity.

[0863] 33. Reparixin for use according to any one of claims 22 to 32, wherein the method is an adjuvant therapy, as the patient has received at least one prior treatment for breast cancer selected from the group consisting of surgery, chemotherapy and radiotherapy.

[0864] 34. Reparixin for use according to claim 33, wherein the patient has not undergone mastectomy.

[0865] 35. Reparixin for use according to any one of claims 22 to 34, wherein the dose of reparixin is 400 mg / day.

[0866] 36. Reparixin for use according to any one of claims 22 to 35, wherein the reparixin is administered in the form of a salt, preferably reparixin succinate.

[0867] 37. Reparixin for use according to any one of claims 22 to 36, wherein the aromatase inhibitor is letrozole or anastrozole.

[0868] 38. Reparixin for use according to claim 37, wherein the aromatase inhibitor is letrozole, preferably administered at a dose of 2.5 mg / day.

[0869] 39. Reparixin for use according to claim 37, wherein the aromatase inhibitor is anastrozole, preferably administered at a dose of 1 mg / day.

[0870] 40. Reparixin for use according to any one of claims 22 to 39, wherein the dose of reparixin is 400 mg / day, the reparixin is administered in the form of reparixin succinate and the aromatase inhibitor is letrozole or anastrozole, preferably letrozole at 2.5 mg / day or anastrozole at 1 mg / day.

[0871] 41. Reparixin for use according to any one of claims 22 to 40, wherein the patient achieves an improvement in OS, DDFS and / or RFS of at least 36 months or a reduction in the risk of breast cancer recurrence.

[0872] K. Further Exemplary Examples 41. Reparixin for use according to any one of claims 22 to 40, wherein the patient achieves an improvement in OS, DDFS and / or RFS of at least 36 months or a reduction in the risk of breast cancer recurrence.

[0873] Further methods of treatment and uses of ribociclib are provided in the following embodiments.

[0874] 1. Ribociclib succinate for use in a method of treating HR+ / HER2- stage II or stage III early breast cancer in an adult patient who has received at least one prior treatment for early breast cancer and who has no signs or symptoms of cancer, wherein the method comprises administering to the patient adjuvant therapy comprising (i) ribociclib succinate at a dose of 400 mg / day of ribociclib succinate on days 1 to 21 of a 28-day cycle, and (ii) letrozole at a dose of 2.5 mg / day or anastrozole at a dose of 1 mg / day on each day of a 28-day cycle.

[0875] 2. Ribociclib succinate for use according to embodiment 1, wherein the adjuvant therapy comprises letrozole at a dose of 2.5 mg / day.

[0876] 3. Ribociclib succinate for use according to embodiment 1, wherein the adjuvant therapy comprises anastrozole at a dose of 1 mg / day.

[0877] 4. Ribociclib succinate for use according to any one of embodiments 1 to 3, wherein the breast cancer has a lymph node status of N0, N1, N2 or N3.

[0878] 5. Ribociclib succinate for use according to embodiment 4, wherein the breast cancer has a lymph node status of N0.

[0879] 6. Ribociclib succinate for use according to any one of embodiments 1 to 5, wherein the early breast cancer is stage II, for example stage IIA.

[0880] 7. Ribociclib succinate for use according to any one of embodiments 1 to 5, wherein the early breast cancer is stage III, for example stage IIIB.

[0881] 8. Ribociclib succinate for use according to any one of embodiments 1 to 5, wherein the early breast cancer is stage III, for example stage IIIC.

[0882] 9. Ribociclib succinate for use according to any one of embodiments 1 to 8, wherein the breast cancer is of ductal subtype.

[0883] 10. Ribociclib succinate for use according to any one of embodiments 1 to 9, wherein the patient is of Asian ethnicity.

[0884] 11. The use of romosoxane according to any one of embodiments 1 to 10, wherein the method is adjuvant therapy because the patient has received at least one prior treatment for breast cancer selected from the group consisting of surgery, chemotherapy, endocrine therapy, and radiation therapy.

[0885] 12. The use of romosoxane according to embodiment 11, wherein the patient has not undergone a mastectomy.

[0886] 13. The use of romosoxane according to any one of embodiments 1 to 12, wherein the method improves the overall survival (OS), distant disease-free survival (DDFS), and / or relapse-free survival (RFS) of the breast cancer in the patient for at least 36 months; or the method reduces the risk of recurrence of the breast cancer in the patient for at least 36 months.

[0887] L. Other exemplary embodiments

[0888] Further methods of treatment and uses of romosoxane are provided in the following embodiments.

[0889] 1. A method of preventing recurrence of breast cancer in an adult patient who has received a prior treatment for HR+ / HER2- stage II or III early stage breast cancer, the method comprising administering to the patient (i) a dose of romosoxane, a free base form thereof, or a pharmaceutically acceptable salt thereof, and (ii) a dose of an aromatase inhibitor, preferably letrozole or anastrozole.

[0890] 2. A method of treating an adult patient in remission from HR+ / HER2- stage II or III early stage breast cancer, the method comprising administering to the patient (i) a dose of romosoxane, a free base form thereof, or a pharmaceutically acceptable salt thereof, and (ii) a dose of an aromatase inhibitor, preferably letrozole or anastrozole.

[0891] 3. A method of treating HR+ / HER2- stage II or III early stage breast cancer in an adult patient in need thereof, the method comprising administering to the patient (i) romosoxane, a free base form thereof, or a pharmaceutically acceptable salt thereof, in a dose ranging from 150 mg / day to 450 mg / day, administered on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor, preferably letrozole or anastrozole, administered every day of a 28-day cycle.

[0892] 4. The method according to any one of embodiments 1 to 3, wherein the romosoxane is a pharmaceutically acceptable salt of romosoxane.

[0893] 5. The method according to embodiment 4, wherein the salt of romosoxane is romosoxane succinate.

[0894] 6. The method of any one of embodiments 1, 2, 4, and 5, wherein the dose of ribociclib is other than 600 mg / day.

[0895] 7. The method of any one of embodiments 1 to 5, wherein the dose of ribociclib is 200 mg / day or 400 mg / day.

[0896] 8. The method of embodiment 7, wherein ribociclib is administered as ribociclib succinate and the total dose of ribociclib is 200 mg / day.

[0897] 9. The method of embodiment 7, wherein ribociclib is administered as ribociclib succinate and the total dose of ribociclib is 400 mg / day.

[0898] 10. The method of embodiment 7, wherein the ribociclib is administered at a dose of 400 mg / day for a period of time followed by administration of ribociclib at a dose of 200 mg / day.

[0899] 11. The method of any one of embodiments 1 to 10, wherein the dose of ribociclib is administered orally.

[0900] 12. The method of any one of embodiments 1 to 11, wherein the dose of ribociclib is administered as a tablet.

[0901] 13. The method of any one of embodiments 1 to 12, wherein the aromatase inhibitor is letrozole or anastrozole.

[0902] 14. The method of any one of embodiments 1 to 13, wherein the aromatase inhibitor is administered orally.

[0903] 15. The method of embodiment 13 or 14, wherein the letrozole is administered at a dose ranging from 1 mg / day to 4 mg / day.

[0904] 16. The method of embodiment 15, wherein the letrozole is administered at a dose of 2.5 mg / day.

[0905] 17. The method of embodiment 13 or 14, wherein the anastrozole is administered at a dose ranging from 0.5 mg / day to 1.5 mg / day.

[0906] 18. The method of embodiment 17, wherein the anastrozole is administered at a dose of 1 mg / day.

[0907] 19. A method of treating breast cancer recurrence in an adult patient who has received at least one prior treatment for HR+ / HER2- Stage II or III early stage breast cancer and has no detectable signs or symptoms of breast cancer, comprising administering to the patient an adjuvant therapy comprising (i) a dose of ribociclib succinate on Days 1-21 of a 28-day cycle, the total dose of ribociclib being 400 mg / day, and (ii) a dose of 2.5 mg / day of letrozole or 1 mg / day of anastrozole on each day of a 28-day cycle.

[0908] 20. A method of treating an adult patient in remission from HR+ / HER2- Stage II or III early stage breast cancer and in need of adjuvant therapy, comprising administering to the patient an adjuvant therapy comprising (i) a dose of ribociclib succinate on Days 1-21 of a 28-day cycle, the total dose of ribociclib being 400 mg / day, and (ii) a dose of 2.5 mg / day of letrozole or 1 mg / day of anastrozole on each day of a 28-day cycle.

[0909] 21. The method of any one of embodiments 1-20, wherein the treatment comprises administering a gonadotropin-releasing hormone agonist.

[0910] 22. The method of embodiment 21, wherein the gonadotropin-releasing hormone agonist is goserelin.

[0911] 23. The method of embodiment 22, wherein the goserelin is administered at a dose ranging from 2 mg to 5 mg.

[0912] 24. The method of embodiment 23, wherein the dose of goserelin is 3.6 mg.

[0913] 25. The method of any one of embodiments 22-24, wherein the goserelin is administered subcutaneously.

[0914] 26. The method of any one of embodiments 22-25, wherein the goserelin is administered once every 4 weeks.

[0915] 27. The method of any one of embodiments 1-20, wherein the patient is a postmenopausal woman.

[0916] 28. The method of any one of embodiments 1-26, wherein the patient is a premenopausal woman or a man.

[0917] 29. The method of any one of embodiments 1-28, wherein the treatment is administered to the patient for at least 12 months.

[0918] 30. The method of embodiment 29, wherein the treatment is administered to the patient for at least 24 months.

[0919] 31. The method of embodiment 29 or embodiment 30, wherein the treatment is administered to the patient for at least 36 months.

[0920] 32. The method of any one of embodiments 29-31, wherein the treatment is administered to the patient for at least 48 months.

[0921] 33. The method of any one of embodiments 29-32, wherein the treatment is administered to the patient for at least 60 months.

[0922] 34. The method of any one of embodiments 1-33, wherein the breast cancer is ER+ and PR+.

[0923] 35. The method of any one of embodiments 1-33, wherein the breast cancer is ER- and PR+.

[0924] 36. The method of any one of embodiments 1-33, wherein the breast cancer is ER+ and PR-.

[0925] 37. The method of any one of embodiments 1-36, wherein the histological subtype of the breast cancer is a ductal subtype.

[0926] 38. The method of any one of embodiments 1-37, wherein the histological subtype of the breast cancer is a lobular subtype.

[0927] 39. The method of any one of embodiments 1-38, wherein the breast cancer is a stage IIA cancer or a stage IIB cancer.

[0928] 40. The method of embodiment 39, wherein the breast cancer is a stage IIA cancer.

[0929] 41. The method of embodiment 39, wherein the breast cancer is a stage IIB cancer.

[0930] 42. The method of any one of embodiments 1-38, wherein the breast cancer is a stage IIIA cancer, a stage IIIB cancer, or a stage IIIC cancer.

[0931] 43. The method of embodiment 42, wherein the breast cancer is a stage IIIA cancer.

[0932] 44. The method of embodiment 42, wherein the breast cancer is a stage IIIB cancer.

[0933] 45. The method of embodiment 42, wherein the breast cancer is a stage IIIC cancer.

[0934] 46. The method of any one of embodiments 1 to 45, wherein the administration of the treatment is irrespective of the lymph node status of the breast cancer.

[0935] 47. The method of any one of embodiments 1 to 46, wherein the breast cancer has a lymph node status selected from N0, N1, N2, and N3.

[0936] 48. The method of embodiment 46 or 47, wherein the breast cancer has a lymph node status of N0.

[0937] 49. The method of embodiment 46 or 47, wherein the breast cancer has a lymph node status of N1 to N3.

[0938] 50. The method of embodiment 46 or 47, wherein the breast cancer has a lymph node status of N1.

[0939] 51. The method of embodiment 46 or 47, wherein the breast cancer has a lymph node status of N2.

[0940] 52. The method of embodiment 46 or 47, wherein the breast cancer has a lymph node status of N3.

[0941] 53. The method of any one of embodiments 1 to 52, wherein the breast cancer comprises one or more cells having a histological grade selected from G1, G2, or G3.

[0942] 54. The method of embodiment 53, wherein the breast cancer comprises one or more cells having a histological grade of G1.

[0943] 55. The method of embodiment 53, wherein the breast cancer comprises one or more cells having a histological grade of G2.

[0944] 56. The method of embodiment 53, wherein the breast cancer comprises one or more cells having a histological grade of G3.

[0945] 57. The method of any one of embodiments 1 to 56, wherein the breast cancer comprises a tumor of T0, T1, T2, T3, or T4 category.

[0946] 58. The method of embodiment 57, wherein the breast cancer comprises a tumor of T1, T2, or T3 category.

[0947] 59. The method of embodiment 57, wherein the breast cancer comprises a tumor of T0 category.

[0948] 60. The method of embodiment 57 or 58, wherein the breast cancer comprises a tumor of T1 category.

[0949] 61. The method of embodiment 57 or 58, wherein the breast cancer comprises a tumor of T2 category.

[0950] 62. The method of embodiment 57 or 58, wherein the breast cancer comprises a tumor of T3 category.

[0951] 63. The method of embodiment 57, wherein the breast cancer comprises a tumor of T4 category.

[0952] 64. The method of any one of embodiments 1 to 63, wherein the breast cancer has a Ki67 status of 20 or less.

[0953] 65. The method of any one of embodiments 1 to 63, wherein the breast cancer has a Ki67 status of more than 20.

[0954] 66. The method of any one of embodiments 1 to 65, wherein the patient received a loading dose of (i) ribociclib and / or (ii) endocrine therapy prior to the administration.

[0955] 67. The method of any one of embodiments 1 to 18 and 20 to 66, wherein the patient received at least one prior treatment for cancer.

[0956] 68. The method of embodiment 19 or 67, wherein the prior treatment is an adjuvant treatment following another prior treatment.

