Treatment of early breast cancer with ribociclib in combination with aromatase inhibitors

Abstract

This disclosure relates to adjuvant therapy for HR+ / HER2- stage II or III early breast cancer in adult patients. The method involves administering ribociclib (a CDK4 / 6 inhibitor) in combination with endocrine therapy.

Description

Background Art

[0001] Breast cancer (BC) is the most frequently diagnosed cancer worldwide. In 2012, approximately 1.7 million new BC cases and 522,000 deaths due to this disease occurred globally (CA Cancer J Clin 65:87-108,2015). The BC incidence rate varies among individuals of different ethnic groups and different geographical locations around the world, with the ratio ranging from 27 cases per 100,000 in Central Africa and East Asia to 92 cases 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 predicted to be the most frequently diagnosed cancer in 2018, with an estimated incidence of 268,670 new cases and 41,400 deaths (CA Cancer J Clin 68:7-30,2018). The estimated BC incidence rate in European countries in 2012 was 458,337 cases (Eur J Cancer Oxf Engl 1990 49:1374-1403,2013). BC in men is not common, and the reported frequency is about 1% of all BC, but its incidence rate continues to increase (Breast Cancer Res Treat 137:465-470,2013).

[0002] The vast majority of newly diagnosed breast cancer (BC) cases are early-stage breast cancer (EBC) localized in breast tissue and regional lymphatic vessels, and are potentially treatable with localized treatment modalities such as surgery and radiotherapy. Based on data from the Surveillance, Epidemiology and End Results (SEER) program collected between 1975 and 2012, 93% of diagnosed cases were EBC, 62% were confined to breast tissue, and 31% were confined to 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 surgery, management of EBC typically includes radiation therapy and additional antineoplasmic therapy modalities such as adjuvant or neoadjuvant systemic therapy. Many EBC patients can achieve disease-free status with surgical resection and radiation therapy, but distant recurrence due to micrometastatic disease is common thereafter, and this is the leading cause of death in EBC patients (BMC Med 13:195, 2015). A meta-analysis of the EBC Trialists' Collaborative Group (EBCTCG) of approximately 150,000 women in 200 randomized clinical trials showed that approximately 36% and 20%, respectively, of EBC patients without any adjuvant systemic therapy experienced recurrence and BC-related death during the 5-year follow-up period (Lancet Lond Engl 365:1687-1717, 2005). Furthermore, relapses and BC-related deaths continued to occur in hormone receptor (HR)-positive EBC patients even 5 years after surgery, and only 45% of patients were reported to be relapse-free at 15 years of follow-up.

[0004] Adjuvant systemic therapy, including cytotoxic therapy, biological therapy, and endocrine therapy, reduces local and distant recurrence, decreases BC-specific mortality, and improves overall survival (OS) in EBC patients (Lancet Lond Engl 365:1687-1717, 2005). The need for and selection of systemic adjuvant therapy is guided by several clinical, pathological, and genomic predictive and prognostic factors of the tumor and patient, based on the individual's recurrence risk, including tumor stage, histopathological grade, tumor HR status, human epidermal growth factor receptor 2 (HER2) status, multiple gene testing recurrence score, growth markers such as Ki67, menopausal status, patient comorbidities, and age. Using these factors, EBC can be classified as low-risk, moderate / moderate-risk, or high-risk for recurrence after surgery (BMC Med 13:195, 2015). While there is no consensus on defining these risk groups, generally speaking, patients with smaller tumors, no regional lymph node metastasis, low tumor grade, HR-positive and HER2-negative status, and a low recurrence genomic score have a low risk of recurrence (i.e., a 5-year recurrence rate of 5-10%). For these patients, chemotherapy-free ET is usually considered because the clinical benefit of chemotherapy is lower compared to ET. On the other hand, patients with metastasis to multiple regional lymph nodes, high tumor grade, HER2-positive status, or a high recurrence genomic score have a higher risk of recurrence. For these patients, adjuvant chemotherapy (and HER2-targeted agents in HER2-positive BC patients) is usually considered, and adjuvant ET is also considered if the tumor expresses HR (usually delivered after completion of chemotherapy).

[0005] It is estimated that 75% of BCs express receptors for steroid hormones (estrogen receptor [ER] and / or progesterone receptor [PgR]), and therefore these patients may benefit from adjuvant ET with tamoxifen or aromatase inhibitors (AIs) (letrozole, anastrozole, or exemestane) (J Clin Oncol Off J Am Soc Clin Oncol 28:2784-2795, 2010). ET reduces the risk of recurrence and BC mortality in HR-positive EBCs independently of chemotherapy (Lancet Lond Engl 365:1687-1717, 2005).

[0006] The current clinical guidelines for adjuvant ET in HR-positive EBC (see Ann Oncol Off J Eur Soc Med Oncol 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: • About premenopausal women: 1.1. Tamoxifen with or without ovarian suppression for 5-10 years, 1.2. AI with ovarian suppression for 5 years (See N Engl J Med 379:122-137, 2018) • About postmenopausal women: 1.3. Initially, AI for 5 years (or up to 10 years), based on the results of the MA.17R trial (see N Engl J Med 375:209-219, 2016), or 1.4. Treatment with either tamoxifen for 2-3 years followed by AI for a total of up to 5 years, or AI for a total of up to 5 years. 1.5. Tamoxifen for approximately 5 years, followed by 5 years of AI, or 1.6. Tamoxifen for up to 10 years (Ann Oncol Off J Eur Soc Med Oncol 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) In men: Limited data suggest that tamoxifen or AI in combination with a gonadotropin-releasing hormone (GnRH) agonist should be the ET of choice for HR-positive HER2-negative EBC (Breast Cancer Res Treat 151:141-147, 2015).

[0007] International Publication No. 2015 / 022609 A1 (incorporated herein by reference) discloses combination therapies for treating cancer, including EBC. Recurrence can still occur in some EBC patients, particularly those with adverse clinical, pathological, and genomic features. Approximately 25%–30% of HR-positive, HER2-negative EBC patients with multiple (four or more) metastatic regional lymph nodes (roughly corresponding to anatomical stage III in the AJCC 8th edition breast cancer staging classification) will recur within 5 years with ET combined with AI (Lancet London Engl 365:1687-1717, 2005). Only 48% of these patients will be distant recurrence-free within 20 years, and nearly half of these patients will die from BC within 20 years despite 5 years of ET (N Engl J Med 377:1836-1846, 2017). Patients with 1-3 metastatic regional lymph nodes (generally corresponding to anatomical stage II in the AJCC 8th edition breast cancer staging classification) may have a lower risk of recurrence than patients with anatomical stage III. However, despite ET, distant recurrence is still observed in 31% of patients within 20 years, and 28% die from BC (N Engl J Med 377:1836-1846, 2017).

[0008] Adjuvant therapy for HR+ HER2- EBC remains limited. Adjuvant therapies similar to those used for HR+ HER2- advanced or metastatic breast cancer have been attempted, but the results from these approaches have been inconsistent. For example, the cdk4 / 6 inhibitor abemaciclib was initially approved for the treatment of HR+ HER2- advanced or metastatic breast cancer patients, either alone or in combination with endocrine therapy, and was later shown to be effective in the treatment of 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, while the cdk4 / 6 inhibitor palbociclib in combination with endocrine therapy demonstrated clinically relevant efficacy in patients with HR+ HER2- metastatic breast cancer (PALOMA3 trial, Turner et al., 2015. N Engl J Med 2015;373:209-219), no supporting results were obtained in trials in patients with HR+ HER2- early-stage breast cancer (see PENELOPE-B trial, where adding palbociclib to endocrine therapy did not improve disease-free survival (iFDS) compared to placebo in patients with HR+ HER2- early-stage breast cancer and residual invasive disease after completion of neoadjuvant chemotherapy (Loibl et al., 2021. Breast Cancer v39(14)). Similarly, HR+ Results from the PALLAS clinical trial in HER2-early breast cancer patients indicated that the combination of palbociclib and endocrine therapy did not improve iDFS compared to endocrine therapy alone (Mayer et al., 2021. Lancet, v22(2), p212-222).

[0009] Therefore, novel treatment strategies may improve clinical outcomes in HR-positive, HER2-negative EBC patients. [Overview of the Initiative]

[0010] Therefore, this specification discloses a method for treating early-stage breast cancer using the CDK4 / 6 inhibitor Kisqali® (ribociclib) plus endocrine therapy (ET). This disclosure provides a method for treating patients with hormone receptor-positive / human epidermal growth factor receptor 2-negative (HR+ / HER2-) early-stage breast cancer (EBC). This disclosure relies, in particular, on the results from the NATALEE trial, a positive Phase III study of CDK4 / 6 inhibitors demonstrating consistent benefits in a broad population of patients with recurrent stage II and III HR+ / HER2- early-stage breast cancer (EBC), including those without lymph node lesions. [Brief explanation of the drawing]

[0011] [Figure 1] This document provides a schematic diagram of the research design for the NATALEE clinical trial. [Figure 2] The mean ANC profiles are shown based on simulations of ribociclib 200 mg, 400 mg, and 600 mg QD, with a 3-week on / 1-week rest period; the mean ANC profiles are predicted by an ANC exposure-response model created based on data from studies CLEE011X2101, CLEE011X1101, CLEE011X2107, CLEE011A2301, CLEE011E2301, and CLEE011F2301. [Figure 3] This provides a schematic diagram of the inclusion of patients according to anatomical stage in the NATALEE clinical trial. [Figure 4] A schematic diagram of ECG and PK for administration (C1D15) is provided. [Figure 5-1] Figure 5: A questionnaire (i.e., EORTC QLQ-C30) is shown, for example, to be used to assess quality of life and healthcare resource utilization. [Figure 5-2] (As stated above.) [Figure 6-1] Figure 6: A questionnaire (i.e., EORTC QLQ-BR23) is shown, for example, to be used to assess quality of life and healthcare resource utilization. [Figure 6-2] (As stated above.) [Figure 7] A questionnaire (i.e., EQ-5D-5L) is shown, for example, to be used to assess quality of life and healthcare resource utilization. [Figure 8] Here is a questionnaire (i.e., the Hospital Anxiety and Depression Scale (HADS)) that can be used, for example, to assess quality of life and healthcare resource utilization. [Figure 9] The Kaplan-Meier plot for survival analysis of non-primary invasive disease is shown (the largest analysis population). [Figure 10] (q) A forest plot of iDFS stratified (by eCRF) is shown (the largest population analyzed). [Figure 11A] iDFS forest plot shown - subgroup analysis. [Figure 11B] iDFS forest plot shown - subgroup analysis. [Figure 11C] iDFS forest plot shown - subgroup analysis. [Figure 11D] iDFS forest plot shown - subgroup analysis. [Figure 12] This shows the Kaplan-Meier survival curves for iDFS by anatomical stage II (eCRF layer) (largest analysis population). [Figure 13] The Kaplan-Meier survival curves for iDFS by anatomical stage III (eCRF layer) are shown (largest analysis population). [Figure 14] The Kaplan-Meier curve for RFS is shown (for the largest analyzed population). [Figure 15] The Kaplan-Meier curve for DDFS is shown (for the largest analyzed population). [Figure 16] The Kaplan-Meier curve for OS is shown (for the largest analysis population). [Modes for carrying out the invention]

[0012] The following provides further details and examples of this disclosure.

[0013] This disclosure relates to a method for treating patients with breast cancer (BC). This method is based, in particular, on the surprising results of the NATALEE clinical trial, which indicated that a combination of CDK inhibitors plus endocrine therapy may provide beneficial effects in patients with early-stage breast cancer, such as hormone receptor-positive / human epidermal growth factor receptor 2-negative (HR+ / HER2-) early-stage breast cancer.

[0014] A. Treatment of early-stage breast cancer One aspect of the present disclosure relates to a method for treating breast cancer in an adult patient in need of treatment for breast cancer, comprising administering to the patient a treatment comprising a cyclin-dependent kinase (CDK) inhibitor in combination with endocrine therapy, wherein the breast cancer is early-stage breast cancer (EBC).

[0015] EBC may be characterized by the localization of cancer cells in the breast tissue and regional lymphatic vessels (e.g., tumor formation). In EBC, cancer cells are typically not detected beyond the breast or axillary lymph nodes. Early-stage breast cancer may be stage 0, stage I, stage II, or stage III (e.g., stage 0, stage I, stage IIA, stage IIB, stage IIIA, stage IIIB, or stage IIIC). Due to its localization, EBC may be distinguished from advanced breast cancer (also called metastatic cancer), where the cancer has spread to one or more body sites, such as the bones, lungs, or liver.

[0016] In some embodiments, EBC is a carcinoma of the breast, such as adenocarcinoma. EBC can be an invasive carcinoma. Invasive carcinoma, also known as infiltrating or invasive ductal carcinoma (IDC), is a type of breast cancer that originates in the milk ducts of the breast and migrates to adjacent tissues. Over time, IDC can spread to other parts of the body (metastasize) through lymph nodes or the bloodstream. EBC can also be a non-invasive carcinoma, such as ductal carcinoma in situ (DCIS). DCIS may spread along the milk ducts of the breast but not outside the ductal system.

[0017] Signs and / or symptoms of early breast cancer may include one or more of the following: a lump in the breast or armpit, thickening or swelling of the breast, rash or dimples of the breast skin (e.g., orange peel-like dimples), redness or dryness of the skin around the nipple, a pulling sensation or pain around the nipple, nipple discharge other than breast milk, including blood, any change in the size or shape of the breast, and / or pain in any part of the breast. Further signs and / or symptoms of early breast cancer may include the presence of one or more breast cancer cells, the presence of a breast cancer tumor, or the presence of biochemical or genetic markers in the patient's tissue or fluids that indicate the presence of breast cancer (e.g., breast cancer biomarkers in tissue biopsy or blood samples). Presence may be a physical presence detected by tests such as ultrasound, mammography, magnetic resonance imaging, analysis of tissue samples (e.g., biopsy), and / or analysis of fluid samples (e.g., blood samples). Any known test may be used to detect signs and / or symptoms of cancer. The term “No evidence of disease” (NED or NEOD) may be used when there are no detectable signs and / or symptoms of cancer.

[0018] Breast cancer may be graded according to its histology. The histological grade (or "grade") may refer to the degree to which cancer cells differ from normal cells, for example, due to differences in the degree of cell differentiation. Grade 1 refers to breast cancer cells that resemble normal breast cells and are usually slow-growing. Grade 2 refers to rapidly growing breast cancer cells that may not resemble normal breast cells. Grade 3 refers to breast cancer cells that do not resemble normal breast cells and are usually rapidly growing. Grade 4 refers to breast cancer cells that barely resemble normal breast cells and tend to grow and spread rapidly compared to lower-grade tumors.

[0019] Breast cancer can be classified according to staging methods. These staging methods may be, for example, pathological staging based on pathological examination of tumor tissue and any lymph nodes removed during surgery, or clinical staging, such as pathological staging based on physical examination, tests, and / or imaging by a clinician.

[0020] Generally, breast cancer is classified using staging methods based on the size of the cancer (e.g., the primary tumor) and how far it has spread within the body.

[0021] One method used to classify breast cancer or tumors based on their stage is the TNM classification, or staging system. Using this method, a tumor may be classified as T0 when there is no evidence of tumor formation, while the classifications T1, T2, T3, or T4 can be used to identify the size and extent of the tumor. Tx may indicate that the tumor is undetermined. N (node, lymph node) indicates the spread of cancer to adjacent lymph nodes. A tumor may be classified as N0 when there is no spread of tumor to regional lymph nodes, while the classifications N1-N3 can be used to indicate lymph node spread.

[0022] M (metastasis) represents metastasis (e.g., the spread of cancer to other parts of the body). A tumor may be classified as M0 when there is no distant metastasis, while the M1 classification may be used when there is evidence of distant metastasis (Rosen and Sapra, TNM Classification, StatPearls Publishing; Treasure Island (FL), January 2023).

[0023] In breast cancer, T1 can be defined as a tumor with a diameter of 20 mm or less. T1a can be defined as a tumor with a maximum diameter greater than 1 mm and less than or equal to 5 mm; T1b can be defined as a tumor with a maximum diameter greater than 5 mm and less than or equal to 10 mm; T1c can be defined as a tumor with a maximum diameter greater than 10 mm and less than or equal to 20 mm. T2 can be defined as a tumor with a maximum diameter greater than 20 mm and less than or equal to 50 mm. T3 can be defined as a tumor with a maximum diameter greater than 50 mm. T4 can be defined as a tumor of any size that has directly extended into the chest wall and / or skin (e.g., ulcer or skin nodule). T4a may be one that has extended into the chest wall. T4b can be defined as edema or ulcer of the skin of the breast, or a satellite skin nodule confined to the same breast. T4c can be defined as both T4a and T4b. T4d can be defined as an inflammatory cancer characterized by diffuse erythema and edema covering more than one-third of the breast skin.

[0024] The lymph nodes in the vicinity of the breast include (1) axillary lymph nodes, interpectoral lymph nodes (Lotter's lymph nodes), and lymph nodes along the axillary vein and its branches. Axillary lymph nodes may be level I (low axillary), level II (mid axillary), or level III (apical axillary); (2) internal mammary lymph nodes; (3) superclavical lymph nodes; and (4) intramammary lymph nodes, which may include one or more.

[0025] For cancers that have spread to or may spread to lymph nodes, N0 indicates that the cancer has not spread to adjacent lymph nodes; N1 indicates that the cancer has spread to 1-3 axillary lymph nodes and / or is found in the internal mammary lymph nodes on sentinel lymph node biopsy; N2 indicates that the cancer has spread to 4-9 axillary lymph nodes or there is hypertrophy of the internal mammary lymph nodes; and N3 indicates that the cancer has spread to 10 or more axillary lymph nodes, at least one extent of cancer spread is greater than 2 mm, or the subclavian lymph nodes This indicates that the cancer has spread to the lymph nodes, at least one extent of cancer spread is greater than 2 mm, or is present in at least one axillary lymph node (at least one extent of cancer spread is greater than 2 mm) and there is enlargement of the endomasty lymph nodes, or has spread to four or more axillary lymph nodes (at least one extent of cancer spread is greater than 2 mm), and sentinel lymph node biopsy indicates that the cancer has spread to the endomasty lymph nodes, or to the supraclavicular lymph nodes on the same side as the cancer, with at least one extent of cancer spread being greater than 2 mm.

[0026] Lymph node classification may be clinical or pathological. Clinical classification may include cN1, defined as metastasis in ipsilateral level I and II axillary lymph nodes; cN2a, defined as metastasis in ipsilateral level I and II axillary lymph nodes that are clustered together (matted); cN2b, defined as metastasis in only clinically detectable ipsilateral internal mammary lymph nodes, without clinically apparent level I and II axillary lymph node metastasis; cN3a, defined as metastasis in ipsilateral subclavian (level III axillary) lymph nodes regardless of the presence or absence of level I and II axillary lymph node lesions; cN3b, defined as metastasis in one or more clinically detectable ipsilateral internal mammary lymph nodes and one or more clinically apparent axillary lymph nodes; or cN3c, defined as metastasis in one or more ipsilateral superclavicular lymph nodes regardless of the presence or absence of axillary or internal mammary lymph node lesions.