[0957] 69. The method of embodiment 67 or 68, wherein the prior treatment is surgery.

[0958] 70. The method of embodiment 69, wherein the surgery comprises a complete surgical resection of the cancer.

[0959] 71. The method of embodiment 69 or 70, wherein the surgery is a mastectomy.

[0960] 72. The method of embodiment 67 or 68, wherein the prior treatment is chemotherapy.

[0961] 73. The method of embodiment 72, wherein the prior treatment is adjuvant chemotherapy.

[0962] 74. The method of embodiment 72, wherein the prior treatment is neoadjuvant chemotherapy.

[0963] 75. The method of embodiment 67 or 68, wherein the prior treatment is endocrine therapy.

[0964] 76. The method of embodiment 67 or 68, wherein the prior treatment is radiation therapy.

[0965] 77. The method of any of embodiments 19 and 67-76, wherein the patient is non-responsive to prior therapy.

[0966] 78. The method of any of embodiments 1-77, wherein the patient is located in a geographic region selected from North America, Western Europe, or Oceania.

[0967] 79. The method of any of embodiments 1-78, wherein the patient is of Asian descent.

[0968] 80. The method of any of embodiments 1-79, wherein the patient is 18-45 years of age.

[0969] 81. The method of any of embodiments 1-79, wherein the patient is 45-54 years of age.

[0970] 82. The method of any of embodiments 1-79, wherein the patient is 54-64 years of age.

[0971] 83. The method of any of embodiments 1-79, wherein the patient is greater than 64 years of age.

[0972] 84. The method of any of embodiments 1-83, wherein the patient has a BMI of 25 or greater.

[0973] 85. The method of any of embodiments 1-83, wherein the patient has a BMI of less than 25.

[0974] 86. The method of any of embodiments 1-85, wherein the treatment improves the patient’s condition relative to a patient who does not receive the treatment and / or relative to the patient’s condition prior to treatment.

[0975] 87. The method of any of embodiments 1-86, wherein the treatment reduces the risk of invasive disease.

[0976] 88. The method of embodiment 87, wherein the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than 1 when the risk is calculated relative to a patient who does not receive the treatment.

[0977] 89. The method of embodiment 88, wherein the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.78 when the risk is calculated relative to a patient who does not receive the treatment.

[0978] 90. The method of any of embodiments 1-26 and 28-89, wherein the patient is a premenopausal female or male and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.72 when the risk is calculated relative to a patient who does not receive the treatment.

[0979] 91. The method of any one of embodiments 87-89, wherein the cancer is HR+ / HER2- stage III early stage breast cancer, and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.74 when the risk is calculated relative to a patient who does not receive the treatment.

[0980] 92. The method of any one of embodiments 87-89, wherein the cancer is HR+ / HER2- stage II early stage breast cancer, and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.76 when the risk is calculated relative to a patient who does not receive the treatment.

[0981] 93. The method of any one of embodiments 87-89, wherein the cancer is HR+ / HER2- stage III early stage breast cancer, and the treatment reduces the risk of invasive disease by at least 25% corresponding to a hazard ratio of 0.75 when the risk is calculated relative to a patient who does not receive the treatment.

[0982] 94. The method of any one of embodiments 1-93, wherein the treatment reduces the risk of invasive disease to a similar level in a patient subpopulation comprising a stage II early stage breast cancer patient, a stage III early stage breast cancer patient, a premenopausal female or male patient, and a postmenopausal female patient.

[0983] 95. The method of any one of embodiments 1-94, wherein the treatment does not result in a reduction in overall survival corresponding to a hazard ratio of 0.76 when the risk is calculated relative to a patient who does not receive the treatment.

[0984] 96. The method of any one of embodiments 1-95, wherein the treatment reduces and / or prevents one or more of recurrence of cancer, spread of cancer, occurrence and / or growth of additional cancer, and risk of death from cancer.

[0985] 97. The method of embodiment 96, wherein the treatment reduces recurrence of cancer, wherein the recurrence is one or more of invasive ipsilateral breast tumor recurrence (IBTR), loco-regional invasive recurrence, and distant recurrence.

[0986] 98. The method of embodiment 96, wherein the treatment reduces spread of cancer, wherein the spread of cancer is invasive contralateral breast cancer or additional primary invasive cancer.

[0987] 99. The method of any one of embodiments 1-98, wherein the treatment prevents death from cancer.

[0988] XI. definition

[0989] Unless otherwise indicated in the instances or otherwise apparent from their context, all numbers expressing quantities of ingredients, dosages, or reaction conditions used herein are to be understood as modified in all instances by the term "about," as would be construed by one of ordinary skill in the art in the field of the application. Unless otherwise indicated, the term "about," as used herein, means ± 10% of the indicated value.

[0990] "Adjuvant therapy" (or adjuvant treatment) refers to treatment given after initial treatment, for example, to reduce the risk of disease recurrence. In cancer, adjuvant therapy can be administered, among other things, to reduce the risk of cancer recurrence, for example, by destroying cancer cells that remain after initial treatment. For example, a treatment comprising a dose of ribociclib in combination with an aromatase inhibitor can be administered as adjuvant therapy after initial treatment, for example, comprising surgery, radiotherapy, and / or chemotherapy.

[0991] "Neoadjuvant therapy" (or neoadjuvant treatment) refers to treatment delivered before initial treatment. In cancer, neoadjuvant therapy can reduce the size of a tumor or kill cancer cells that have spread, among other things.

[0992] "Co-administer" or "co-administration" or the like is intended to encompass administration of the selected therapeutic agents to a single patient and encompasses treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.

[0993] "Combination" refers to either a fixed combination (also known as co-agent or combination partner), for example, in one dosage unit, or a non-fixed combination (or kit-of-parts) for combined administration wherein a first agent (also referred to as first therapeutic agent) and a second agent (also referred to as second therapeutic agent) can be administered independently at the same time or within time intervals that allow that the combination partners provide a cooperative (e.g., synergistic) effect. As used herein, the terms "co-administration" or the like is intended to encompass administration of the selected combination partners to a single subject (e.g., patient) in need thereof and is intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term "fixed combination" means that the active ingredients (e.g., combination partners) are both administered to a patient simultaneously in the form of a single entity. The term "non-fixed combination" or "kit-of-parts" means that the active ingredients (e.g., combination partners) are provided to a patient as separate entities either concurrently or sequentially with no specific time limits regarding their administration.

[0994] A "dose range" refers to the upper and lower limits of acceptable variation in the amount of a specified therapeutic agent. Typically, any amount of the agent within the specified range can be administered to a patient receiving treatment.

[0995] A "loading dose" can be an initial dose of a drug that can be given at or before the start of a course of treatment, and then dropped to a different, typically lower, dose (e.g., a therapeutic or maintenance dose). A loading dose can be a single dose or short-term regimen of a compound administered to a subject to rapidly increase the blood level of the drug. Suitably, a short-term regimen as used herein will be: 1 to 14 days; for example, 1 to 7 days; for example, 1 to 3 days; for example, three days; for example, two days; for example, one day. In some embodiments, a "loading dose" can increase the blood concentration of a drug to a therapeutically effective level. In some embodiments, a "loading dose" can increase the blood concentration of a drug to a therapeutically effective level in conjunction with a therapeutic dose of the drug. A "loading dose" can be administered once per day, or more than once per day (e.g., up to 4 times per day). In some embodiments, a loading dose can be used for a drug molecule that has a long half-life or is eliminated slowly in vivo.

[0996] A "pharmaceutical formulation" or "pharmaceutical composition" refers to a mixture or solution containing at least one therapeutic agent suitable for administering to a warm-blooded animal (e.g., a human).

[0997] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a mammal (e.g., a human) without an excessive level of toxicity, irritation, allergic response, and other problem or complication commensurate with a reasonable benefit / risk ratio.

[0998] A "subject," "patient," or "warm-blooded animal" is intended to include an animal. Examples of subjects include mammals, such as humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In certain embodiments, the subject is a human.

[0999] "Therapeutically effective" preferably relates to an amount of a therapeutic agent that is capable of providing a therapeutic response or prevention of progression of cancer in a subject. A therapeutically effective treatment or a therapeutically effective amount of treatment need not entirely cure the subject, but can partially or completely delay, ameliorate, reverse, or reduce at least one or more signs, symptoms, or manifestations of the disease.

[1000] “Treatment” or“treating” can be prophylactic and / or therapeutic (including, but not limited to, palliative, symptom-modifying, symptom-reducing) and delaying progression of a disease or condition (e.g., cancer). The term“prophylactic” means preventing or delaying the onset or recurrence of a disease (e.g., cancer). As used herein, the term“delaying progression” means administering the combination to a patient who is in a pre-stage or early stage of the cancer to be treated, who has been diagnosed with a precancerous form of the corresponding cancer, and / or who has been diagnosed with a condition that is likely to develop into the corresponding cancer.

[1001] “Tumor” refers to an abnormal mass of tissue. A tumor can include cancerous cells. If a tumor does not spread or invade nearby tissues or other parts of the body, it can be described as benign. If a tumor spreads to other tissues or parts of the body, it can be described as malignant.

[1002] XII. abbreviation

[1003]

[1004]

[1005]

[1006] XIII. References

[1007] All publications, patents, and patent applications mentioned herein are incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

[1008] XIV. Example

[1009] Hereinafter, the present application will be described in more detail and with particular reference to the examples, which are not intended to limit the present application.

[1010] a. Example 1. Overview of Clinical Trials

[1011] A clinical Phase 3 trial entitled“A Phase III, Multicenter, Randomized, Open-Label Trial to Evaluate the Efficacy and Safety of Ribociclib in Combination with Endocrine Therapy as Adjuvant Treatment in Patients with Hormone Receptor Positive, HER2 Negative, Early Breast Cancer” is described on ClinicalTrials.gov, Identifier: NCT03701334 (the entire disclosure of this webpage is incorporated herein by reference). The trial has been and is being conducted according to the protocol described below.

[1012] Study design: See Figure 1 .

[1013] Summary of the clinical protocol of the NATALEE trial (a neoadjuvant trial with ribociclib [LEE011])

[1014]

[1015]

[1016]

[1017]

[1018]

[1019]

[1020]

[1021] result

[1022] Results Overview

[1023] Interim analysis results of the NATALEE trial: Kisqali plus ET significantly reduced the risk of disease recurrence compared to standard endocrine therapy (ET) alone in the adjuvant setting.

[1024] NATALEE is the first and only positive Phase III study of a CDK4 / 6 inhibitor demonstrating consistent benefit of a CDK4 / 6 inhibitor in a broad population of patients with HR+ / HER2- early breast cancer (EBC) at risk of recurrence, including those without nodal involvement.

[1025] The primary endpoint of invasive disease-free survival (iDFS) was met. Kisqali plus ET significantly reduced the risk of disease recurrence compared to standard adjuvant ET alone, with consistent benefit in patients with II and III EBC, regardless of nodal involvement.

[1026]

[1027] Regarding safety, the trial confirmed a well-tolerated safety profile. Furthermore, the 400 mg dose of reboxil showed improved characteristics with lower overall toxicity, particularly dose-dependent adverse events (cardiac QT interval and neutropenia). No new safety findings were observed compared to the known and established safety profiles of reboxil therapy. The discontinuation rate due to adverse events within 3 years was similar in patients with early-stage breast cancer to that in patients with metastatic breast cancer. Diarrhea was not common compared to the earlier “monarch-E” trial. > 5% of patients experienced grade 3 or 4 adverse reactions, and no patients discontinued or reduced their reboxil dose as a result.

[1028] In summary, the iDFS in the RIB+ET group was significantly longer than that in the ET-only group (HR 0.748, p = 0.0014), with the 3-year iDFS rate increasing to 90.4% (compared to 87.1%). The iDFS benefit was consistent across different stratification factors and other subgroups. Secondary endpoints of overall survival, recurrence-free survival, and distant disease-free survival consistently favored the RIB+ET group. Furthermore, the addition of RIB had a favorable safety profile with no new signals. Overall, the addition of RIB to standard-of-care ET demonstrated a statistically and clinically significant improvement in iDFS, along with a well-tolerated safety profile. Therefore, combination therapy can be considered suitable for a broad population of stage II or III HR+ / HRE2- early breast cancer patients, including N0 patients whose cancer has not spread to nearby lymph nodes. This was unexpected based on results from other parallel studies.

[1029] Assessment of Health-Related Quality of Life (HRQOL) in NATALEE

[1030] QoL was analyzed after a median follow-up of 34 months. Approximately 20% of patients completed 3 years of reboxing and endocrine therapy.

[1031] Pre-defined analyses of HRQOL were based on patient-reported outcomes, which in turn were based on a number of survey scales: the EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire), for functional (physical, social, and emotional) and overall health status; the EORTC QLQ-BR23, for breast cancer symptoms; the EQ-VAS (Euro-QoL Visual Analogue Scale) of the EQ-5D-5L; and the Hamilton Anxiety and Depression Scale (see also the exemplary questionnaire). Figures 5-8 Compared to NSAI alone, HR+ / HER2- EBC patients who received reboxil as part of standard of care supplemented with NSAI maintained their HRQOL. Over time, both the reboxil + NSAI and NSAI alone groups maintained their physical function and overall health scores.

[1032] XV. Example 2. Test Plan

[1033] The NATALEE trial has been and is being conducted according to the protocol described in Appendix A.

[1034] XVI. Example 3. The first interpretable result and the updated analysis

[1035] The first interpretable results are described in Appendix B.

[1036] With an additional 5.6 months of follow-up (median follow-up of 33.3 months) and 78.3% of patients completing study treatment with Kisqali® (ribociclib), the updated analysis showed a continued iDFS benefit and stable secondary endpoints, including overall survival (OS).

[1037] The iDFS benefit was consistent across different key patient subgroups; in patients with stage II and III tumors, Kisqali reduced the risk by 30% and 24.5%, respectively.

[1038] The results reinforce the benefit observed in the earlier interim analysis, with a 25.1% reduction in the risk of disease recurrence (HR = 0.749; 95% CI: 0.628, 0.892; p = 0.0006) in patients with hormone receptor positive / human epidermal growth factor receptor 2 negative (HR+ / HER2-) stage II and III early breast cancer (EBC) compared with endocrine therapy (ET) alone, with adjuvant Kisqali plus a non-steroidal aromatase inhibitor as the standard ET.

[1039] In pre-specified subgroups, Kisqali showed iDFS benefit across all:

[1040] Data for Kisqali were also consistent across all secondary efficacy endpoints, including distant disease-free survival (DDFS) (25.1% reduction in risk) and recurrence-free survival (RFS) (27.3% reduction in risk). Overall survival (OS) results will continue to evolve over the long term, as both treatment arms had fewer than 4% events (3.3% in the Kisqali-ET arm and 3.4% in the ET alone arm).

[1041] In addition to laboratory abnormalities, the safety profile of Kisqali 400 mg dose was consistent with previously reported results, generally mild adverse events (AEs). Adverse events of special interest (Grade 3 or higher) were neutropenia (44.3%), liver-related AEs (such as transaminase elevation) (8.6%), and QT interval prolongation (1.0)1,2. No new safety signals were found.

[1042] XVII. Appendix A - Clinical Trial Protocol

[1043] Approximately 425 research centers globally will participate in the trial. The list of investigators participating in the trial will be maintained by Translational Research in Oncology (TRIO).

[1044] List of abbreviations

[1045]

[1046]

[1047]

[1048] Solution Summary

[1049]

[1050]

[1051]

[1052]

[1053]

[1054]

[1055]

[1056]

[1057]

[1058] 1. Background and Basic Principles

[1059] 1.1. Disease Overview

[1060] 1.1.1. Epidemiology

[1061] Breast cancer (BC) is the most commonly diagnosed cancer worldwide. An estimated 1.7 million new cases of BC and 52.2 million deaths attributed to the disease occurred globally in 2012. 1 BC incidence varies by ethnicity and geography worldwide, from 27 per 100,000 in Central Africa and East Asia to 92 per 100,000 in North America. 2 In the United States, BC is projected to be the most common cancer diagnosed in 2018, with an estimated 268,670 new cases and 41,400 deaths. 3 In 2012, the BC incidence in European countries was estimated at 458,337 cases. 4 BC is not common in men, accounting for approximately 1% of all BCs, but its incidence is continuing to rise. 5

[1062] The vast majority of newly diagnosed BC cases are early breast cancer (EBC), which is confined to the breast tissue and regional lymphatics and can be cured with local-regional treatment modalities such as surgery and radiotherapy. According to Surveillance, Epidemiology, and End Results (SEER) Program data collected between 1975 and 2012, 93% of diagnosed cases were EBC, of which 62% were confined to the breast tissue and 31% were confined to the breast tissue and regional lymph nodes. 6

[1063] 1.1.2. Treatment of EBC

[1064] In addition to primary surgical therapy, treatment of EBC often includes other anti-tumor approaches such as radiotherapy and adjuvant or neoadjuvant systemic therapy. Despite many EBC patients achieving disease-free status with surgical resection and radiotherapy, distant recurrence due to micrometastatic disease is common and a major cause of death in EBC patients. 7 According to a meta-analysis of nearly 150,000 women in 200 randomized clinical trials by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), approximately 36% and 20% of EBC patients who did not undergo any adjuvant systemic therapy will experience recurrence and BC-related death, respectively, during 5-year follow-up. 8 Furthermore, hormone receptor (HR)-positive EBC patients experience recurrence and BC-related death 5 years after surgery, with only 45% of patients reported to be recurrence-free at 15-year follow-up.

[1065] Adjuvant systemic therapy, including cytotoxic, biologic, and endocrine therapies, in EBC patients reduces local-regional and distant recurrence, decreases BC-induced mortality, and improves overall survival (OS). 8The need and choice of systemic adjuvant therapy is based on the individual's risk of recurrence and guided by a variety of clinical, pathological, and genomic predictive and prognostic factors of the tumor and patient, such as tumor stage, histopathological grade, tumor HR status, human epidermal growth factor receptor-2 (HER2) status, multigene test recurrence score, Ki67 and other proliferation markers, menopausal status, patient's comorbidities, age, etc. Using these factors, the risk of recurrence after EBC surgery can be classified as low, intermediate / intermediate, or high risk. 7 While there is no consensus on the definition of these risk groups, in general, patients with smaller tumors, no regional lymph node metastasis, low tumor grade, HR-positive and HER2-negative status, and low recurrence genomic score have a lower risk of recurrence (i.e., 5-year recurrence rate of 5-10%). These patients are generally considered for adjuvant endocrine therapy (ET) without chemotherapy, as the latter has a relatively lower clinical benefit than the former. On the other hand, patients with multiple regional lymph node metastasis, high tumor grade, HER2-positive status, or high recurrence genomic score have a higher risk of recurrence. These patients are generally considered for adjuvant chemotherapy (and HER2-targeted agents for HER2-positive BC patients), and adjuvant ET if the tumor expresses HR (usually after completion of chemotherapy).

[1066] It is estimated that 75% of BCs express steroid hormone receptors (estrogen receptor [ER] and / or progesterone receptor [PgR]), so these patients can benefit from adjuvant ET with tamoxifen or aromatase inhibitors (AIs) (letrozole, anastrozole, or exemestane). 9 ET, unlike chemotherapy, reduces the risk of recurrence and BC death in HR-positive EBC. 8

[1067] Current clinical guidelines for adjuvant ET in HR-positive EBC recommend: 10, 11

[1068] • For premenopausal women: • 5-10 years of tamoxifen treatment, with or without ovarian suppression, or • 5 years of AI treatment with ovarian suppression. 12 • For postmenopausal women: • Initial AI treatment for 5 years (or up to 10 years based on the results of the MA.17R trial 13 ), or • Initial tamoxifen treatment for 2-3 years followed by AI treatment (up to 5 years in total, or AI treatment for up to 5 years), or • Tamoxifen treatment for about 5 years followed by 5 years of AI treatment, or • Tamoxifen treatment for up to 10 years.10, 11 • For men: Limited data suggest that the combination of tamoxifen or an AI with a gonadotropin-releasing hormone (GnRH) agonist should be the preferred ET for HR-positive, HER2-negative EBC. 14 Despite the comprehensive study of EBC and the recent advances in multimodal management, recurrence remains common, especially in patients with poor clinical, pathological, and genomic features. In HR-positive, HER2-negative EBC patients with multiple (>4) regional lymph node metastases (roughly corresponding to anatomic stage III in the AJCC 8th edition breast cancer staging), about 25-30% of patients will relapse within 5 years of ET (including AI). 8 Despite 5 years of ET, only 48% of these patients are free of distant recurrence at 20 years, and almost half of the patients will die from BC within 20 years. 15 While patients with 1-3 regional lymph node metastases (typically corresponding to anatomic stage II in the AJCC 8th edition breast cancer staging) can have a lower risk of recurrence than patients with anatomic stage III, despite receiving ET, 31% of these patients will still experience distant recurrence, and 28% of these patients will die from BC within 20 years. 15 Thus, there is a need for new therapeutic strategies to improve the clinical outcome of HR-positive, HER2-negative EBC patients.

[1069] 1.1.3. The role of the CDK4 / 6 pathway in BC

[1070] Dysregulation of the CDK4 / 6-Rb-E2F pathway is an important contributing factor to ET resistance in BC. BC of luminal A and B subtypes (85% of which are ER-positive and HER2-negative) have a high rate of cyclin D / CDK activation; in luminal A and B subtypes, cyclin D1 (CCND1) amplification is observed in 29% and 58% of tumors, respectively, and CDK4 amplification is observed in 14% and 25% of tumors, respectively. 16, 17 Luminal A subtype tumors also have CDKN2A deletion, which encodes the CDK inhibitor pl6 INK4A . 18 Luminal subtypes also maintain Rb expression, which is key to benefiting from CDK4 / 6 inhibitor treatment. 19

[1071] Cell cycle checkpoint dysregulation can have clinical and therapeutic implications. For example, HR-positive BC patients exhibiting a gene expression signature of Rb loss have a shorter relapse-free survival (RFS) after tamoxifen adjuvant therapy. 20E2F-activated oncogene expression signatures are also associated with higher residual tumor cell proliferation after neoadjuvant AI therapy. Thus, activation of the CDK4 / 6-Rb-E2F pathway contributes to endocrine resistance, and treatment with CDK4 / 6 inhibitors or knockdown of CDK4 expression leads to reactivation of Rb, reassociation of E2F, and subsequent cell cycle arrest, thereby terminating the proliferation of endocrine-resistant cells.

[1072] Selective inhibitors of CDK4 / 6, such as palbociclib, abemaciclib, and ribociclib, have shown synergy with ET in preclinical studies, efficacy in clinical studies, and have been approved for initial therapy (in combination with an AI) or treatment after disease progression following prior ET (in combination with fulvestrant) in HR-positive, HER2-negative advanced BC patients 21-26 (Further information on the efficacy of ribociclib can be found in the most recent Ribociclib Investigator Brochure (IB)).

[1073] Given the efficacy of CDK4 / 6 inhibitors in HR-positive, HER2-negative advanced BC, co-targeting the CDK4 / 6-Rb-E2F pathway with CDK4 / 6 inhibitors might be a feasible strategy to improve endocrine responsiveness and prevent or delay the occurrence of acquired resistance, which should be explored in the adjuvant setting.

[1074] Ongoing clinical trials (PALLAS and monarchE) are investigating other CDK4 / 6 inhibitors in HR-positive, HER2-negative EBC, and emerging data from these trials suggest that treatment benefit in the adjuvant setting might be increased in patients with anatomic stage III compared to patients with anatomic stage II. 27, 28 The PALLAS trial investigated palbociclib in EBC of stage II (including a subset of patients at lower risk of stage IIA) and stage III, recently reported a negative outcome, while the monarchE trial investigating abemaciclib and seemingly including patients at stage III reported a positive outcome. While there are differences in the design of these two studies and the biochemical properties of the two CDK4 / 6 inhibitors investigated, early signs of a greater therapeutic effect of CDK4 / 6 inhibition in high-risk EBC at stage III cannot be ignored.

[1075] 1.2. Overview of Investigational Treatments and Other Experimental Treatments

[1076] This trial includes treatment with ribociclib (LEE011) and ET with a non-steroidal aromatase inhibitor (NSAI; anastrozole or letrozole) + / - goserelin.

[1077] 1.2.1. Overview of Ripocid

[1078] Ribociclib is an orally bioavailable and highly selective small-molecule inhibitor with nanomolar inhibitory activity highly specific for CDK4 / cyclin-D1 and CDK6 / cyclin-D3 enzyme complexes. As of the date of this document, ribociclib has been approved by several regulatory authorities, including the US Food and Drug Administration (FDA) and the European Commission. The FDA has approved it in combination with (1) AI for the treatment of pre- / perimenopausal or postmenopausal women with HR-positive, HER2-negative advanced or metastatic BC as initial endocrine-based therapy; or (2) fulvestrant for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic BC as initial endocrine-based therapy or after disease progression on ET. In Europe, ribociclib is indicated for the treatment of women with HR-positive, HER2-negative locally advanced or metastatic BC in combination with an AI as initial endocrine-based therapy or for women who have received prior ET. For pre- or perimenopausal women, ET should be combined with a gonadotropin-releasing hormone agonist.

[1079] 1.2.1.1. Non-clinical data

[1080] For detailed information, please refer to the latest Ribociclib IB.

[1081] 1.2.1.2. Clinical Experience

[1082] Ribociclib is being investigated in BC and other solid tumor patients in several clinical trials at different stages of development. For detailed information on clinical trials, please refer to the latest Ribociclib IB.

[1083] 1.2.1.2.1. Clinical safety of ribociclib

[1084] The clinical safety of ribociclib in combination with endocrine agents such as letrozole, tamoxifen, exemestane, fulvestrant and goserelin has been evaluated in several combination trials. The safety profile of ribociclib in combination with NSAI (+ / - goserelin) was investigated in two phase III trials (MONALEESA-2 and MONALEESA-7) in advanced BC. 24, 29

[1085] Based on the results of the MONALEESA-7 trial, the combination of ribociclib with tamoxifen is not recommended due to an increased risk of QT interval prolongation. 29

[1086] For a comprehensive review of the safety profile of ribociclib in combination with endocrine agents, please refer to the latest Ribociclib IB.

[1087] 1.2.1.2.2. Clinical efficacy of ribociclib

[1088] Three published phase III combination trials in patients with advanced BC have evaluated the efficacy of ribociclib in combination with endocrine agents, two of which evaluated ribociclib in combination with NSAI (+ / - goserelin). 24, 29

[1089] For more detailed information on the efficacy profile of ribociclib, please refer to the latest ribociclib IB.

[1090] 1.2.1.2.3. Clinical pharmacokinetics of ribociclib

[1091] A phase I study in patients with advanced solid tumors or lymphomas (study CLEE011X2101) evaluated the clinical pharmacokinetics (PK) of ribociclib. Ribociclib was absorbed after a single oral 400 mg capsule formulation with a median T max of 4.00 h (range: 0.58 to 4.20 h). After repeated oral administration daily, ribociclib reached steady state approximately on day 8. At steady state, the geometric mean of ribociclib plasma C max was 1040 ng / mL (geometric coefficient of variation [CV] 49.3%) and AUC 0-24h was 11400 ng h / mL (geometric CV 57.8%). The geometric mean of the effective T 1 / 2 of ribociclib was 31.6 h (geometric CV 33.2%) and the accumulation ratio was 2.46 (geometric CV 24.6%). LEQ803, an active metabolite of ribociclib, has similar PK characteristics to the parent drug. Neither ribociclib nor LEQ803 accumulated substantially after repeated administration daily.