[0027] An extension of the TMN classification system is the R classification system, or residual tumor classification system, which can be used to indicate the tumor status after treatment. The R classification can indicate the effectiveness of treatment and can be used to predict prognosis. For example, a patient may be classified using the TMN classification system and diagnosed with a tumor to be treated next, and then any residual tumor may be classified according to the R classification system. Using this system, the extent of tumor resection can be classified as R0, R1, or R2. In R0, there is no residual tumor after surgery; for example, the resection margin is microscopically negative with respect to residual tumor. In R1, there is no residual macroscopic tumor, but the microscopic resection margin still indicates the presence of tumor. In R2, a macroscopic (visible macroscopic) tumor remains after surgery.

[0028] The TNM classification system predates many genetic tests and / or biochemical marker (or "biomarker") tests currently in common use to provide additional predictive or prognostic information regarding cancer type, and can be used in conjunction with such and / or other tests for classifying cancers. For example, the TNM classification system can be used in combination with measures such as tumor malignancy, estrogen receptor (ER) status, progesterone receptor (PR) status, and human epidermal growth factor receptor 2 (HER2) status. Examples of such combinations are provided in Table 1 of Ann Surg Oncol. 2018 Jul;25(7):1783-1785.doi:10.1245 / s10434-018-6486-6.Epub 2018 Apr 18.

[0029] One example of a biomarker used in breast cancer is the nuclear antigen Ki-67. Ki-67 levels can be measured in breast cancer cells, for example, using immunohistochemical staining. The anti-human Ki-67 antibody MIB1 can be used for immunohistochemistry. The Ki-67 value is calculated as the percentage of the total number of malignant cells that are positively marked as malignant (Breast Cancer Res Treat. 2013;139(2):539-552). In general, Ki-67 expression correlates with high cell proliferation (J Clin Oncol. 2005 Oct 1;23(28):7212-20).

[0030] Genetic testing, such as multi-gene or multi-parameter expression assays, can be used to assess the characteristics, metastasis risk, and / or recurrence risk of breast cancer. One example test is the Oncotype DX® test, where a breast recurrence score of 26 or higher (on a scale of 0 to 100) indicates a risk of recurrence. Another example test is the Prosigna® / PAM50 (Prediction Analysis of Microarray 50) test, which assigns tumors a low, moderate, or high risk score for metastasis depending on the expression levels of 50 genes in the tumor. Other example tests, but not limited to, include MammaPrint®, EndoPredict®, and Breast Cancer Index® tests, which can be used to determine risk scores for cancer recurrence.

[0031] Another method for classifying tumors is the “staging” classification system. This method may be used alone or in conjunction with the TNM classification system and other tests, and it classifies breast cancer into anatomical staging groups (or “stages”). Thus, breast cancer can be classified according to staging group (or “anatomical staging group”) 0, I, II, III, or IV. In detail, the staging groups may be stage 0, Ia, Ib, IIa, IIb, IIIa, IIIb, IIIC, or IV.

[0032] Stage 0: Stage zero (0) can represent a disease that is limited to the milk ducts of the breast tissue and has not spread to the surrounding tissues of the breast. This is also called non-invasive carcinoma or carcinoma in situ (Tis, N0, M0).

[0033] Stage IA may refer to a small, invasive tumor that has not spread to the lymph nodes (T1, N0, M0).

[0034] Stage IB may refer to cancer that has spread to the lymph nodes, where the lymph node cancer is larger than 0.2 mm but smaller than 2 mm in size. There may be no evidence of a tumor in the breast, or the tumor in the breast may be 20 mm or smaller (T0 or T1, N1mi (also called "N1 micrometastatic"), M0).

[0035] Stage IIA may refer to cancer that meets any one of the following conditions: a. There is no evidence of a tumor in the breast, however, the cancer has spread to 1-3 axillary lymph nodes. It has not spread to distant parts of the body (T0, N1, M0). b. The tumor is less than 20 mm in size and has spread to 1 to 3 axillary lymph nodes (T1, N1, M0). c. The tumor is larger than 20 mm but less than or equal to 50 mm, and has not spread to the axillary lymph nodes (T2, N0, M0).

[0036] Stage IIB can refer to any of the following conditions: a. The tumor is larger than 20 mm but less than or equal to 50 mm in size, and has spread to 1 to 3 axillary lymph nodes (T2, N1, M0). b. The tumor is larger than 50 mm, but has not spread to the axillary lymph nodes (T3, N0, M0).

[0037] Stage IIIA can refer to a tumor of any size 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 may also refer to a tumor larger than 50 mm that has spread to 1-3 axillary lymph nodes (T3, N1, M0).

[0038] Stage IIIB may refer to a tumor that has spread to the chest wall or has caused swelling or ulceration of the breast, or it may be diagnosed as inflammatory breast cancer. It may or may not have spread to up to nine axillary or internal breast lymph nodes. It has not spread to other parts of the body (T4;N0, N1, or N2;M0).

[0039] Stage IIIC may refer to a tumor of any size that has spread to 10 or more axillary lymph nodes, internal mammary lymph nodes, and / or subclavian lymph nodes. It has not spread to other parts of the body (any of T, N3, or M0).

[0040] Stage IV (metastatic) refers to a tumor of any size that has spread to other organs, such as the bones, lungs, brain, liver, distant lymph nodes, or chest wall (any T, any N, M1). Metastatic cancer is found at the time of the initial diagnosis in about 6% of cases. This is sometimes called de novo metastatic breast cancer. Most commonly, metastatic breast cancer is found after a previous diagnosis of early-stage breast cancer.

[0041] Recurrent cancer is cancer that reappears after treatment and can be described as local, regional, and / or distant (Breast Cancer: Stages from Cancer.Net).

[0042] Recurrence is evaluated by medical imaging and confirmed histologically (or cytologically, where applicable). Recurrence may be classified as local, regional, or distant recurrence, or as contralateral invasive breast cancer or secondary primary non-breast cancer invasive carcinoma, according to the following guidelines: - Locally invasive breast cancer recurrence or ipsilateral invasive breast tumor recurrence: Invasive breast cancer with a lesion in the same breast as the original primary tumor. Carcinomas and tumors in the ducts and lobules of the contralateral breast and / or contralateral lymph nodes are not considered locally invasive recurrence. Histological confirmation is required. - Regional breast cancer recurrence: Invasive breast cancer in the ipsilateral breast, ipsilateral axilla, regional lymph nodes (at all levels), chest wall, or skin. Tumors in the contralateral breast are not considered regional recurrences. Histological (preferably) or cytological confirmation is also required. - Distant recurrence: Distant metastasis of breast cancer (bone, distant lymph nodes, internal organs, CNS, bone marrow, etc.) or any extent of local or non-territorial invasive breast cancer recurrence. Distant recurrence may be confirmed histologically (preferably) or cytologically. If bone metastases are identified by bone scan, and biopsy is not possible, confirmation by histological examination (preferably) or by X-ray imaging (CT, MRI, or FDG-PET-CT) may be used. Metastasis to the central nervous system, which may be confirmed histologically (preferably), cytologically, or by X-ray imaging (CT or MRI, both with IV contrast agent) if confirmation by biopsy is not possible. 〇All other metastatic sites, whether histologically (preferably) or cytologically confirmed, unless there is an unacceptable risk to the patient due to the procedure. - Contralateral invasive breast cancer: Any invasive breast cancer in the contralateral breast, regardless of the presence or absence of contralateral lymph node lesions. Contralateral invasive breast cancer must be histologically confirmed. Contralateral breast cancer in situ / non-invasive is not included in contralateral invasive breast cancer. - Secondary primary non-invasive breast cancer: Any secondary primary non-invasive breast cancer. Secondary primary non-invasive breast cancer must be histologically confirmed. Carcinoma in situ / non-invasive and basal cell or squamous cell carcinoma are not considered secondary primary non-invasive breast cancer.

[0043] Table B1 summarizes the anatomical stages from the 8th edition of the AJCC.

[0044] [Table 1]

[0045] It should be noted that T2, T3, and T4 tumors with lymph node micrometastasis (N1mi) can be staging using the N1 classification.

[0046] Therefore, in some embodiments, adult patients treated by the method described herein have EBC which is ductal carcinoma in situ, stage I breast cancer, 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 early stage II or III 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 may be lymph node positive (e.g., the cancer has spread to the lymph nodes) or lymph node negative (e.g., the cancer has not spread to the lymph nodes). In some embodiments, the treatment method described herein is performed regardless of the lymph node status of the patient's breast cancer.

[0047] In certain embodiments, EBCs are hormone receptor-positive (HR+) breast cancers, such as breast cancers comprising cells expressing one or more hormone receptors. Exemplary hormone receptors may be estrogen receptors (ER), such as ERα or ERβ, and / or progesterone receptors (PR), such as PRA and PRB. EBCs may comprise breast cancer cells expressing either estrogen receptors (ER+) or progesterone receptors (PR+), or a combination of both estrogen receptors and progesterone receptors (ER+ / PR+). In some embodiments, EBCs are ER+ / PR-, ER- / PR+, or ER+ / PR+.

[0048] In certain embodiments, EBCs are positive for human epidermal growth factor receptor 2 (HER2).