[1092] Based on in vitro and in vivo studies, ribociclib is extensively metabolized in humans by CYP3A in the liver. In humans, ribociclib is mainly eliminated by hepatic clearance with a minor role of renal clearance. The majority of the administered dose is excreted in feces (69.1%) with a small amount excreted in urine (22.6%). Ribociclib accounts for approximately 23% of total radioactivity in plasma (CLEE011A2102). The most predominant metabolites in plasma are CCI284 (N-hydroxylation), LEQ803 (N-demethylation), and M1 (secondary glucuronide), each accounting for < 10% of total radioactivity. The clinical activity (pharmacology and safety) after ribociclib treatment is mainly attributed to the parent drug, with negligible contribution from circulating metabolites.

[1093] Concomitant use of reboxil with potent CYP3A4 inhibitors or inducers should be avoided, as reboxil exposure may be significantly affected. Following a single oral dose of 400 mg reboxil, co-administration with a potent CYP3A4 inhibitor (ritonavir) reduced the AUC of reboxil. inf Increased by 3.2 times (CLEE011A2101). Following a single oral dose of 600 mg reboxil, co-administration of a potent CYP3A4 inducer (rifampin) increased the AUC of reboxil by 3.2 times. inf Reduced by 89% (CLEE011A2101).

[1094] Reboxil is a moderate to potent inhibitor of CYP3A4, but has no substantial effect on CYP1A2 substrates in humans (CLEE011A2106). Co-administration of midazolam (a CYP3A4 substrate) with multiple doses of reboxil (400 mg) increased midazolam exposure by 3.8-fold. Co-administration of caffeine (a CYP1A2 substrate) with multiple doses of reboxil (400 mg) increased caffeine exposure by 20% (1.2-fold). Concomitant use with sensitive CYP3A4 substrates with narrow therapeutic indices should be avoided. Concomitant use of CYP1A2 substrates is not expected to lead to clinically significant drug-drug interactions (DDIs).

[1095] Food does not affect the pharmacokinetic (PK) of reboxed or tableted reboxes; therefore, reboxed capsules or tablets can be taken without regard to meals (CLEE011A2111, CLEE011A2103).

[1096] Based on pharmacokinetic (PK) data from the MONALEESA-2 and MONALEESA-7 trials, no significant dose-discrimination (DDI) was observed between reboxil and its concomitant adjuvants letrozole or anastrozole. Based on population PK analysis, concomitant use of letrozole or anastrozole had no effect on reboxil exposure.

[1097] For more detailed information, please refer to the latest Riposey IB.

[1098] 1.2.2. Overview of Adjunctive Endocrine Therapy

[1099] Tamoxifen, NSAI (letrozole, anastrozole), and steroid AI (exemestane) are used as adjunctive ET in women with HR-positive EBC. AIs can be used as pre-treatment or after 2–3 or 5 years of prior tamoxifen use (see Section 1.1.2). The long-term efficacy of both AI administration methods is similar. 30The clinical treatment guidelines recommend that there is no compelling evidence of a meaningful clinical efficacy or toxicity difference between letrozole, anastrozole, and exemestane, and therefore similar precautions and monitoring activities should be taken regardless of the type of AI administered. 11 GnRH agonists are used to achieve gonadal suppression in premenopausal women or men.

[1100] The following sections provide general information about NSAI and goserelin. For comprehensive safety and efficacy information and guidance for each drug, refer to the current local prescribing information and local clinical guidelines.

[1101] 1.2.2.1. Overview of Letrozole

[1102] Letrozole is a non-steroidal competitive inhibitor of the aromatase system. Letrozole exerts its action by highly selective inhibition of the conversion of androgens (mainly from the adrenal gland, the main source of estrogens in postmenopausal women) to estrogens. A decrease of 75% to 95% in estrogen levels is induced after two weeks of treatment with letrozole at a daily dose of 0.1 to 5 mg, with no significant clinical and laboratory toxicities or changes in the levels of other hormones of the endocrine system. 31, 32

[1103] Letrozole is administered orally once a day at a dose of 2.5 mg. It is rapidly and completely absorbed from the gastrointestinal (GI) tract. The extent of absorption of letrozole is not affected by the ingestion of food at the same time. Letrozole is metabolized by CYP3A4 to a pharmacologically inactive metabolite, and the renal excretion of glucuronide conjugate of this metabolite is the main route of clearance of letrozole.

[1104] In the Ib / II phase dose escalation / expansion study (CLEE011X2107), letrozole (2.5 mg / day) and ribociclib (600 mg / day, 3 weeks on / 1 week off) do not affect each other's metabolism.

[1105] In adjuvant and extended adjuvant clinical trials, the most frequently reported adverse events (AEs) with letrozole were hot flashes, arthralgia / arthritis, and myalgia. In general, the intensity of the adverse reactions observed was mild to moderate. Adjuvant use of letrozole (or anastrozole) is associated with a decrease in bone mineral density, which can lead to osteoporosis and related bone fractures. Monitoring of bone mineral density should be considered.

[1106] Due to its mechanism of action, women with intact ovarian function or non-castrated men should not use letrozole and other AIs for the indications mentioned above.

[1107] For more information on letrozole, refer to the current local prescribing information.

[1108] 1.2.2.2. Anastrozole Overview

[1109] Anastrozole, like letrozole, is a selective NSAI. It significantly reduces serum estradiol concentrations with no detectable effect on the formation of adrenocortical steroids or aldosterone.

[1110] Anastrozole is administered orally once daily at a dose of 1 mg with or without food. Anastrozole is metabolized by N-dealkylation, hydroxylation, and glucuronidation. Hepatic metabolism accounts for approximately 85% of anastrozole elimination. Renal elimination accounts for approximately 10% of the total clearance. The major circulating metabolite of anastrozole lacks pharmacological activity. Based on in vitro data, anastrozole metabolism is primarily mediated by CYP3A4 and UGT1A4. 33 Therefore, anastrozole metabolism can be affected by the coadministration of ribociclib. However, the doses of anastrozole studied were up to 10 mg / day (10 times the daily dose), and all doses evaluated were well tolerated, with no serious acute toxicity attributed to anastrozole. 34

[1111] For more information on anastrozole, refer to the current local prescribing information.

[1112] 1.2.2.3. Overview of GnRH agonists

[1113] GnRH agonists are synthetic analogs of gonadotropin-releasing hormone that desensitize the pituitary gland to GnRH by continuous stimulation of the GnRH receptor. GnRH agonists differ from naturally occurring GnRH by modification of the decapeptide structure (usually by amino acid substitution at position 6, but also at positions 9 and 10) to reduce degradation of the molecule.

[1114] Goserelin is the GnRH agonist used in this trial. The most common AEs occurring in women receiving goserelin therapy include hot flashes, headache, sweating, acne, emotional burden, depression, decreased libido, vaginitis, breast atrophy, seborrhea, and peripheral edema. In men, goserelin can be associated with hot flashes, sexual dysfunction, decreased erections, and lower urinary tract symptoms.

[1115] For more information on goserelin, refer to the current local prescribing information and / or clinical guidelines.

[1116] 1.3. Basic Principles

[1117] 1.3.1. Basic Principles of Conducting Experiments

[1118] While adjuvant ET for HR-positive EBC is effective in reducing the risk of recurrence and improving survival, recurrence is still common, especially in patients with intermediate or high risk features for recurrence, such as patients with features such as anatomic stage group II and III. These recurrences are mostly in the form of distant metastases, often incurable, and ultimately leading to BC death. 15

[1119] The addition of ribociclib to ET has been shown to have clinical efficacy and tolerable toxicity profile in HR-positive, HER2-negative advanced BC; therefore, the addition of ribociclib in the adjuvant setting can prolong invasive disease-free survival (iDFS) in HR-positive, HER2-negative EBC patients with intermediate-high risk of recurrence by increasing the primary endocrine responsiveness and preventing or delaying the development of ET acquired resistance.

[1120] The objective of this randomized, open-label trial is to evaluate the impact of the addition of ribociclib to standard adjuvant ET on iDFS in EBC patients who are HR-positive, HER2-negative, and have anatomic stage group III, IIB, or a subset of cases of IIA stage, as defined in inclusion criterion #8.

[1121] 1.3.2. Basic principles of experimental design

[1122] This is a phase III, multicenter, randomized, open-label trial evaluating the addition of ribociclib to standard adjuvant ET in HR-positive, HER2-negative EBC women and men. Adjuvant ET in postmenopausal women in the trial will employ NSAI (letrozole, anastrozole), and adjuvant ET in premenopausal women and men will employ NSAI in combination with goserelin.

[1123] The randomized, stratified, multicenter design of this trial balances known and unknown prognostic factors at the time of treatment assignment, minimizing allocation bias.

[1124] In this open-label trial, proper adjudication of outcomes, especially the primary endpoint, is critical to the validity of the trial results. To reduce bias, the primary endpoint selected is objective (iDFS), and standardized definitions will be used (STEEP system according to the Standardized Definitions of Efficacy Endpoints in Adjuvant Breast Cancer Trials). 35In addition, iDFS events are not based on clinical or radiological assessment alone, but are histologically or cytologically confirmed (unless the procedure would pose an unacceptable risk to the patient), and thus require objective confirmation to be considered an iDFS event. Furthermore, if a patient discontinues trial treatment for reasons other than distant recurrence, then recurrence assessment should continue according to the STEEP criteria until distant recurrence. All of these elements support the validity and objectivity of the basic recurrence assessment for the iDFS endpoint and ensure that the trial results are not influenced by an open-label design. In addition, since ribociclib is associated with a rate of neutropenia of approximately 75% 36 Thus, concealing treatment assignment can not be effective.

[1125] The trial will include premenopausal and postmenopausal women and men with HR-positive, HER2-negative EBC who are anatomical stage group III, IIB, or a subset of IIA cases (as defined in Enrolment Criterion #8) with a high risk of recurrence. These anatomical stage groups include (most) tumours with regional lymph node metastases and / or large primary lesions that, despite ET, have a high risk of recurrence and can benefit from the addition of ribociclib.

[1126] Ki67 or gene expression tests (if available) will be used to identify patients with lymph node-negative IIA anatomical stage and grade 2 histology who are considered at high risk. Although the reproducibility of Ki67 index is poor, it is widely used globally for the prognostic estimation of ER-positive, HER2-negative EBC and to guide adjuvant treatment selection decisions. Although the cut-off values used to define high Ki67 index lack standardization and have variability, its prognostic or predictive value has been confirmed in multiple studies. 37 A 20% cut-off is considered suitable for stratification of high-risk patients with ER-positive, HER2-negative EBC. 38, 39 Gene expression tests that evaluate the BC genomic risk category provide the clinician with prognostic information that aids in individualized treatment and have been widely adopted, especially for identifying those patients with a good prognosis who do not require adjuvant chemotherapy. 10, 11, 40, 41 Given the good prognosis of some IIA anatomical stage patients compared to IIB or III anatomical stage patients, only patients with lymph node-negative IIA stage tumours that are grade 3 or grade 2 and have a high Ki67 index (≥ 20%) or are considered high risk by a validated gene expression test (as defined in Enrolment Criterion #8) will be included.

[1127] Emerging data from other CDK4 / 6 inhibitor EBC trials suggest that the treatment benefit is increased in anatomical stage III group patients, with an upper limit of approximately 2,000 patients with stage II disease in a total study population of approximately 5,000 patients.

[1128] Pre-menopausal and post-menopausal women will be included as there is no expected difference in efficacy and safety of ribociclib in these populations. To reduce potential differences in clinical outcomes between pre-menopausal and post-menopausal women, stratification by menopausal status will be employed.

[1129] Classification into AJCC 8th edition anatomic stage groups requires determination of T, N, and M categories. Axillary lymph node dissection (ALND) is the preferred method for axillary lymph node staging; however, sentinel lymph node (SLN) dissection can be used to determine the N-category in certain patients (see Enrollment Criteria #8).

[1130] In the ACOSOG Z0011 clinical trial, patients with metastatic SLN were randomized to receive ALND or no additional surgery, and based on the results of this trial, SLN dissection without subsequent ALND in the setting of a positive SLN became an acceptable practice for selected patients. The trial demonstrated comparable 5-year disease-free survival (83.9% for SLN dissection only vs. 82.2% for SLN dissection followed by ALND) and OS (92.5% vs. 91.8%, respectively) for the two groups, and fewer surgical complications with SLN dissection only. 42

[1131] While this approach has been recommended by some clinical guidelines and consensus and is listed as an option for the management of axillary surgery in eligible patients 10, 11, 43, 44 However, omitting ALND makes accurate staging of BC more challenging. Since approximately 85% of patients in the ALND arm of Z0011 had N1 disease, patients who meet the trial eligibility criteria (T1-T2, < 3 metastatic SLN, no clinically apparent nodal disease preoperatively, no apparent extranodal tumor extension, no neoadjuvant systemic therapy, and breast tumor resection and adjuvant radiotherapy) can be considered N-category N1.

[1132] Randomization will be stratified by menopausal status, anatomic stage group, use of prior neoadjuvant / adjuvant chemotherapy, and geographic region (see Section 3.1). Menopausal status was chosen as a stratification factor because it can reflect different treatment options and prognosis. Since the relapse rate can be higher in men and pre-menopausal women than in post-menopausal women, and the number of men is expected to be too small to make it a separate stratum, pre-menopausal women will be combined with male patients in the same stratum. Finally, since neoadjuvant or adjuvant chemotherapy can reduce the relapse of HR-positive EBC (with no significant difference in non-relapse survival between adjuvant and neoadjuvant chemotherapy), randomization will also be stratified according to whether the patient has ever received any neoadjuvant / adjuvant chemotherapy.

[1133] The primary efficacy of the investigational intervention will be evaluated by its impact on iDFS, as defined in the STEEP (Standardized Definitions of Endpoints in Effect) system. 35 The iDFS definition in the STEEP system is broad, clinically relevant, and includes the most commonly accepted DFS events in the published EBC trials.

[1134] 1.3.3. Basic Principles of Regimen and Dosage Selection

[1135] In a clinical trial in patients with advanced BC, the use of 600 mg / day dose of ribociclib in combination with ET was shown to be tolerable and effective on days 1-21 of a 28-day cycle (see Section 1.2.1.2).

[1136] Due to the late time to recurrence in HR-positive, HER2-negative EBC, most of the recurrence events are observed from one year after surgery and continue for at least 15 years from diagnosis, therefore a short period of adjuvant ribociclib treatment can not be sufficient to detect a meaningful impact on the recurrence rate. 45 Therefore, in order to provide sufficient ribociclib exposure in this trial while balancing the potential toxicity of long-term treatment, ribociclib (in combination with ET) will be administered for 36 months at a dose of 400 mg / day on days 1-21 of a 28-day cycle. This schedule and duration of ribociclib therapy should be sufficient to detect a meaningful impact on the recurrence rate.

[1137] PK-QTcF (PK-ECG QT interval corrected according to the Fridericia formula) and PK-ANC (PK-absolute neutrophil count) modeling indicated that QTcF interval prolongation and neutropenia are related to the concentration of ribociclib. Post-hoc exploratory analyses indicated that patients who started with 600 mg ribociclib followed by dose reduction to 400 mg and 200 mg continued to benefit in terms of efficacy (progression-free survival [PFS] and overall response rate [ORR]). In order to reduce the incidence of QTc interval prolongation, neutropenia and other AEs, this trial will explore a lower dose of ribociclib, i.e. 400 mg once daily for 3 weeks on / 1 week off in a 28-day cycle, in patients with HR-positive, HER2-negative EBC.

[1138] Regarding the risk of QTcF interval prolongation, the mean ΔQTcF values ​​were consistent across the MONALEESA-2, MONALEESA-3, and MONALEESA-7 trials. The ΔQTcF interval prolongation relative to baseline was 19.6 msec, 20.6 msec, and 18.6 msec, respectively, 2 hours after administration on day 15 of cycle 1 (C1D15) in MONALEESA-2, MONALEESA-3, and MONALEESA-7 (NSAI subgroups). Based on the highest ECG values ​​in any assessment, newly observed post-baseline QTcF > 480 msec was observed in 23 (6.9%), 27 (5.6%), and 13 (5.3%) patients in the reboxil group, respectively, in MONALEESA-2, MONALEESA-3, and MONALEESA-7 (NSAI subgroups). Although clinical sequelae are uncommon, there is an opportunity to reduce the risk of this event because clinical trials have shown that reboxil-induced QTcF interval prolongation is concentration-dependent (reboxil IB 2017). Based on PK-QTcF modeling, lower estimated daily reboxil dose...

Claims

1. A method of treating HR+ / HER2- stage II or stage III early stage breast cancer in an adult patient in need thereof, comprising administering to the patient a treatment comprising a dose ranging from 150 mg / day to 450 mg / day of ribociclib, a free base form thereof, or a pharmaceutically acceptable salt thereof, on days 1-21 of a 28-day cycle, in combination with an aromatase inhibitor administered every day of a 28-day cycle, preferably letrozole or anastrozole.

2. A method of preventing or reducing signs or symptoms of early stage breast cancer, comprising administering to the patient a treatment comprising ribociclib, a free base form thereof, or a pharmaceutically acceptable salt thereof, in combination with an aromatase inhibitor, preferably letrozole or anastrozole.

3. The method of claim 2, wherein the ribociclib, a free base form thereof, or a pharmaceutically acceptable salt thereof, is administered to the patient at a dose ranging from 150 mg / day to 450 mg / day on days 1-21 of a 28-day cycle.

4. The method of claim 2 or 3, wherein the aromatase inhibitor is administered every day of the 28-day cycle.

5. A method of preventing or reducing signs or symptoms of early stage breast cancer, comprising administering to the patient a treatment comprising a dose ranging from 150 mg / day to 450 mg / day of ribociclib, a free base form thereof, or a pharmaceutically acceptable salt thereof, on days 1-21 of a 28-day cycle, in combination with an aromatase inhibitor administered every day of a 28-day cycle, preferably letrozole or anastrozole.

6. The method of any one of claims 1 to 5, wherein the patient is in remission from HR+ / HER2- stage II or stage III early stage breast cancer.

7. A method of maintaining remission in an adult patient previously diagnosed with HR+ / HER2- stage II or stage III early stage breast cancer, comprising administering to the patient a treatment comprising a dose of ribociclib, a free base form thereof, or a pharmaceutically acceptable salt thereof, in combination with an aromatase inhibitor, preferably letrozole or anastrozole.

8. The method of claim 6 or claim 7, wherein the remission is complete remission.

9. The method of claim 6 or claim 7, wherein the remission is partial remission.

10. The method of any one of claims 1 to 9, wherein the treatment reduces recurrence of HR+ / HER2- stage II or stage III early stage breast cancer.

11. The method of claim 10, wherein the treatment prevents recurrence for at least 3 months.

12. The method of claim 11, wherein the treatment prevents recurrence for at least 6 months.

13. The method of claim 12, wherein the treatment prevents recurrence for at least 1 year.

14. The method of any one of claims 1 to 13, wherein the patient has no signs or symptoms of cancer prior to receiving the treatment.

15. The method of any one of claims 1 to 14, wherein the treatment prevents growth of HR+ / HER2- breast cancer cells.

16. The method of any one of claims 1 to 15, wherein the treatment is adjuvant therapy.

17. The method of any one of claims 1 to 16, wherein the romosilast is a pharmaceutically acceptable salt of romosilast.

18. The method of claim 17, wherein the romosilast salt is romosilast succinate.

19. The method of any one of claims 1 to 18, wherein the dose of romosilast is 200 mg / day or 400 mg / day.

20. The method of any one of claims 1 to 18, wherein the romosilast is not administered at a dose of 600 mg / day.

21. The method of any one of claims 1 to 19, wherein romosilast is administered as romosilast succinate and the total dose of romosilast is 200 mg / day.

22. The method of any one of claims 1 to 19, wherein romosilast is administered as romosilast succinate and the total dose of romosilast is 400 mg / day.

23. The method of any one of claims 1 to 19, wherein the romosilast is administered at a dose of 400 mg / day for a period of time followed by administration of romosilast at a dose of 200 mg / day.

24. The method of any one of claims 1 to 23, wherein the dose of romosilast is administered orally.

25. The method of any one of claims 1 to 24, wherein the dose of romosilast is administered as a tablet.

26. The method of any one of claims 1 to 24, wherein the aromatase inhibitor is letrozole or anastrozole.

27. The method of any one of claims 1 to 26, wherein the aromatase inhibitor is administered orally.

28. The method of claim 26 or 27, wherein the letrozole is administered at a dose ranging from 1 mg / day to 4 mg / day.

29. The method of claim 28, wherein the letrozole is administered at a dose of 2.5 mg / day.

30. The method of claim 26 or 27, wherein the anastrozole is administered at a dose ranging from 0.5 mg / day to 1.5 mg / day.

31. The method of claim 30, wherein the anastrozole is administered at a dose of 1 mg / day.

32. The method of any one of claims 1 to 31, wherein the treatment comprises a gonadotropin-releasing hormone agonist.

33. The method of claim 32, wherein the gonadotropin-releasing hormone agonist is goserelin.

34. The method of claim 33, wherein the goserelin is administered at a dose ranging from 2 mg to 5 mg.

35. The method of claim 34, wherein the dose of goserelin is 3.6 mg.

36. The method of any one of claims 33 to 35, wherein the goserelin is administered subcutaneously.

37. The method of any one of claims 33 to 36, wherein the goserelin is administered once every 4 weeks.

38. The method of any one of claims 1 to 31, wherein the patient is a postmenopausal woman.

39. The method of any one of claims 1 to 37, wherein the patient is a premenopausal woman or a man.

40. The method of any one of claims 1 to 39, wherein the treatment is administered to the patient for at least 12 months.

41. The method of claim 40, wherein the treatment is administered to the patient for at least 24 months.

42. The method of claim 40 or claim 41, wherein the treatment is administered to the patient for at least 36 months.

43. The method of any one of claims 40 to 41, wherein the treatment is administered to the patient for at least 48 months.

44. The method of any one of claims 40 to 41, wherein the treatment is administered to the patient for at least 60 months.

45. The method of any one of claims 1 to 44, wherein the treatment continues until the patient is free of detectable cancer.

46. The method of any one of claims 1 to 45, wherein the breast cancer is ER+ and PR+.

47. The method of any one of claims 1 to 45, wherein the breast cancer is ER- and PR+.

48. The method of any one of claims 1 to 45, wherein the breast cancer is ER+ and PR-.

49. The method of any one of claims 1 to 48, wherein the histological subtype of the breast cancer is a ductal subtype or its histological subtype is a lobular subtype.

50. The method of any one of claims 1 to 49, wherein the breast cancer is a stage IIA cancer or a stage IIB cancer.

51. The method of claim 50, wherein the breast cancer is a stage IIA cancer.

52. The method of claim 50, wherein the breast cancer is a stage IIB cancer.

53. The method of any one of claims 1 to 49, wherein the breast cancer is a stage IIIA cancer, a stage IIIB cancer, or a stage IIIC cancer.

54. The method of claim 53, wherein the breast cancer is a stage IIIA cancer.

55. The method of claim 53, wherein the breast cancer is a stage IIIB cancer.

56. The method of claim 53, wherein the breast cancer is a stage IIIC cancer.

57. The method of any one of claims 1 to 56, wherein the administration of the treatment is irrespective of the lymph node status of the breast cancer.

58. The method of any one of claims 1 to 57, wherein the breast cancer has a lymph node status selected from the group consisting of NO, N1, N2, and N3.

59. The method of claim 57 or 58, wherein the breast cancer has a lymph node status of NO.

60. The method of claim 57 or 58, wherein the breast cancer has a lymph node status of N1 to N3.

61. The method of claim 57 or 58, wherein the breast cancer has a lymph node status of N1.

62. The method of claim 57 or 58, wherein the breast cancer has a lymph node status of N2.

63. The method of claim 57 or 58, wherein the breast cancer has a lymph node status of N3.

64. The method of any one of claims 1 to 63, wherein the breast cancer comprises one or more cells having a histological grade selected from G1, G2, or G3.

65. The method of claim 64, wherein the breast cancer comprises one or more cells having a histological grade of G1.

66. The method of claim 64, wherein the breast cancer comprises one or more cells having a histological grade of G2.

67. The method of claim 64, wherein the breast cancer comprises one or more cells having a histological grade of G3.

68. The method of any one of claims 1 to 67, wherein the breast cancer comprises a tumor of T0, T1, T2, T3, or T4 category.

69. The method of claim 68, wherein the breast cancer comprises a tumor of T1, T2, or T3 category.

70. The method of claim 68, wherein the breast cancer comprises a tumor of T0 category.

71. The method of claim 68 or 69, wherein the breast cancer comprises a tumor of T1 category.

72. The method of claim 68 or 69, wherein the breast cancer comprises a tumor of T2 category.

73. The method of claim 68 or 69, wherein the breast cancer comprises a tumor of T3 category.

74. The method of claim 68, wherein the breast cancer comprises a tumor of T4 category.

75. The method of any one of claims 1 to 74, wherein the breast cancer has a Ki67 status of 20 or less.

76. The method of any one of claims 1 to 74, wherein the breast cancer has a Ki67 status of greater than 20.

77. The method of any one of claims 1 to 76, wherein the patient received a loading dose of (i) ribociclib and / or (ii) endocrine therapy prior to the administration.

78. The method of any one of claims 1 to 77, wherein the patient received at least one prior treatment for cancer.

79. The method of claim 78, wherein the prior treatment is an adjuvant treatment following another prior treatment.

80. The method of claim 78 or 79, wherein the prior treatment is surgery.

81. The method of claim 80, wherein the surgery comprises complete surgical resection of the cancer.

82. The method of claim 80 or 81, wherein the surgery is a mastectomy.

83. The method of claim 80 or 81, wherein the prior treatment is chemotherapy.

84. The method of claim 83, wherein the prior treatment is adjuvant chemotherapy.

85. The method of claim 83, wherein the prior treatment is neoadjuvant chemotherapy.

86. The method of claim 78 or 79, wherein the prior treatment is endocrine therapy.

87. The method of claim 78 or 79, wherein the prior treatment is radiation therapy.

88. The method of any one of claims 78 to 87, wherein the patient did not respond to the prior treatment.

89. The method of any one of claims 1 to 88, wherein the patient is located in a geographic region selected from North America, Western Europe, or Oceania.

90. The method of any one of claims 1 to 89, wherein the patient is of Asian descent.

91. The method of any one of claims 1 to 90, wherein the patient is 18 to 45 years of age.

92. The method of any one of claims 1 to 90, wherein the patient is 45 to 54 years of age.

93. The method of any one of claims 1 to 90, wherein the patient is 54 to 64 years of age.

94. The method of any one of claims 1 to 90, wherein the patient is greater than 64 years of age.

95. The method of any one of claims 1 to 94, wherein the patient has a BMI of 25 or greater.

96. The method of any one of claims 1 to 94, wherein the patient has a BMI of less than 25.

97. The method of any one of claims 1 to 96, wherein the treatment improves the patient’s condition relative to a patient who does not receive the treatment and / or relative to the patient’s condition prior to treatment.

98. The method of any one of claims 1 to 97, wherein the treatment reduces the risk of the aggressive disease.

99. The method of claim 98, wherein the treatment reduces the risk of the aggressive disease corresponding to a hazard ratio of less than 1 when the risk is calculated relative to a patient who does not receive the treatment.