[0049] Certain embodiments relate to a method for preventing early breast cancer or reducing its signs or symptoms, comprising administering to a patient a treatment comprising ribociclib, its free base form or a pharmaceutically acceptable salt thereof, in combination with an aromatase inhibitor, preferably letrozole or anastrozole. In some embodiments, ribociclib, in its free base form or a pharmaceutically acceptable salt thereof, is administered to the patient in doses ranging from 150 mg / day to 450 mg / day on days 1 to 21 of a 28-day cycle. In some embodiments, the aromatase inhibitor is administered daily during the 28-day cycle.

[0050] B. CDK inhibitors and endocrine therapy One aspect of the present disclosure relates to a method for treating early-stage breast cancer in an adult patient requiring treatment for early-stage breast cancer, the method comprising administering to the patient a treatment comprising a cyclin-dependent kinase (CDK) inhibitor in combination with endocrine therapy (ET).

[0051] Cyclin-dependent kinases (CDKs) are serine / threonine protein kinases that bind to cyclins and form active complexes within cells. In healthy cells, various extracellular and intracellular cues meticulously regulate the formation of CDK / cyclin complexes, controlling the phosphorylation of target proteins involved in the cell cycle, such as retinoblastoma (Rb) protein, lamins, histone H1, and spindle components. However, in cancer cells, CDKs become overactivated, potentially leading to uncontrolled tumor growth.

[0052] CDK4 and CDK6, which bind to D-cyclin, are exemplary CDKs that have been shown to promote the growth of certain types of breast cancer tumors. In such tumors, D-cyclin is overexpressed, leading to activation of CDK4 and CDK6, followed by phosphorylation of Rb, release of Rb repression by the E2F transcription factor, and rapid progression of tumor cells throughout the cell cycle (Shah et al., Oncology. 2018 May 15;32(5):216-222).

[0053] CDK inhibitors have been shown to block unregulated cell growth and division resulting from overactivation of CDK and / or overexpression of cyclin proteins. For example, CDK / cyclin complex inhibitors and CDK4 / 6 inhibitors are used, in detail, to treat patients with certain types of cancer. The CDK4 / 6 inhibitors palbociclib, ribociclib, and abemaciclib are approved by regulatory authorities 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. 2022 Jan 14;375(6577):eabc1495). To date, ribociclib has been approved by several regulatory authorities, including the U.S. Food and Drug Administration (FDA) and the European Commission. According to the FDA, it is approved (1) in combination with AI as an initial endocrine-based therapy for the treatment of premenopausal / perimenopausal or postmenopausal women with HR-positive HER2-negative advanced or metastatic breast cancer; or (2) in combination with fulvestrant as an initial endocrine-based therapy or after disease progression during ET for the treatment of postmenopausal women with HR-positive HER2-negative advanced or metastatic breast cancer. In Europe, ribociclib is indicated as an initial endocrine-based therapy in combination with AI or fulvestrant for the treatment of women with HR-positive HER2-negative locally advanced or metastatic breast cancer, or women who have previously undergone ET. In premenopausal or perimenopausal women, ET may be combined with a luteinizing hormone-releasing hormone agonist.

[0054] Therefore, in some embodiments of this disclosure, the CDK inhibitor used in the methods disclosed herein may be a CDK4 / 6 inhibitor, for example, an inhibitor of the CDK4 / 6 / cyclin complex. The cyclin may be a D-cycline, such as cyclin-D1 in the CDK4 / cyclin-D1 complex or cyclin-D3 in the CDK6 / cyclin-D3 complex.

[0055] In some embodiments, the CDK4 / 6 inhibitor may be a compound represented by the following formula A1 or a salt thereof. [ka]

[0056] The compound of formula A1 is known by the international generic name ribociclib. Thus, in some embodiments, the CDK4 / 6 inhibitor may be a compound having the international generic name ribociclib.

[0057] Ribociclib may be in the form of its free base or a pharmaceutically acceptable salt of ribociclib. The salt may exist alone or in a mixture with the free compound, such as ribociclib, and is preferably a pharmaceutically acceptable salt. Such salts of ribociclib are formed from a compound of ribociclib having a basic nitrogen atom, for example, as an acid addition salt with an organic or inorganic acid. Suitable inorganic acids are halogen acids such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are succinic acid, carboxylic acid, or sulfonic acid, such as fumaric acid or methanesulfonic acid. For isolation or purification purposes, pharmaceutically unacceptable salts, such as picrate or perchlorate, may also be used. For therapeutic use, only pharmaceutically acceptable salts or free compounds (in the form of pharmaceutical formulations, where applicable) are used and are therefore preferred.

[0058] In some embodiments, ribociclib may be in the form of racemates, diastereoisomers, enantiomers, and tautomers, as well as corresponding crystalline transformations, if present, such as solvates, hydrates, and polymorphs.

[0059] Ribociclib may be available in succinate form, such as a pharmaceutically acceptable salt, e.g., ribociclib succinate. The chemical name of ribociclib succinate is butaneoic acid-7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin 1-yl)pyridine-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (1:1), with molecular formula C 27 H 36 This corresponds to N8O5, which has a relative molecular mass of 552.6 g / mol (EMA determination reported for Kisqali, procedure number EMEA / H / C / 004213 / 0000, dated June 22, 2017).

[0060] Ribociclib in oral tablet form is known in the art (e.g., International Publication No. 2016 / 166703) and is approved as a KISQALI® product. Various ribociclib salts are described (e.g., see claim 85 of International Publication No. 2022 / 207788), and approved KISQALI® products contain ribociclib succinate. The amount of any salt will be adjusted to provide ribociclib of the desired quality (e.g., 254.40 mg of ribociclib succinate corresponds to 200 mg of ribociclib). Various polymorphisms of ribociclib succinate are known (see, for example, International Publication Nos. 2019 / 040567, 2019 / 082143, 2019 / 150181, 2019 / 166987, 2020 / 225827, 2021 / 038590, etc.). The methods described herein may be carried out using previously approved KISQALI® products, for example, in conjunction with previously approved endocrine therapies.

[0061] As described herein, CDK inhibitors (such as ribociclib or pharmaceutically acceptable salts thereof, such as ribociclib succinate, or CDK4 / 6 inhibitors) may be administered in conjunction with endocrine therapy. In some embodiments of this disclosure, the endocrine therapy is an aromatase inhibitor.

[0062] Endocrine therapy (also known as hormone therapy, hormonal therapy, or hormone treatment) is used to slow or stop the growth of hormone-sensitive cancers (also known as hormone-dependent cancers). Hormone-sensitive tumors express receptors for hormones such as estrogen and / or progesterone, and hormones can promote cancer growth. Therefore, endocrine therapy refers to either (1) a therapy that interferes with the effects of hormones on cancer cells, or / or (2) a therapy that blocks the body's ability to produce hormones.

[0063] Exemplary compounds that interfere with the effects of hormones on breast cancer cells are selective estrogen receptor modulators (SERMs), which bind to estrogen receptors and prevent 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 may bind to estrogen receptors without mimicking the effects of estrogen, and instead may target estrogen receptors for destruction. An exemplary anti-estrogen compound is Faslodex®.

[0064] Hormone production can be blocked by ablation of the hormone-producing tissue or organ. In premenopausal women, for example, the ovaries are the main source of estrogen, and estrogen levels can be removed or reduced by ovarian ablation (e.g., oophorectomy (also called oophorotomy or oophorectomy) or radiation therapy).

[0065] Alternatively, hormone production can be blocked by administering compounds that inhibit hormone synthesis and / or release. Gonadotropin-releasing hormone (GnRH) agonists administered over extended periods can induce desensitization, resulting in suppression of gonadotropin secretion. In contrast, GnRH antagonists inhibit 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 inhibit estrogen release from the ovaries in women and testosterone release from the testes in men. In some embodiments, goserelin is used in the methods disclosed herein.

[0066] A further class of compounds that block estrogen production is, in detail, aromatase inhibitors. Aromatase inhibitors work by inhibiting the action of aromatase, an enzyme that converts androgens into estrogen in a process called aromatization. In particular, in premenopausal women, the ovaries produce levels of aromatase that are too high to be blocked by aromatase inhibitors alone. For premenopausal women, aromatase inhibitors may be combined with compounds that suppress ovarian function (e.g., goserelin or leuprolide). In contrast, postmenopausal women produce estrogen mainly in peripheral tissues rather than in the ovaries, so aromatase inhibitors may be sufficient to inhibit estrogen production in these women.

[0067] There are two types of aromatase inhibitors: (1) steroidal inhibitors such as exemestane (Aromasin®) that form a permanent inactivating bond with the aromatase enzyme; and (2) nonsteroidal inhibitors (NSAIDs) such as anastrozole (Arimidex®) or letrozole (Femara®).

[0068] Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system. Letrozole acts by highly selectively inhibiting the conversion of androgens (primarily from the adrenal glands, the primary estrogen source in postmenopausal women) to estrogen. After two weeks of treatment with a daily dose of 0.1–5 mg of letrozole, estrogen levels are reduced by 75–95% without significant clinical and laboratory toxicity or changes in the levels of other endocrine hormones (Lancet Lond Engl 386:1341-1352, 2015; Cancer 75:2132-2138, 1995).

[0069] Anastrozoles, such as letrozole, are selective non-steroidal antimicrobial agents (NSAIDs). They significantly lower serum estradiol levels without any detectable effect on the formation of adrenal corticosteroids or aldosterone.