100. The method of claim 99, wherein the treatment reduces the risk of the aggressive disease corresponding to a hazard ratio of less than or equal to 0.78 when the risk is calculated relative to a patient who does not receive the treatment.

101. The method of any one of claims 1 to 37 and 39 to 100, wherein the patient is a premenopausal woman or man and the treatment reduces the risk of the aggressive disease corresponding to a hazard ratio of less than or equal to 0.72 when the risk is calculated relative to a patient who does not receive the treatment.

102. The method of any one of claims 98 to 100, wherein the patient has HR+ / HER2- stage III early stage breast cancer and the treatment reduces the risk of the aggressive disease corresponding to a hazard ratio of less than or equal to 0.74 when the risk is calculated relative to a patient who does not receive the treatment.

103. The method of any one of claims 98 to 100, wherein the patient has HR+ / HER2- stage II early stage breast cancer and the treatment reduces the risk of the aggressive disease corresponding to a hazard ratio of less than or equal to 0.76 when the risk is calculated relative to a patient who does not receive the treatment.

104. The method of any one of claims 98 to 100, wherein the patient has HR+ / HER2- stage III early stage breast cancer, and the treatment reduces the risk of the invasive disease by at least 25%, corresponding to a hazard ratio of 0.75 when the risk is calculated relative to a patient who did not receive the treatment.

105. The method of any one of claims 1 to 104, wherein the treatment reduces the risk of the invasive disease to a similar level in a subset of patients comprising a patient with stage II early stage breast cancer, a patient with stage III early stage breast cancer, a premenopausal female or male patient, and a postmenopausal female patient.

106. The method of any one of claims 1 to 105, wherein the treatment does not result in a reduction in overall survival, corresponding to a hazard ratio of 0.76 when the risk is calculated relative to a patient who did not receive the treatment.

107. The method of any one of claims 1 to 106, wherein the treatment reduces and / or prevents one or more of a risk of cancer recurrence, cancer spread, additional cancer development and / or growth, and cancer-caused death.

108. The method of claim 107, wherein the treatment reduces cancer recurrence, wherein the recurrence is one or more of invasive ipsilateral breast tumor recurrence (IBTR), loco-regional invasive recurrence, and distant recurrence.

109. The method of claim 107 or claim 108, wherein the treatment reduces cancer spread, wherein the cancer spread is invasive contralateral breast cancer or additional primary invasive cancer.

110. The method of any one of claims 1 to 109, wherein the treatment prevents cancer-caused death.

111. A method of maintaining remission in an adult patient previously diagnosed with HR+ / HER2- stage II or stage III early stage breast cancer, the method comprising administering to the patient a treatment comprising a dosage ranging from 150 mg / day to 450 mg / day of ribociclib, its free base form, or a pharmaceutically acceptable salt thereof, in combination with an aromatase inhibitor administered every day of a 28-day cycle, preferably letrozole or anastrozole, on days 1-21 of the 28-day cycle.

112. A method of preventing breast cancer recurrence in an adult patient, the method comprising providing an adjuvant treatment to a patient who received a prior treatment for HR+ / HER2- stage II or stage III early stage breast cancer, wherein the adjuvant treatment comprises administering 400 mg of ribociclib, or a pharmaceutically acceptable salt thereof, to the patient on days 1 to 21 of a 28-day cycle for at least 36 months, in combination with an aromatase inhibitor administered every day of the 28-day cycle as defined in any one of claims 26 to 31.

113. The method of claim 112, wherein the prior treatment is surgical resection of the cancer.

114. Ribociclib, or a pharmaceutically acceptable salt thereof, and an aromatase inhibitor for use in a method of treating HR+ / HER2- Stage II or III early stage breast cancer in an adult patient, wherein the method is a method of any one of claims 1 to 112.

115. Use of ribociclib, or a pharmaceutically acceptable salt thereof, and an aromatase inhibitor in the manufacture of a medicament for treating HR+ / HER2- Stage II or III early stage breast cancer in an adult patient, wherein the medicament is for administration by a method of any one of claims 1 to 112.

116. A kit for performing a method of treating HR+ / HER2- Stage II or III early stage breast cancer in an adult patient according to any one of claims 1 to 112.

117. A method of treating HR+ / HER2- Stage II or III early stage breast cancer in an adult patient in remission, the method comprising administering to the adult patient a combination of ribociclib and an aromatase inhibitor, whereby the administration maintains the adult patient in remission for at least 3 months.

118. A method of treating HR+ / HER2- Stage II or III early stage breast cancer in an adult patient, the method comprising providing adjuvant therapy by administering a combination of ribociclib and an aromatase inhibitor, wherein the patient is in complete remission at the start of the adjuvant therapy, and the administration of the combination of ribociclib and an aromatase inhibitor maintains the adult patient in complete remission for at least 3 months.

119. The method of claim 117 or 118, wherein the administration maintains the adult patient in complete remission for at least 6 months.

120. The method of claim 117 or 118, wherein the administration maintains the adult patient in complete remission for at least 9 months.

121. The method of claim 117 or 118, wherein the administration maintains the adult patient in complete remission for at least 12 months.

122. The method of claim 117 or 118, wherein the administration maintains the adult patient in complete remission for at least 15 months.

123. The method of claim 117 or 118, wherein the administration maintains the adult patient in complete remission for at least 18 months.

124. The method of claim 117 or 118, wherein the administration maintains the adult patient in complete remission for at least 21 months.

125. The method of claim 117 or 118, wherein the administration maintains the adult patient in complete remission for at least 24 months.

126. The method of claim 117 or 118, wherein the administration maintains the adult patient in complete remission for at least 27 months.

127. The method of claim 117 or 118, wherein the administration maintains the adult patient in complete remission for at least 30 months.

128. The method of claim 117 or 118, wherein the administration maintains the adult patient in complete remission for at least 33 months.

129. The method of claim 117 or 118, wherein the administration maintains the adult patient in complete remission for at least 36 months.

130. The method of any one of claims 117 to 129, wherein a dose of ribociclib and an aromatase inhibitor are administered for a treatment duration, and the administration maintains the adult patient in complete remission for at least the treatment duration.

131. The method of any one of claims 117 to 129, wherein a 400 mg dose of ribociclib is administered orally once daily on days 1-21 of a 28-day cycle, and an aromatase inhibitor is administered once daily on each day of the 28-day cycle.

132. The method of any one of claims 117 to 129, wherein a 400 mg dose of ribociclib is administered orally once daily on days 1-21 of a 28-day cycle, for a treatment duration of up to three years, and an aromatase inhibitor is administered once daily on each day of the 28-day cycle for up to three years.

133. The method of any one of claims 117 to 129, wherein a 400 mg dose of ribociclib is administered orally once daily on days 1-21 of a 28-day cycle, for a treatment duration of up to five years, and an aromatase inhibitor is administered once daily on each day of the 28-day cycle for up to five years.

134. The method of any one of claims 117 to 133, wherein a pharmaceutically acceptable salt of ribociclib is administered orally in an amount equivalent to 400 mg of ribociclib.

135. The method of claim 134, wherein the pharmaceutically acceptable salt is ribociclib succinate.

136. The method of any one of claims 117 to 135, wherein the adult patient has never received treatment with a 600 mg dose of ribociclib.

137. The method of any one of claims 117 to 136, wherein the adult patient has never been diagnosed with HR+ / HER2- advanced or metastatic breast cancer.

138. The method of any one of claims 117 to 137, wherein ribociclib and an aromatase inhibitor are administered as adjuvant therapy.

139. The method of any one of claims 117 to 138, wherein the ribociclib is not administered at a dose of 600 mg / day.

140. The method of any one of claims 117 to 139, wherein the dose of ribociclib is administered as a tablet.

141. The method of any one of claims 117 to 139, wherein two tablets are administered orally once daily to the adult patient on days 1-21 of a 28-day cycle, repeated for a treatment duration, and each tablet contains an amount of a pharmaceutically acceptable salt of ribociclib equivalent to 200 mg of ribociclib.

142. The method of claim 141, wherein the salt of ribociclib is ribociclib succinate.

143. The method of any one of claims 117 to 142, wherein the aromatase inhibitor is letrozole.

144. The method of any one of claims 117 to 142, wherein the aromatase inhibitor is anastrozole.

145. The method of any one of claims 117 to 144, wherein the aromatase inhibitor is letrozole, and the letrozole is administered at a dose ranging from 1 mg to 4 mg once daily.

146. The method of any one of claims 117 to 144, wherein the aromatase inhibitor is letrozole, and the letrozole is administered at a dose of 2.5 mg once daily.

147. The method of any one of claims 117 to 144, wherein the aromatase inhibitor is anastrozole, and the anastrozole is administered at a dose ranging from 0.5 mg once daily to 1.5 mg once daily.

148. The method of any one of claims 117 to 144, wherein the aromatase inhibitor is anastrozole, and the anastrozole is administered at a dose of 1 mg once daily.

149. The method of any one of claims 117 to 148, further comprising administering to the adult patient a gonadotropin-releasing hormone agonist.

150. The method of claim 149, wherein the gonadotropin-releasing hormone agonist is goserelin.

151. The method of claim 150, wherein the goserelin is administered at a dose ranging from 2 mg to 5 mg.

152. The method of claim 151, wherein the dose of goserelin is 3.6 mg.

153. The method of any one of claims 150 to 152, wherein the goserelin is administered subcutaneously.

154. The method of any one of claims 150 to 153, wherein the goserelin is administered once every 4 weeks.

155. The method of any one of claims 117 to 148, wherein the patient is a postmenopausal woman.

156. The method of any one of claims 117 to 154, wherein the patient is a premenopausal woman or a man.

157. The method of any one of claims 117 to 156, wherein the histological subtype of the breast cancer is a ductal subtype or its histological subtype is a lobular subtype.

158. The method of any one of claims 117 to 156, wherein the breast cancer is a stage IIA cancer or a stage IIB cancer.

159. The method of any one of claims 117 to 156, wherein the breast cancer is a stage IIA cancer.

160. The method of any one of claims 117 to 156, wherein the breast cancer is a stage IIB cancer.

161. The method of any one of claims 117 to 156, wherein the breast cancer is a stage IIIA cancer, a stage IIIB cancer, or a stage IIIC cancer.

162. The method of any one of claims 117 to 156, wherein the breast cancer is a stage IIIA cancer.

163. The method of any one of claims 117 to 156, wherein the breast cancer is a stage IIIB cancer.

164. The method of any one of claims 117 to 156, wherein the breast cancer is a stage IIIC cancer.

165. The method of any one of claims 117 to 156, wherein the administration of the treatment is irrespective of the lymph node status of the breast cancer.

166. The method of any one of claims 117 to 156, wherein the treatment with ribociclib and an aromatase inhibitor is not adjusted according to the lymph node status of the early stage breast cancer.

167. The method of any one of claims 117 to 156, wherein the breast cancer has a lymph node status selected from the group consisting of NO, Nl, N2, and N3.

168. The method of any one of claims 117 to 156, wherein the breast cancer has a lymph node status of NO.

169. The method of any one of claims 117 to 156, wherein the breast cancer has a lymph node status of N1-N3.

170. The method of any one of claims 117 to 156, wherein the breast cancer has a lymph node status of Nl.

171. The method of any one of claims 117 to 156, wherein the breast cancer has a lymph node status of N2.

172. The method of any one of claims 117 to 156, wherein the breast cancer has a lymph node status of N3.

173. The method of any one of claims 117 to 156, wherein the breast cancer comprises one or more cells having a histologic grade selected from the group consisting of Gl, G2, or G3.

174. The method of any one of claims 117 to 156, wherein the breast cancer comprises one or more cells having a histologic grade of Gl.

175. The method of any one of claims 117 to 156, wherein the breast cancer comprises one or more cells having a histologic grade of G2.

176. The method of any one of claims 117 to 156, wherein the breast cancer comprises one or more cells having a histologic grade of G3.

177. The method of any one of claims 117 to 156, wherein the breast cancer comprises a tumor of the T0, Tl, T2, T3, or T4 category.

178. The method of any one of claims 117 to 156, wherein the breast cancer comprises a tumor of the Tl, T2, or T3 category.

179. The method of any one of claims 117 to 156, wherein the breast cancer comprises a tumor of the T0 category.

180. The method of any one of claims 117 to 156, wherein the breast cancer comprises a tumor of the Tl category.

181. The method of any one of claims 117 to 156, wherein the breast cancer comprises a tumor of the T2 category.

182. The method of any one of claims 117 to 156, wherein the breast cancer comprises a tumor of the T3 category.

183. The method of any one of claims 117 to 156, wherein the breast cancer comprises a tumor of T4 category.

184. The method of any one of claims 117 to 156, wherein the breast cancer has a Ki67 status of 20 or less.

185. The method of any one of claims 117 to 156, wherein the breast cancer has a Ki67 status of greater than 20.

186. The method of any one of claims 117 to 185, wherein the patient underwent surgery for the early stage breast cancer prior to administration of the rebimastat and aromatase inhibitor to the adult patient.

187. The method of any one of claims 117 to 185, wherein the patient underwent (1) surgery for the early stage breast cancer, followed by (2) chemotherapy prior to administration of the rebimastat and aromatase inhibitor to the adult patient.

188. The method of any one of claims 117 to 185, wherein the patient underwent (1) surgery for the early stage breast cancer, followed by (2) chemotherapy and / or endocrine therapy prior to administration of the rebimastat and aromatase inhibitor to the adult patient.

189. The method of claim 188, wherein the endocrine therapy is therapy with a prior aromatase inhibitor.

190. The method of claim 188, wherein the prior aromatase inhibitor is letrozole or anastrozole.

191. The method of any one of claims 117 to 185, wherein the patient underwent surgery for the early stage breast cancer immediately prior to administration of the rebimastat and aromatase inhibitor to the adult patient.