[0070] In some embodiments, the endocrine therapy administered with a CDK inhibitor (e.g., a CDK4 / 6 inhibitor such as ribociclib or ribociclib succinate, or a pharmaceutically acceptable salt thereof) is an aromatase inhibitor, such as anastrozole or letrozole. In some embodiments, the therapy further comprises a gonadotropin-releasing hormone agonist, such as goserelin.

[0071] Exemplary aromatase inhibitors are described in Breast Cancer Res Treat. 2007 Oct;105(Suppl 1):7-17.

[0072] The aromatase inhibitor may be a nonsteroidal aromatase inhibitor described by one of the following formulas, or a pharmaceutically acceptable salt thereof. [ka]

[0073] 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-triazole-1-ylmethylene)dibenzonitrile. Letrozole is readily soluble in dichloromethane, sparingly soluble in ethanol, and particularly insoluble in water. It has a molecular weight of 285.31 g / mol, empirical formula C 17 H 11 It contains N5 and has a melting range of 184°C to 185°C.

[0074] In some embodiments, letrozole may be in the form of a racemic mixture, diastereoisomers, enantiomers, or tautomers, and, if present, corresponding crystalline transformations, such as solvates, hydrates, and polymorphs.

[0075] In some embodiments, the aromatase inhibitor may be anastrozole or a pharmaceutically acceptable salt thereof. The chemical name of anastrozole is α,α,α',α'-tetramethyl-5-(1H-1,2,4-triazole-1-ylmethyl)-m-benzenediacetonitrile. Anastrozole is readily soluble in methanol, acetone, ethanol, and tetrahydrofuran, and very soluble in acetonitrile. It has a molecular weight of 293.374 g / mol and is empirically formulated C 17 H 19 N5, with a melting range of 80°C to 86°C. In some embodiments, anastrozole may be in the form of a solvate, hydrate, or polymorph.

[0076] In some embodiments, the endocrine therapy may include an aromatase inhibitor (such as letrozole or anastrozole) for postmenopausal women. For premenopausal women or men, the endocrine therapy may include an aromatase inhibitor (such as letrozole or anastrozole) and may further include compounds that suppress gonadal function (e.g., GnRH agonists such as goserelin).

[0077] The GnRH agonist is a compound according to the following formula or a pharmaceutically acceptable salt thereof: [Chemical formula] It may be.

[0078] In some embodiments, the aromatase inhibitor may be goserelin or a pharmaceutically acceptable salt thereof. Goserelin is sold under the trademark Zoladex®. It has a molecular weight of 1269.433 g / mol and the empirical formula C 59 H 84 N 18 O 14 In some embodiments, goserelin may be in the form of a solvate, hydrate or polymorph.

[0079] C. Administration - Dosage and Treatment Schedule A further aspect of the present disclosure relates to a method of treating early breast cancer in an adult patient who requires treatment for early breast cancer, the method comprising administering to the patient a treatment comprising a certain dose of a cyclin - dependent kinase (CDK) inhibitor in combination with a certain dose of endocrine therapy.

[0080] In some embodiments, the CDK inhibitor is a CDK4 / 6 inhibitor such as ribociclib or a pharmaceutically acceptable salt thereof (such as ribociclib succinate), and the endocrine therapy is an aromatase inhibitor such as letrozole. In some embodiments, the endocrine therapy is letrozole.

[0081] A daily dose of 600 mg of ribociclib on days 1–21 of a 28-day cycle has been shown to be well-tolerated and effective in combination with ET in clinical trials in patients with advanced BC (N Engl J Med 375:1738-1748, 2016). However, since HR-positive HER2-negative EBC can recur later, and events can always occur from one year after surgery to at least 15 years after diagnosis, longer therapy durations may also be beneficial for EBC. In some embodiments, ribociclib (in combination with ET) may be administered daily at doses less than 600 mg. For example, ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate) may be administered daily at a dose of approximately 400 mg. This exemplary dose may be administered as 2 × 200 mg daily.

[0082] In some embodiments, ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate) may be administered at a dose of approximately 400 mg / day. The dose of ribociclib or a pharmaceutically acceptable salt thereof (such as ribociclib succinate) may be administered once daily in tablet form, for example, as 2 x 200 mg tablets (it is understood that these two tablets may be taken simultaneously or sequentially within the range of a single daily dose). The dose may be administered as an oral solution. The dose may be administered orally (by mouth). In some embodiments, the dose of ribociclib or a pharmaceutically acceptable salt thereof (such as ribociclib succinate) is approximately 200 mg / day. This dose may be administered in tablet form, for example, as 1 x 200 mg tablet. The dose may be administered orally (by mouth). The dose may be a fixed, uniform dose, rather than being calculated based on, for example, body weight or body surface area.

[0083] For example, dose adjustments may be made to administer ribociclib or a pharmaceutically acceptable salt thereof (such as ribociclib succinate) at doses of less than approximately 400 mg / day. For example, doses of approximately 350 mg / day, approximately 300 mg / day, approximately 250 mg / day, approximately 200 mg / day, or approximately 150 mg / day of ribociclib or a pharmaceutically acceptable salt thereof (such as ribociclib succinate) may be administered. In some embodiments, the dose of approximately 200 mg / day is administered after the previous dose of 400 mg / day has been administered. In some embodiments, the dose is administered in tablet form, such as a 1 x 200 mg tablet. The dose of approximately 200 mg / day may be administered orally. Therefore, a patient who previously received a dose of approximately 400 mg of ribociclib or a pharmaceutically acceptable salt thereof (such as ribociclib succinate) (e.g., 2 x 200 mg tablets orally) may instead receive a dose of approximately 200 mg / day (e.g., 1 x 200 mg tablet orally). The dose may be taken once daily (e.g., 1 x 200 mg tablet once daily, or 2 x 200 mg tablets once daily).

[0084] For patients who cannot tolerate a dose of approximately 400 mg / day, dose adjustment may be made. For example, a patient receiving approximately 400 mg / day of ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate) who experiences one or more of the following adverse events: thrombocytopenia, decreased absolute neutrophil count (ANC), febrile neutropenia, anemia, hepatotoxicity (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 the QT interval), interstitial lung disease / pneumonitis, and / or other adverse events may receive an adjusted dose of approximately 200 mg / day of ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate).

[0085] Thus, the dose of ribociclib (or its pharmaceutically acceptable salt, such as ribociclib succinate) may range from approximately 150 mg / day to approximately 450 mg / day. The dose may be approximately 150 mg / day, approximately 200 mg / day, approximately 250 mg / day, approximately 300 mg / day, approximately 350 mg / day, or approximately 450 mg / day. The dose may be taken once daily.

[0086] In some embodiments, the dose of ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate) is not approximately 600 mg / day.

[0087] In some embodiments, the aromatase inhibitor is letrozole. The dose of letrozole may be selected according to data indicating disease-free survival in patients (e.g., clinical data), and such data may be combined with data on adverse effects such as renal and / or hepatic impairment to establish an effective dose. The dose may also be selected by examining the efficacy and tolerability of individual patients.

[0088] The dose of letrozole may range from approximately 1 mg / day to approximately 4 mg / day. For example, the dose of letrozole may be approximately 1 mg / day, approximately 1.25 mg / day, approximately 1.5 mg / day, approximately 1.75 mg / day, approximately 2 mg / day, approximately 2.25 mg / day, approximately 2.5 mg / day, approximately 2.75 mg / day, approximately 3 mg / day, approximately 3.25 mg / day, approximately 3.5 mg / day, approximately 3.75 mg / day, or approximately 4 mg / day. In some embodiments, the dose of letrozole is approximately 2.5 mg / day. The dose may be a fixed, uniform dose rather than being calculated, for example, by body weight or body surface area.

[0089] Letrozole may be administered orally (for example, by mouth). Therefore, any of the above-mentioned dosages, such as approximately 2.5 mg / day of letrozole, may be administered. Letrozole may be administered orally. The dosage may be administered in tablet form. The dosage may be taken once a day.

[0090] In certain embodiments, the aromatase inhibitor is anastrozole. The dose of anastrozole may be selected according to data indicating disease-free survival in patients (e.g., clinical data), and such data may be combined with data on adverse effects such as renal and / or hepatic impairment to establish an effective dose. The dose may also be selected by examining the efficacy and tolerability of individual patients.

[0091] The dose of anastrozole may range from approximately 0.5 mg / day to approximately 1.5 mg / day. For example, the dose of anastrozole may be approximately 0.5 mg / day, approximately 0.75 mg / day, approximately 1 mg / day, approximately 1.25 mg / day, or approximately 1.50 mg / day. In some embodiments, the dose of anastrozole is approximately 1 mg / day.

[0092] Anastrozole may be administered orally (for example, by mouth). Therefore, any of the above-mentioned dosages may be administered, such as an anastrozole dose of approximately 1 mg / day. Anastrozole may be administered orally. The dose may be administered in tablet form. The dose may be taken once a day.

[0093] In addition to ribociclib (or ribociclib succinate or other pharmaceutically acceptable salts thereof) (e.g., about 400 mg / day or about 200 mg / day) and letrozole (about 2.5 mg / day) or anastrozole (about 1 mg / day), patients may receive a gonadotropin-releasing hormone agonist such as goserelin. For example, patients who are premenopausal women and patients who are men may receive a certain dose of goserelin. The dose of goserelin may be selected according to data indicating efficacy in patients (e.g., clinical data) or by examining the efficacy and tolerability in individual patients.