192. The method of any one of claims 186 to 191, wherein the surgery comprises complete surgical resection of the cancer.

193. The method of any one of claims 186 to 191, wherein the surgery is mastectomy.

194. The method of any one of claims 186 to 191, wherein the patient received neoadjuvant therapy.

195. The method of claim 194, wherein the neoadjuvant therapy is chemotherapy.

196. The method of any one of claims 117 to 195, wherein the adult patient is located in a geographic region selected from North America, Western Europe, or Oceania.

197. The method of any one of claims 117 to 195, wherein the patient is Asian.

198. The method of any one of claims 117 to 195, wherein the patient is aged 18 to 45 years.

199. The method of any one of claims 117 to 195, wherein the patient is aged 45 to 54 years.

200. The method of any one of claims 117 to 195, wherein the patient is aged 54 to 64 years.

201. The method of any one of claims 117 to 195, wherein the patient is aged greater than 64 years.

202. The method of any one of claims 117 to 195, wherein the patient has a BMI of 25 or greater.

203. The method of any one of claims 117 to 195, wherein the patient has a BMI of less than 25.

204. The method of any one of claims 117 to 203, wherein the treatment improves the condition of the patient relative to a patient who does not receive the treatment and / or relative to the patient’s condition prior to treatment.

205. The method of any one of claims 117 to 203, wherein the treatment reduces the risk of the aggressive disease.

206. The method of any one of claims 117 to 203, wherein the treatment reduces the risk of the aggressive disease in the adult patient, corresponding to a hazard ratio of less than 1 when the risk is calculated relative to other patients who have received the same treatment as the adult patient except for not receiving the relacorilant.

207. The method of any one of claims 117 to 203, wherein the treatment reduces the risk of the aggressive disease in the adult patient, corresponding to a hazard ratio of less than or equal to 0.78 when the risk is calculated relative to other patients who have received the same treatment as the adult patient except for not receiving the relacorilant.

208. The method of any one of claims 117 to 203, wherein the adult patient is a premenopausal woman or a man, and the treatment reduces the risk of the aggressive disease, corresponding to a hazard ratio of less than or equal to 0.72 when the risk is calculated relative to other premenopausal women and men, respectively, who have received the same treatment as the premenopausal woman or man, respectively, except for not receiving the relacorilant.

209. The method of any one of claims 117 to 203, wherein the adult patient is diagnosed with HR+ / HER2- stage III early stage breast cancer, and the treatment reduces the risk of the aggressive disease in the adult patient, corresponding to a hazard ratio of less than or equal to 0.74 when the risk is calculated relative to other patients who have received the same treatment as the adult patient except for not receiving the relacorilant.

210. The method of any one of claims 117 to 203, wherein the adult patient is diagnosed with HR+ / HER2- stage II early stage breast cancer, and the treatment reduces the risk of the aggressive disease, corresponding to a hazard ratio of less than or equal to 0.76 when the risk is calculated relative to other patients who have received the same treatment as the adult patient except for not receiving the relacorilant.

211. The method of any one of claims 117 to 203, wherein the adult patient is diagnosed with HR+ / HER2- stage III early stage breast cancer, and the treatment reduces the risk of the aggressive disease by at least 25%, corresponding to a hazard ratio of 0.75 when the risk is calculated relative to other patients who have received the same treatment as the adult patient except for not receiving the relacorilant.

212. The method of any one of claims 117 to 203, wherein the treatment reduces the risk of the invasive disease to a similar level in a subset of patients comprising patients with Stage II early breast cancer, patients with Stage III early breast cancer, premenopausal or male patients, and postmenopausal female patients.

213. The method of any one of claims 117 to 203, wherein the treatment does not result in a shortened overall survival when the risk is calculated relative to other patients who have received the same treatment as the adult patient except for not receiving the romosiyline, corresponding to a hazard ratio of 0.

76.

214. The method of any one of claims 117 to 203, wherein the treatment reduces and / or prevents one or more of a risk of cancer recurrence, cancer spread, development and / or growth of additional cancer, and death due to cancer.

215. The method of any one of claims 117 to 203, wherein the treatment reduces cancer recurrence, wherein the recurrence is one or more of invasive ipsilateral breast tumor recurrence (IBTR), loco-regional invasive recurrence, and distant recurrence.

216. The method of any one of claims 117 to 203, wherein the treatment reduces cancer spread, wherein the cancer spread is invasive contralateral breast cancer or additional primary invasive cancer.

217. Romosiyline or a pharmaceutically acceptable salt thereof and an aromatase inhibitor for use in a method of treating HR+ / HER2- Stage II or III early breast cancer in an adult patient, wherein the method is a method of any one of claims 117 to 216.

218. Use of romosiyline or a pharmaceutically acceptable salt thereof and an aromatase inhibitor in the manufacture of a medicament for treating HR+ / HER2- Stage II or III early breast cancer in an adult patient, wherein the medicament is to be administered by a method of any one of claims 117 to 216.

219. A kit for performing a method of treating HR+ / HER2- Stage II or III early breast cancer in an adult patient according to any one of claims 117 to 216.

220. A method of treating an adult patient who has been diagnosed with HER+ / HER2- Stage II or III early breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) romosiyline at a dose ranging from 150 mg per day to 450 mg per day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor on every day of a 28-day cycle, wherein the method results in an improvement in one or more of overall survival (OS), disease-free survival (DDFS), or recurrence-free survival (RFS) in the patient.

221. A method for improving one or more of overall survival (OS), distant disease-free survival (DDFS), or relapse-free survival (RFS) in a patient who has been diagnosed with HR+ / HER2- Stage II or Stage III early stage breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) administering repoxilifine at a dose ranging from 150 mg per day to 450 mg per day on Days 1-21 of a 28-day cycle, and (ii) administering an aromatase inhibitor every day of a 28-day cycle.

222. A method for reducing the risk of local or regional invasive recurrence of early stage breast cancer in an adult patient who has been diagnosed with HR+ / HER2- Stage II or Stage III early stage breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) administering repoxilifine at a dose ranging from 150 mg per day to 450 mg per day on Days 1-21 of a 28-day cycle, and (ii) administering an aromatase inhibitor every day of a 28-day cycle.

223. A method for reducing the risk of invasive recurrence of early stage breast cancer in one or more of bone, liver, and lung or pleura in an adult patient who has been diagnosed with HR+ / HER2- Stage II or Stage III early stage breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) administering repoxilifine at a dose ranging from 150 mg per day to 450 mg per day on Days 1-21 of a 28-day cycle, and (ii) administering an aromatase inhibitor every day of a 28-day cycle.

224. The method of any one of claims 220 to 223, wherein the administration of the treatment is irrespective of the lymph node status of the breast cancer.

225. A method for reducing the risk of recurrence of early stage breast cancer in an adult patient who has been diagnosed with HR+ / HER2- Stage II or Stage III early stage breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) administering repoxilifine at a dose ranging from 150 mg per day to 450 mg per day on Days 1-21 of a 28-day cycle, and (ii) administering an aromatase inhibitor every day of a 28-day cycle, wherein the administration of the treatment is irrespective of the lymph node status of the breast cancer.

226. The method of any one of claims 220 to 225, wherein the breast cancer has a lymph node status of NO, N1, N2, or N3.

227. The method of claim 226, wherein the breast cancer has a lymph node status of NO.

228. The method of any one of claims 220 to 227, wherein the early stage breast cancer is Stage II, e.g., Stage IIA.

229. The method of any one of claims 220 to 227, wherein the early stage breast cancer is Stage III, e.g., Stage IIIB or Stage IIIC.

230. The method of any one of claims 220 to 229, wherein the breast cancer is of a ductal subtype.

231. The method of any one of claims 220 to 230, wherein the patient is of Asian descent.

232. The method of any one of claims 220 to 231, wherein the method is adjuvant therapy because the patient has received at least one prior treatment for breast cancer selected from the group consisting of surgery, chemotherapy, and radiotherapy.

233. The method of claim 232, wherein the patient has not undergone mastectomy.

234. The method of any one of claims 220 to 233, wherein the dose of romosilast is 400 mg per day.

235. The method of any one of claims 220 to 234, wherein the romosilast is administered as a salt, preferably romosilast succinate.

236. The method of any one of claims 220 to 235, wherein the aromatase inhibitor is letrozole or anastrozole.

237. The method of claim 236, wherein the aromatase inhibitor is letrozole, preferably administered at a dose of 2.5 mg per day.

238. The method of claim 236, wherein the aromatase inhibitor is anastrozole, preferably administered at a dose of 1 mg per day.

239. The method of any one of claims 220 to 238, wherein the dose of romosilast is 400 mg per day, the romosilast is administered as romosilast succinate, and the aromatase inhibitor is letrozole or anastrozole, preferably 2.5 mg per day of letrozole or 1 mg per day of anastrozole.

240. The method of any one of claims 220 to 239, wherein the patient achieves an improvement in OS, DDFS, and / or RFS or a reduction in the risk of breast cancer recurrence for at least 36 months.

241. Romosilast for use in a method of improving one or more of overall survival (OS), distant disease-free survival (DDFS), or relapse-free survival (RFS) in an adult patient who has been diagnosed with HR+ / HER2- Stage II or Stage III early stage breast cancer, wherein the method comprises administering to the patient an adjuvant therapy comprising (i) romosilast at a dose ranging from 150 mg per day to 450 mg per day on Days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor on every day of a 28-day cycle.

242. Romosilast for use in a method of reducing the risk of local or regional invasive recurrence of early stage breast cancer in an adult patient who has been diagnosed with HR+ / HER2- Stage II or Stage III early stage breast cancer, wherein the method comprises administering to the patient an adjuvant therapy comprising (i) romosilast at a dose ranging from 150 mg per day to 450 mg per day on Days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor on every day of a 28-day cycle.

243. Ribociclib for use in a method of reducing the risk of invasive recurrence of early breast cancer in one or more of the bone, liver, and lung or pleura in an adult patient who has been diagnosed with HR+ / HER2- stage II or stage III early stage breast cancer, wherein the method comprises administering to the patient an adjuvant therapy comprising (i) ribociclib at a dose ranging from 150 mg per day to 450 mg per day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor every day of a 28-day cycle.

244. Ribociclib for use according to any one of claims 241 to 243, wherein the administration of the treatment is irrespective of the lymph node status of the breast cancer.

245. Ribociclib for use in a method of reducing the risk of recurrence of early breast cancer in an adult patient who has been diagnosed with HR+ / HER2- stage II or stage III early stage breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) ribociclib at a dose ranging from 150 mg per day to 450 mg per day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor every day of a 28-day cycle, wherein the administration of the treatment is irrespective of the lymph node status of the breast cancer.

246. Ribociclib for use according to any one of claims 241 to 245, wherein the breast cancer has a lymph node status of NO, N1, N2 or N3.

247. Ribociclib for use according to claim 246, wherein the breast cancer has a lymph node status of NO.

248. Ribociclib for use according to any one of claims 241 to 247, wherein the early breast cancer is stage II, for example stage IIA.

249. Ribociclib for use according to any one of claims 241 to 247, wherein the early breast cancer is stage III, for example stage IIIB or stage IIIC.

250. Ribociclib for use according to any one of claims 241 to 249, wherein the breast cancer belongs to the ductal subtype.

251. Ribociclib for use according to any one of claims 241 to 250, wherein the patient is of Asian descent.

252. Ribociclib for use according to any one of claims 241 to 251, wherein the method is adjuvant therapy because the patient has received at least one prior treatment for breast cancer selected from the group consisting of surgery, chemotherapy and radiotherapy.

253. Ribociclib for use according to claim 252, wherein the patient has not undergone mastectomy.

254. Ribociclib for use according to any one of claims 241 to 253, wherein the dose of ribociclib is 400 mg per day.

255. Ribociclib for use according to any one of claims 241 to 254, wherein the ribociclib is administered in the form of a salt, preferably ribociclib succinate.

256. Romosozumab for use according to any one of claims 241 to 255, wherein the aromatase inhibitor is letrozole or anastrozole.

257. Romosozumab for use according to claim 256, wherein the aromatase inhibitor is letrozole, preferably administered at a dose of 2.5 mg / day.

258. Romosozumab for use according to claim 256, wherein the aromatase inhibitor is anastrozole, preferably administered at a dose of 1 mg / day.

259. Romosozumab for use according to any one of claims 241 to 258, wherein the dose of romosozumab is 400 mg / day, the romosozumab is administered as form of romosozumab succinate, and the aromatase inhibitor is letrozole or anastrozole, preferably 2.5 mg / day of letrozole or 1 mg / day of anastrozole.

260. Romosozumab for use according to any one of claims 241 to 259, wherein the patient achieves an improvement in OS, DDFS, and / or RFS of at least 36 months or a reduction in the risk of breast cancer recurrence.

261. Romosozumab succinate for use in a method of treating HR+ / HER2- stage II or stage III early breast cancer in an adult patient who has received at least one prior treatment for early breast cancer and who has no signs or symptoms of cancer, wherein the method comprises administering to the patient an adjuvant therapy comprising (i) a dose of romosozumab succinate on days 1 to 21 of a 28-day cycle, the total dose of romosozumab being 400 mg / day, and (ii) letrozole at a dose of 2.5 mg / day or anastrozole at a dose of 1 mg / day on each day of a 28-day cycle.

262. Romosozumab succinate for use according to claim 261, wherein the adjuvant therapy comprises letrozole at a dose of 2.5 mg / day.

263. Romosozumab succinate for use according to claim 261, wherein the adjuvant therapy comprises anastrozole at a dose of 1 mg / day.

264. Romosozumab succinate for use according to any one of claims 261 to 263, wherein the breast cancer has a lymph node status of N0, N1, N2 or N3.