[0094] The dose of goserelin may range from approximately 2 mg to approximately 5 mg. The dose of goserelin may be approximately 2 mg, approximately 2.25 mg, approximately 2.5 mg, approximately 2.75 mg, approximately 3 mg, approximately 3.25 mg, approximately 3.5 mg, approximately 3.75 mg, approximately 4 mg, approximately 4.25 mg, approximately 4.5 mg, approximately 4.75 mg, or approximately 5 mg. In some embodiments, the dose of goserelin is approximately 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 may be a fixed, uniform dose rather than being calculated based on, for example, body weight or body surface area.

[0095] Goserelin may be administered subcutaneously. The dose may be administered subcutaneously at time intervals ranging from 2 to 4 weeks.

[0096] In one embodiment, goserelin is administered subcutaneously at a dose of 3.6 mg.

[0097] The compounds may be administered individually, for example, when the compounds are administered by different routes of administration and / or according to different treatment schedules. When administered individually, the compounds may be administered simultaneously or sequentially. In one exemplary example, two compounds are administered to a patient in two separate doses, but on the same day. In this example, the two compounds may be administered at the same time, or they may be administered at different time periods. The compounds may be administered individually in two or more separate unit doses (for example, where a unit dose is the amount of the compound administered to a patient in a single dose) and / or in unit dosing forms.

[0098] The compounds may be combined for administration together. The compounds may also be administered together in a single pharmaceutical composition, for example, in a single dose (e.g., a unit dose). The unit dosing form may also be a fixed combination.

[0099] In some embodiments, a dose of ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate) (about 400 mg / day, or about 200 mg / day) is administered together with an endocrine therapy (e.g., letrozole (about 2.5 mg / day) or anastrozole (about 1 mg / day). Generally, the doses may be administered at the same time, such as in the morning. The doses may also be administered in the afternoon or at night. In some embodiments, the doses are not administered at night.

[0100] Further aspects of the present disclosure relate to a method for treating early-stage breast cancer in an adult patient requiring treatment for early-stage breast cancer, comprising administering to the patient, in accordance with a treatment schedule, a treatment comprising a certain dose of a cyclin-dependent kinase (CDK) inhibitor in combination with a certain dose of endocrine therapy.

[0101] In some embodiments, the treatment schedule includes a treatment cycle of approximately 28 days. In this cycle, the CDK inhibitor is administered once daily on days 1 to 21 of the 28-day cycle, followed by a possible 7-day rest period from the CDK inhibitor, during which the endocrine therapy is continued once daily. Thus, the endocrine therapy (e.g., letrozole or anastrozole) may be administered daily throughout the 28-day cycle.

[0102] Therefore, in some embodiments, the CDK inhibitor is ribociclib (or ribociclib succinate or other pharmaceutically acceptable salt thereof) administered at a dose of approximately 400 mg / day (or approximately 200 mg / day), and the endocrine therapy is letrozole administered at a dose of approximately 2.5 mg / day or anastrozole administered at a dose of approximately 1 mg / day, where ribociclib (or ribociclib succinate or other pharmaceutically acceptable salt thereof) is administered once daily on days 1 to 21 of a 28-day cycle, followed by a 7-day rest period of ribociclib (or ribociclib succinate or other pharmaceutically acceptable salt thereof) (days 22 to 28 of the cycle), and letrozole or anastrozole is administered once daily for the duration of the 28-day period (e.g., every day during the 28-day cycle). Ribociclib (or ribociclib succinate, or any pharmaceutically acceptable salt thereof) may be administered orally, for example, in tablet form. Letrozole or anastrozole may be administered orally, for example, in tablet form.

[0103] For patients whose treatment further includes the administration of goserelin (for example, at a dose of approximately 3.6 mg), this may be administered once during a 28-day cycle. Goserelin may be administered every 2 to 4 weeks, for example, every 4 weeks. In some embodiments, goserelin is administered on day 1 (±3 days) of each 28-day cycle. Goserelin may be administered on day -3, day -2, day -1, day 1, day 2, or day 3 of a 28-day cycle.

[0104] Treatment may be administered for at least approximately 12 months. Treatment may be administered for at least approximately 12 months, at least approximately 18 months, at least approximately 24 months, at least approximately 30 months, at least approximately 36 months, at least approximately 42 months, at least approximately 48 months, at least approximately 54 months, at least approximately 60 months, or longer. In some embodiments, ribociclib and letrozole are administered for at least approximately 48 months (approximately 4 years) or at least approximately 60 months (approximately 5 years). In some embodiments, treatment is administered for at least 36 months.

[0105] Exemplary dosages and treatment schedules are shown in Table B1.1.

[0106] [Table 2]

[0107] 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 may have received a loading dose of ribociclib (e.g., or ribociclib salts such as ribociclib succinate) and / or endocrine therapy (e.g., letrozole or anastrozole).

[0108] A loading dose may be an initial dose of a drug that can be given at the beginning or before the course of treatment until it is reduced to another, typically lower dose (e.g., therapeutic or maintenance dose). A loading dose may be a single dose or a short-term regimen compound administered to a subject to rapidly raise the blood drug concentration level. Preferably, short-term regimens as used herein are 1 to 14 days; e.g., 1 to 7 days; e.g., 1 to 3 days; e.g., 3 days; e.g., 2 days; e.g., 1 day. In some embodiments, the “loading dose” can raise the blood drug concentration to a therapeutically effective level. In some embodiments, the “loading dose” can raise the blood drug concentration to a therapeutically effective level in combination with a therapeutic dose of the drug. The “loading dose” may be administered once daily or more frequently (e.g., up to four times daily). In some embodiments, the loading dose may be used for drug molecules that exhibit a long half-life or slow elimination in vivo.

[0109] In some embodiments, treatment is continued until the patient has no remaining signs and / or symptoms of breast cancer. In some embodiments, treatment is continued until the patient has no detectable cancer and / or no signs (e.g., indicating) of cancer recurrence. In some embodiments, treatment is resumed if the patient exhibits one or more signs of cancer recurrence. In some embodiments, treatment is continued until cancer recurs. Signs and / or symptoms of cancer and cancer recurrence may be determined by monitoring the patient over several months and years after treatment using tests such as physical examinations, scans and / or imaging of the site where the cancer was located (e.g., X-ray, computed tomography, g-mammography), and blood tests. In an exemplary example, different modalities of follow-up may be mammography, clinical examinations, whole-body or local MRI and / or CT scans. According to the National Comprehensive Cancer Network guidelines, breast cancer patients may have (1) a clinically recorded history and physical examinations performed 1-4 times annually over a 5-year period, (2) mammograms every 12 months, and (3) no clinical signs or symptoms suggestive of disease recurrence, in which case clinical examinations or imaging studies for metastasis screening are not indicated. If cancer is not detected, the patient may be assumed to be treated, but should be monitored for disease recurrence.

[0110] In some embodiments, the treatment as disclosed herein may be administered to patients who no longer have detectable signs and / or symptoms of cancer, but who may still be at risk of cancer recurrence. In such patients, treatment may be continued for a period ranging, for example, at least about 3 months to at least about 10 years, e.g., 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, or any intermediate period. During this period, patients may be monitored for cancer recurrence, for example, by clinical examinations, mammography, scans, imaging, sampling (e.g., tissue biopsy), and / or blood tests. Patients who do not have detectable signs and / or symptoms of cancer during this period may discontinue the treatment described herein. In some embodiments, patients may continue treatment for a further period. In some embodiments, patients who experience cancer recurrence may discontinue treatment, for example, to try another treatment option.

[0111] D.Patient Another aspect of the present disclosure relates to a method for treating early-stage breast cancer in an adult patient requiring treatment for early-stage breast cancer, comprising administering to the patient a treatment comprising a cyclin-dependent kinase (CDK) inhibitor in combination with endocrine therapy, wherein the adult patient is selected or characterized according to one or more criteria.

[0112] Criteria may include the patient's demographic information, the patient's characteristics of early-stage breast cancer (e.g., type, stage, grade, hormone receptor status, etc.), past treatments, and / or other criteria as described herein.

[0113] I. Age In some embodiments, the patient is an adult, for example, 18 years of age or older. In some embodiments, the patient is approximately 18 to 45 years of age. In some embodiments, the patient is approximately 45 to 54 years of age. In some embodiments, the patient is approximately 55 to 64 years of age. In some embodiments, the patient is approximately 64 years of age or older. The patient may belong to an age group lower than the median age of a given EBC patient population, or the patient may belong to an older age group that is equal to or greater than the median age of the EBC patient population.

[0114] II. Sex and Menopausal Status In some embodiments, the patient is female. In other embodiments, the patient is male. For female patients, the patient's menopausal status may be premenopausal or postmenopausal.

[0115] A postmenopausal patient may be defined as (1) a patient who has undergone bilateral oophorectomy; (2) a patient aged 60 years or older; (3) a patient under 60 years of age who has had amenorrhea for 12 months or more (without chemotherapy, tamoxifen, toremifene, or ovarian suppression) and whose follicle-stimulating hormone (FSH) and plasma estradiol levels are within the postmenopausal range according to the normal range of each institution; or (4) a patient under 60 years of age who is taking tamoxifen or toremifene and whose FSH and plasma estradiol levels are within the postmenopausal range.

[0116] The premenopausal state may define patients who do not meet the criteria for the postmenopausal state. For women in the premenopausal state, amenorrhea may not be a reliable indicator of menopausal status because ovarian function may still be intact or may resume despite anovulation / amenorrhea. For such women with therapy-induced amenorrhea, postmenopausal status may be determined using continuous monitoring of FSH and / or estradiol in accordance with the clinical guidelines of each institution.

[0117] III. Fertility possibility In some embodiments, the patient is a woman with childbearing potential (CBP), defined as being physiologically capable of becoming pregnant.