265. Romosozumab succinate for use according to claim 264, wherein the breast cancer has a lymph node status of N0.

266. Romosozumab succinate for use according to any one of claims 261 to 265, wherein the early breast cancer is stage II, for example stage IIA.

267. Romosozumab succinate for use according to any one of claims 261 to 265, wherein the early breast cancer is stage III, for example stage IIIB.

268. Romosozumab succinate for use according to any one of claims 261 to 265, wherein the early breast cancer is stage III, for example stage IIIC.

269. Romosozumab for use according to any one of claims 261 to 268, wherein the breast cancer is of ductal subtype.

270. Romosozumab for use according to any one of claims 261 to 269, wherein the patient is of Asian descent.

271. Romosozumab for use according to any one of claims 261 to 270, wherein the method is adjuvant therapy, as the patient has received at least one prior treatment for breast cancer selected from the group consisting of surgery, chemotherapy, endocrine therapy and radiotherapy.

272. Romosozumab for use according to claim 271, wherein the patient has not undergone mastectomy.

273. Romosozumab for use according to any one of claims 261 to 272, wherein the method improves the overall survival (OS), distant disease-free survival (DDFS) and / or relapse-free survival (RFS) of the patient’s breast cancer by at least 36 months; or the method reduces the risk of breast cancer recurrence in the patient by at least 36 months.

274. A method of preventing breast cancer recurrence in an adult patient who has received a prior treatment for HR+ / HER2- stage II or III early stage breast cancer, the method comprising administering to the patient (i) a dose of romosozumab, a free base form thereof or a pharmaceutically acceptable salt thereof and (ii) a dose of an aromatase inhibitor, preferably letrozole or anastrozole.

275. A method of treating an adult patient in remission from HR+ / HER2- stage II or III early stage breast cancer, the method comprising administering to the patient (i) a dose of romosozumab, a free base form thereof or a pharmaceutically acceptable salt thereof and (ii) a dose of an aromatase inhibitor, preferably letrozole or anastrozole.

276. A method of treating HR+ / HER2- stage II or III early stage breast cancer in an adult patient in need thereof, the method comprising administering to the patient (i) romosozumab, a free base form thereof or a pharmaceutically acceptable salt thereof, at a dose ranging from 150 mg / day to 450 mg / day, administered on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor, preferably letrozole or anastrozole, administered every day of a 28-day cycle.

277. The method of any one of claims 274 to 276, wherein the romosozumab is a pharmaceutically acceptable salt of romosozumab.

278. The method of claim 277, wherein the salt of romosozumab is romosozumab succinate.

279. The method of any one of claims 274, 275, 277 and 278, wherein the dose of romosozumab is other than 600 mg / day.

280. The method of any one of claims 274 to 278, wherein the dose of romosozumab is 200 mg / day or 400 mg / day.

281. The method of claim 280, wherein the romosilast is administered as romosilast succinate and the total dose of romosilast is 200 mg / day.

282. The method of claim 280, wherein the romosilast is administered as romosilast succinate and the total dose of romosilast is 400 mg / day.

283. The method of claim 280, wherein the romosilast is administered at a dose of 400 mg / day for a period of time followed by administration of romosilast at a dose of 200 mg / day.

284. The method of any one of claims 274 to 283, wherein the dose of romosilast is administered orally.

285. The method of any one of claims 274 to 284, wherein the dose of romosilast is administered as a tablet.

286. The method of any one of claims 274 to 285, wherein the aromatase inhibitor is letrozole or anastrozole.

287. The method of any one of claims 274 to 286, wherein the aromatase inhibitor is administered orally.

288. The method of claim 286 or 287, wherein the letrozole is administered at a dose ranging from 1 mg / day to 4 mg / day.

289. The method of claim 288, wherein the letrozole is administered at a dose of 2.5 mg / day.

290. The method of claim 286 or 287, wherein the anastrozole is administered at a dose ranging from 0.5 mg / day to 1.5 mg / day.

291. The method of claim 290, wherein the anastrozole is administered at a dose of 1 mg / day.

292. A method of treating breast cancer recurrence in an adult patient who has received at least one prior treatment for HR+ / HER2- Stage II or III early stage breast cancer and has no detectable signs or symptoms of breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) a dose of romosilast succinate on days 1 to 21 of a 28-day cycle, the total dose of romosilast being 400 mg / day, and (ii) letrozole at a dose of 2.5 mg / day or anastrozole at a dose of 1 mg / day on each day of a 28-day cycle.

293. A method of treating an adult patient in complete remission from HR+ / HER2- Stage II or III early stage breast cancer and in need of adjuvant therapy, the method comprising administering to the patient an adjuvant therapy comprising (i) a dose of romosilast succinate on days 1 to 21 of a 28-day cycle, the total dose of romosilast being 400 mg / day, and (ii) letrozole at a dose of 2.5 mg / day or anastrozole at a dose of 1 mg / day on each day of a 28-day cycle.

294. The method of any one of claims 274 to 293, wherein the treatment further comprises administration of a gonadotropin-releasing hormone agonist.

295. The method of claim 294, wherein the gonadotropin-releasing hormone agonist is goserelin.

296. The method of claim 295, wherein the goserelin is administered at a dose ranging from 2 mg to 5 mg.

297. The method of claim 296, wherein the dose of goserelin is 3.6 mg.

298. The method of any one of claims 294 to 297, wherein the goserelin is administered subcutaneously.

299. The method of any one of claims 294 to 298, wherein the goserelin is administered once every 4 weeks.

300. The method of any one of claims 274 to 299, wherein the patient is a postmenopausal woman.

301. The method of any one of claims 274 to 293, wherein the patient is a premenopausal woman or a man.

302. The method of any one of claims 274 to 301, wherein the patient is administered the treatment for at least 12 months.

303. The method of claim 302, wherein the patient is administered the treatment for at least 24 months.

304. The method of claim 302 or 303, wherein the patient is administered the treatment for at least 36 months.

305. The method of any one of claims 302 to 304, wherein the patient is administered the treatment for at least 48 months.

306. The method of any one of claims 302 to 305, wherein the patient is administered the treatment for at least 60 months.

307. The method of any one of claims 274 to 306, wherein the breast cancer is ER+ and PR+.

308. The method of any one of claims 274 to 306, wherein the breast cancer is ER- and PR+.

309. The method of any one of claims 274 to 306, wherein the breast cancer is ER+ and PR-.

310. The method of any one of claims 274 to 309, wherein the histological subtype of the breast cancer is a ductal subtype.

311. The method of any one of claims 274 to 310, wherein the histological subtype of the breast cancer is a lobular subtype.

312. The method of any one of claims 274 to 311, wherein the breast cancer is a stage IIA cancer or a stage IIB cancer.

313. The method of claim 312, wherein the breast cancer is a stage IIA cancer.

314. The method of claim 312, wherein the breast cancer is a stage IIB cancer.

315. The method of any one of claims 274 to 311, wherein the breast cancer is a stage IIIA cancer, a stage IIIB cancer, or a stage IIIC cancer.

316. The method of claim 315, wherein the breast cancer is a stage IIIA cancer.

317. The method of claim 315, wherein the breast cancer is a stage IIIB cancer.

318. The method of claim 315, wherein the breast cancer is a stage IIIC cancer.

319. The method of any one of claims 274 to 318, wherein the administration of the treatment is irrespective of the lymph node status of the breast cancer.

320. The method of any one of claims 274 to 319, wherein the breast cancer has a lymph node status selected from the group consisting of NO, Nl, N2, and N3.

321. The method of claim 319 or 320, wherein the breast cancer has a lymph node status of NO.

322. The method of claim 319 or 320, wherein the breast cancer has a lymph node status of Nl to N3.

323. The method of claim 319 or 320, wherein the breast cancer has a lymph node status of Nl.

324. The method of claim 319 or 320, wherein the breast cancer has a lymph node status of N2.

325. The method of claim 319 or 320, wherein the breast cancer has a lymph node status of N3.

326. The method of any one of claims 274 to 325, wherein the breast cancer comprises one or more cells having a histologic grade selected from the group consisting of Gl, G2, or G3.

327. The method of claim 326, wherein the breast cancer comprises one or more cells having a histologic grade of Gl.

328. The method of claim 326, wherein the breast cancer comprises one or more cells having a histologic grade of G2.

329. The method of claim 326, wherein the breast cancer comprises one or more cells having a histologic grade of G3.

330. The method of any one of claims 274 to 329, wherein the breast cancer comprises a tumor of T0, Tl, T2, T3, or T4 category.

331. The method of claim 330, wherein the breast cancer comprises a tumor of Tl, T2, or T3 category.

332. The method of claim 330, wherein the breast cancer comprises a tumor of T0 category.

333. The method of claim 330 or claim 331, wherein the breast cancer comprises a tumor of Tl category.

334. The method of claim 330 or claim 331, wherein the breast cancer comprises a tumor of T2 category.

335. The method of claim 330 or claim 331, wherein the breast cancer comprises a tumor of T3 category.

336. The method of claim 330, wherein the breast cancer comprises a tumor of T4 category.

337. The method of any one of claims 274 to 336, wherein the breast cancer has a Ki67 status of 20 or less.

338. The method of any one of claims 274 to 336, wherein the breast cancer has a Ki67 status of greater than 20.

339. The method of any one of claims 274 to 338, wherein prior to the administration, the patient has received a loading dose of (i) ribociclib and / or (ii) endocrine therapy.

340. The method of any one of claims 274 to 291 and 293 to 339, wherein the patient has received at least one prior treatment for cancer.

341. The method of claim 292 or claim 340, wherein the prior treatment is an adjuvant treatment following another prior treatment.

342. The method of claim 340 or 341, wherein the prior treatment is surgery.

343. The method of claim 342, wherein the surgery comprises complete surgical resection of the cancer.

344. The method of claim 342 or claim 343, wherein the surgery is a mastectomy.

345. The method of claim 340 or claim 341, wherein the prior treatment is chemotherapy.

346. The method of claim 345, wherein the prior treatment is adjuvant chemotherapy.

347. The method of claim 345, wherein the prior treatment is neoadjuvant chemotherapy.

348. The method of claim 340 or claim 341, wherein the prior treatment is endocrine therapy.

349. The method of claim 340 or claim 341, wherein the prior treatment is radiation therapy.

350. The method of any one of claims 292 and 340 to 349, wherein the patient did not respond to the prior treatment.

351. The method of any one of claims 274 to 350, wherein the patient is located in a geographic region selected from North America, Western Europe, or Oceania.

352. The method of any one of claims 274 to 351, wherein the patient is of Asian descent.

353. The method of any one of claims 274 to 352, wherein the patient is 18 to 45 years of age.

354. The method of any one of claims 274 to 352, wherein the patient is 45 to 54 years of age.

355. The method of any one of claims 274 to 352, wherein the patient is 54 to 64 years of age.

356. The method of any one of claims 274 to 352, wherein the patient is greater than 64 years of age.

357. The method of any one of claims 274 to 357, wherein the patient has a BMI of 25 or greater.

358. The method of any one of claims 274 to 357, wherein the patient has a BMI of less than 25.

359. The method of any one of claims 274 to 358, wherein the treatment improves the patient’s condition relative to a patient who does not receive the treatment and / or relative to the patient’s condition prior to treatment.

360. The method of any one of claims 274 to 359, wherein the treatment reduces the risk of the aggressive disease.

361. The method of claim 360, wherein the treatment reduces the risk of the aggressive disease corresponding to a hazard ratio of less than 1 when the risk is calculated relative to a patient who does not receive the treatment.

362. The method of claim 361, wherein the treatment reduces the risk of the invasive disease, corresponding to a hazard ratio of less than or equal to 0.78 when the risk is calculated relative to a patient who did not receive the treatment.

363. The method of any one of claims 274 to 299 and 301 to 362, wherein the patient is a premenopausal woman or man, and the treatment reduces the risk of the invasive disease, corresponding to a hazard ratio of less than or equal to 0.72 when the risk is calculated relative to a patient who did not receive the treatment.

364. The method of any one of claims 360 to 362, wherein the cancer is HR+ / HER2- stage III early stage breast cancer, and the treatment reduces the risk of the invasive disease, corresponding to a hazard ratio of less than or equal to 0.74 when the risk is calculated relative to a patient who did not receive the treatment.

365. The method of any one of claims 360 to 362, wherein the cancer is HR+ / HER2- stage II early stage breast cancer, and the treatment reduces the risk of the invasive disease, corresponding to a hazard ratio of less than or equal to 0.76 when the risk is calculated relative to a patient who did not receive the treatment.

366. The method of any one of claims 360 to 362, wherein the cancer is HR+ / HER2- stage III early stage breast cancer, and the treatment reduces the risk of the invasive disease by at least 25%, corresponding to a hazard ratio of 0.75 when the risk is calculated relative to a patient who did not receive the treatment.

367. The method of any one of claims 360 to 366, wherein the treatment reduces the risk of the invasive disease to a similar level in a patient subset comprising a stage II early stage breast cancer patient, a stage III early stage breast cancer patient, a premenopausal woman or man patient, and a postmenopausal woman patient.

368. The method of any one of claims 274 to 367, wherein the treatment does not result in a reduction in overall survival, corresponding to a hazard ratio of 0.76 when the risk is calculated relative to a patient who did not receive the treatment.

369. The method of any one of claims 274 to 368, wherein the treatment reduces and / or prevents one or more of a risk of cancer recurrence, cancer spread, development and / or growth of additional cancer, and cancer-caused death.

370. The method of claim 369, wherein the treatment reduces cancer recurrence, wherein the recurrence is one or more of an invasive ipsilateral breast tumor recurrence (IBTR), a locally-regional invasive recurrence, and a distant recurrence.

371. The method of claim 369, wherein the treatment reduces cancer spread, wherein the cancer spread is an invasive contralateral breast cancer or an additional primary invasive cancer.

372. The method of any one of claims 274 to 371, wherein the treatment prevents cancer-caused death.

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