[0118] Women may be considered CBP unless they have a suitable clinical profile (i.e., appropriate age, history of vasomotor symptoms) and have experienced spontaneous amenorrhea for 12 months or longer, or have undergone surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation within at least 6 weeks prior to randomization. In cases of oophorectomy alone, women may be considered not to have CBP after confirmation by hormone level assessment.

[0119] In some embodiments, the patient is a non-pregnant woman with CBP.

[0120] In some embodiments, the patient is not a woman who is pregnant or lactating (lactating) during treatment as described herein, or is not expected to become pregnant or lactating.

[0121] IV. Diagnosis of Breast Cancer In some embodiments, patients requiring treatment for early-stage breast cancer are those who have been diagnosed with early-stage breast cancer. Patients may not have received prior treatment for early-stage breast cancer. Patients may have received prior treatment for early-stage breast cancer, such as surgery, chemotherapy, radiation therapy, and / or hormone therapy, but still require treatment because the prior treatment was ineffective against their early-stage breast cancer. In some embodiments, patients have received prior treatment for early-stage breast cancer and have experienced a recurrence of early-stage breast cancer. In some embodiments, patients have received prior treatment for cancer but have been diagnosed with early-stage breast cancer. In some embodiments, patients are at risk of developing early-stage breast cancer and / or at risk of early-stage breast cancer recurrence. Patients at risk may not have any detectable signs or symptoms of early-stage breast cancer, but may be at risk due to their previous diagnosis of cancer.

[0122] In some embodiments, patients have received prior treatment for early-stage breast cancer, such as HR+HER2-stage II or III early-stage breast cancer, and have no detectable signs or symptoms of early-stage breast cancer, but still are at risk of early-stage breast cancer recurrence. Risk factors may relate to the early-stage breast cancer the patient was treated for, where high tumor grade, large tumor size (e.g., greater than 2 mm), and axillary lymph node lesions may correlate with a higher risk of recurrence.

[0123] In some embodiments, the patient has breast cancer that has been diagnosed and / or confirmed to be (e.g., histologically confirmed) a carcinoma of the breast. The carcinoma may have been diagnosed within 18 months prior to the initiation of treatment. The carcinoma may be a unilateral primary invasive adenocarcinoma. The carcinoma may be a multicentric and / or multifocal tumor.

[0124] V. Hormone receptor (HR) status and human epidermal growth factor receptor 2 (HER2) expression In some embodiments, the patient has hormone receptor-positive breast cancer. The breast cancer may be ER and / or PR-positive. The breast cancer may be ER+ / PR-, ER- / PR+, or ER+ / PR+.

[0125] In some embodiments, the patient has breast cancer that is HER2-positive. For example, breast cancer may be defined as cancer that is negative for in situ hybridization testing and / or has an immunohistochemical (IHC) status of 0 or 1+. If the IHC of breast cancer is 2+ and in situ hybridization (FISH, CISH, or SISH) is negative, it may be used to confirm the HER2-positive status.

[0126] VI. Tumor Characterization In some embodiments, patients are classified into the following categories: Anatomical stage III, or Anatomical stage IIB, or • The anatomical stage is IIA, and it is one of the following: • N1, or • N0, accompanied by the following: • Grade 3, or Grade 2 She has breast cancer, including a tumor belonging to one of the following categories.

[0127] In some embodiments, patients with tumors of anatomical stage IIA, N0, and grade 2 may have additional measures for classifying breast cancer. For example, tumors may have a Ki67 rate of approximately 20% or higher. Tumors may also have scores from multi-parameter tests that indicate a risk of cancer recurrence and / or spread, such as a breast recurrence score of ≥26 (on a scale of 0 to 100) on the Oncotype DX® test, a high-risk score on the Prosigna® / PAM50 (predictive analysis of microarrays 50) test, a high-risk score on the MammaPrint® test, or a high-risk score on the EndoPredict® EPclin test.

[0128] 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.

[0129] In some embodiments, the patient does not have a stage IV tumor, such as a breast cancer tumor that has metastasized beyond the lymph nodes.

[0130] In some embodiments, the patient has a tumor with a lymph node state selected from NX, N0, N1, N2, or N3. For example, the patient may have a tumor with an N0 state. Alternatively, the patient may have a tumor with an N1, N2, or N3 state, or a tumor with any one of the N1, N2, or N3 states.

[0131] In some embodiments, the patient has a tumor of classification T0, classification Tis, T1, T2, T3, or classification T4. In some embodiments, the patient has a tumor of classification T0. The patient may have a tumor in a classification T1, T2, or T3 state, or a tumor that is any one of T1, T2, or T3. In some embodiments, the patient has a tumor of classification T4.

[0132] In some embodiments, the patient has a tumor with stage M0.

[0133] In some embodiments, the patient has a tumor of histological grade GX, G1, G2, or G3 (e.g., grade X, grade 1, grade 2, or grade 3). The patient may have a tumor of histological grade 1. The patient may have a tumor of histological grade 2. The patient may have a tumor of histological grade 3.

[0134] In certain embodiments, the patient has a tumor with a Ki67 status of 20% or less. The Ki67 status may be 14% or less, or it may be higher than 14%. Alternatively, the patient may have a tumor with a Ki67 status greater than 20%. Ki67 may be measured in archived samples of excised tumors from the patient. Ki67 is a proliferation marker in normal human cell populations and can be used as a clinical marker for breast cancer and a predictor of the success of endocrine therapy.

[0135] In some embodiments, the patient has a tumor assessed by genomic testing, such as one or more of the following: EndoPredict® test, MammaPrint® test, Oncotype DX® test, Prosigna / PAM50® test, and Breast Cancer Index® test. The patient may have risk scores from one or more tests indicating a high risk for cancer recurrence and / or metastasis.

[0136] In some embodiments, the tumor has an EndoPredict EPclin® risk score indicating high risk. In some embodiments, the tumor has a MammaPrint® test result indicating high risk. In some embodiments, the tumor has a Prosigna / PAM50® test result indicating high risk. In some embodiments, the tumor has an Oncotype DX breast recurrence score of approximately 26 or higher.

[0137] Scales such as histopathological grade, T stage, N stage, M stage, and Ki67 may be determined at the time of initial diagnosis or in relation to the surgical specimen.

[0138] In some embodiments, the patient may have a ductal carcinoma subtype tumor. The patient may have a lobular carcinoma subtype tumor. Alternatively, the patient may have a tumor of a subtype that is neither ductal carcinoma nor lobular carcinoma.

[0139] In some embodiments, the dominant histological features of the tumor are selected from invasive ductal carcinoma, unspecified (NOS), invasive lobular carcinoma, medullary carcinoma, mucinous carcinoma, papillary carcinoma, tubular carcinoma of the mammary gland, ductal carcinoma in situ, and lobular carcinoma in situ.

[0140] In some embodiments, the patient has a tumor with HER2 ISH results including an IHC score of 0, 1+, 2+, or 3+. The HER2 ISH results may be obtained before surgery or from the surgical specimen.

[0141] In some embodiments, the patient has a hormone receptor-positive state, for example, ER-positive and / or PR-positive. The positive state can be obtained before surgery or from surgical specimens.

[0142] In certain embodiments, the patient has a tumor without metastasis to the sentinel lymph node (e.g., the patient is considered pN0). The patient may have only micrometastases to the sentinel lymph node (e.g., the patient is considered pN1mi). The patient may have a T1-2 tumor, no clinically apparent lymph nodes prior to surgery, no neoadjuvant chemotherapy, at least one macrometastasis in one or two sentinel lymph nodes, and / or no matted lymph nodes or macroscopic extranodal disease at the time of sentinel lymph node dissection (e.g., the patient is considered pN1).

[0143] In some embodiments, breast cancer staging is performed by lymph node dissection, such as axillary lymph node dissection (ALND). In some embodiments, staging is performed by sentinel lymph node (SLN) dissection.

[0144] In some embodiments, the tumor is located only in the right breast and not in the left breast. Alternatively, the tumor may be located only in the left breast and not in the right breast. In some embodiments, the tumor is bilateral and includes, for example, cancer cells located in both the right and left breasts.

[0145] VII. Body Mass Index In some embodiments, the patient has a body mass index (BMI) of 25 or higher. In some embodiments, the patient has a BMI of less than 25.

[0146] VIII. Pre-treatment for cancer In some embodiments, the patient has received treatment (which may also be called therapy) for breast cancer prior to receiving the method described herein.

[0147] Prior treatment may be first-line treatment for breast cancer (also called first-line therapy, primary treatment or therapy, induction therapy or therapy, or first-line treatment or therapy). In some embodiments, the patient has completed first-line treatment for breast cancer prior to the treatment described herein. Therefore, the treatment described herein may be an adjuvant treatment prior to prior treatment.

[0148] In some embodiments, the prior treatment is not the primary treatment, but follows the primary treatment or other treatments. In such examples, the treatment described herein may be an adjuvant treatment to the prior treatment, and the prior treatment itself follows one or more additional prior treatments for breast cancer.

[0149] Prior treatment itself may be adjuvant treatment to primary treatment. Prior treatment may be neoadjuvant treatment to primary treatment. Prior treatment may be neoadjuvant treatment to the treatment disclosed herein. In some embodiments, the patient completes prior treatment (e.g., adjuvant and / or neoadjuvant treatment) before the treatment disclosed herein.

[0150] In a further exemplary example, the prior treatment is a neoadjuvant treatment to the first-line treatment. For example, the prior treatment may be administered to shrink the tumor before the first-line treatment. In some embodiments, both the prior treatment, which is a neoadjuvant treatment, and the first-line treatment are completed before the treatment described herein.

[0151] In some mechanisms, prior treatment is neoadjuvant treatment for the treatment described herein.

[0152] Prior treatment may be radiotherapy (also known as "radiotherapy"), surgery, or chemotherapy.

[0153] In some embodiments, prior treatment is radiotherapy. Radiotherapy may be administered to one or more of the following: breast, chest wall, axillary lymph nodes, supraclavicular lymph nodes, and endomastal lymph nodes.

[0154] In some embodiments, the patient has undergone surgical treatment. Therefore, prior treatment may be surgical excision of cancer cells (e.g., tumor). For example, the patient may have undergone one or more of the following: mastectomy, breast-conserving surgery, axillary lymph node dissection, or sentinel lymph node biopsy. In some embodiments, the patient has undergone mastectomy. In some embodiments, the patient has undergone mammary tumor removal. In some embodiments, the entire organ or even the surrounding structures may be removed to achieve the necessary cancer (e.g., tumor) excision. To increase the success of the surgery, a portion of the surrounding normal, healthy tissue (referred to as the "excision margin") may be removed. Therefore, in some embodiments, prior treatment includes complete tumor excision. The cancer is completely removed, and the tumor may not be present in the final surgical specimen microscope margin.

[0155] In some embodiments, after surgical resection, the cancer may be R0 (e.g., the resection margin is microscopically negative with respect to residual tumor).

[0156] In some embodiments, the patient is administered the treatment described herein as an adjuvant treatment following pre-surgical treatment. For example, the treatment described herein may be initiated after surgical resection in which the tumor has been completely removed, and the final surgical specimen microscopic resection margin does not contain the tumor.

[0157] Prior treatment may be chemotherapy. In some embodiments, the patient has received prior treatment, which is chemotherapy. The chemotherapy may be neoadjuvant chemotherapy. For example, neoadjuvant chemotherapy may have been administered before another treatment, such as a surgical procedure, radiotherapy, or administration of another drug therapy. The chemotherapy may be adjuvant chemotherapy. For example, prior treatment may be chemotherapy administered before another treatment, such as a surgical procedure, radiotherapy, or administration of another drug therapy. The chemotherapy may be neo / adjuvant chemotherapy. In each of these exemplary cases, prior treatment (e.g., neoadjuvant chemotherapy and / or adjuvant chemotherapy) is performed prior to the treatment according to the method described herein.

[0158] In some embodiments, the patient has received prior anti-neoplasmic chemotherapy, such as anthracycline or taxane.

[0159] In some embodiments, the patient has previously received endocrine therapy (ET). ET may be, for example, neoadjuvant and / or adjuvant ET. The patient may have received ET within 12 months of the initiation of this method. In some embodiments, the patient may have received tamoxifen or toremifene as adjuvant ET, where the patient undergoes a washout period of 5 half-lives (e.g., 35 days) before the initiation of this method. The patient may receive an aromatase inhibitor during the washout period.

[0160] In some embodiments, the patient has previously received endocrine therapy selected from aromatase inhibitors, anti-estrogens, gonadotropin-releasing hormone analogs, and / or biological / targeted therapies.

[0161] In some embodiments, the patient has received previous treatment, but the treatment was ineffective for this breast cancer, for example, due to resistance of the breast cancer cells to the drug. In some embodiments, the patient has received previous treatment, but the breast cancer has recurred (or "relapsed").

[0162] In some embodiments, the patient has previously received treatment (which may also be called therapy) for breast cancer prior to receiving the treatment described herein and is in remission. The patient may be in remission from early-stage breast cancer, for example, HR+ / HER2-early-stage breast cancer. HR+ / HER2-early-stage breast cancer may be stage II or stage III cancer.

[0163] Cancer can be in remission. Patients who have had cancer can be in remission. In either case, remission may refer to a reduction in cancer or the disappearance of its signs in a patient after treatment for cancer. Remission may also be partial remission, where the cancer (e.g., cancer cells and / or tumor) has decreased in size or extent. For example, partial remission may reflect a 50% reduction in measurable parameters of cancer, such as the growth, size, or extent of cancer cells and / or tumor. Remission may also be complete remission, where the signs of cancer (e.g., cancer cells and / or tumor) are no longer detectable. In complete remission, there may be no evidence of the disease.

[0164] In complete remission, there are no detectable signs or symptoms of cancer.

[0165] Remission may refer to the period of time that has elapsed since the patient had detectable signs or symptoms of cancer. For example, a patient may be described as being in remission after about one month of being free from detectable signs or symptoms of cancer. In some embodiments, the period may be 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 longer. In some embodiments, the duration is approximately 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, or longer.

[0166] Therefore, the treatments described herein may be administered to patients in remission. In some embodiments, the patient is in complete remission. In some embodiments, the patient is in partial remission.

[0167] In some embodiments, the patient is in complete remission at the time of initiating the treatment described herein. For example, the patient may have detectable cancer cells and / or tumors. The patient may have been previously diagnosed with early-stage breast cancer and have been treated with prior therapies, resulting in the cancer being undetectable. Thus, the treatment described herein may be administered to a patient who does not have symptoms of cancer. In some embodiments, the patient may have been diagnosed with HR+ / HER2-early-stage breast cancer, and the cancer may have been removed by surgical treatment, and the HR+ / HER2-early-stage breast cancer may be undetectable. In some embodiments, the patient may be at risk of developing HR+ / HER2-stage breast cancer based on the presence of previously diagnosed HR+ / HER2-stage breast cancer. For example, the patient may be at risk of HR+ / HER2-stage breast cancer recurrence based on a previous diagnosis of HR+ / HER2-stage breast cancer.

[0168] In some embodiments, the patient is in partial remission and exhibits detectable signs of cancer at the time of initiating the treatment described herein. In some embodiments, the patient was diagnosed with HR+ / HER2-early breast cancer and treated with prior therapies, but the cancer was not completely eliminated and / or the cancer recurred. In some embodiments, the patient in partial remission may be at risk of regrowth and / or spread of HR+ / HER2-early breast cancer based on the previous diagnosis of HR+ / HER2-early breast cancer.

[0169] In some embodiments, the treatments described herein prevent the proliferation of HR+ / HER2- breast cancer cells in patients, for example, in patients in remission (e.g., in total remission or partial remission).

[0170] In some embodiments, the treatments described herein maintain remission in the patient (e.g., complete remission or partial remission). The treatments may 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 longer.

[0171] In some embodiments, the treatment reduces the recurrence of breast cancer (e.g., early breast cancer such as HR+ / HER2- early breast cancer). The treatment may 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 longer.

[0172] Breast cancer recurrence may 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 may be contralateral breast cancer, defined herein as a primary breast cancer occurring in the opposite (i.e., contralateral) breast at least three months after the initial breast cancer.

[0173] Thus, in some embodiments, the methods described herein include maintaining remission in an adult patient previously diagnosed with HR+ / HER2-stage II or stage III early breast cancer, and comprising administering to the patient a treatment comprising a certain dose of ribociclib, its free base form or a pharmaceutically acceptable salt thereof in combination with an aromatase inhibitor.

[0174] In some embodiments, the treatment described herein is an adjuvant therapy (also called adjuvant treatment) to prior treatment. Adjuvant therapy may follow any prior treatment, e.g., a prior treatment described herein. Adjuvant therapy may follow two or more prior treatments. For example, one prior treatment may be a neoadjuvant treatment preceding a primary treatment (e.g., first-line treatment), such as surgery, followed by chemotherapy, radiation therapy and / or endocrine therapy, after which the treatment described herein may be administered as adjuvant therapy.

[0175] Therefore, in some embodiments, the methods described herein are for preventing breast cancer recurrence in adult patients and include providing adjuvant therapy to patients who have previously received treatment for HR+ / HER2-stage II or III early breast cancer, the adjuvant therapy comprising administering 400 mg of ribociclib or a pharmaceutically acceptable salt thereof to the patient daily during a 28-day cycle for at least 36 months on days 1 to 21 of a 28-day cycle, in combination with an aromatase inhibitor as defined herein.

[0176] Therefore, in some embodiments, the methods described herein are for maintaining remission in adult patients who have previously been diagnosed with HR+ / HER2-stage II or stage III early breast cancer, and include providing adjuvant therapy to patients who have received prior treatment for HR+ / HER2-stage II or III early breast cancer, the adjuvant therapy comprising 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 as defined herein, administered daily during a 28-day cycle.

[0177] In some embodiments, adjuvant therapy does not involve the administration of ribocicilib at a dose of 600 mg / day.

[0178] Further aspects of the present disclosure relate to a method for treating an adult patient diagnosed with HR+ / HER2-stage II or stage III early breast cancer, comprising administering to the patient an adjuvant therapy comprising (i) ribociclib in doses ranging from 150 mg / day to 450 mg / day administered on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle, thereby improving one or more of the patient's overall survival (OS), distant disease-free survival (DDFS), or recurrence-free survival (RFS).

[0179] In some embodiments, early-stage breast cancer may no longer be stage II or III at the initiation of the treatment described herein. For example, the patient may have received at least one prior treatment in which the treatment described herein constitutes an adjuvant treatment.

[0180] Another aspect of the present disclosure relates to a method for improving one or more of the overall survival (OS), distant disease-free survival (DDFS), or recurrence-free survival (RFS) of a patient diagnosed with HR+ / HER2-stage II or stage III early breast cancer, comprising administering to the patient an adjuvant therapy comprising (i) ribociclib in a dose ranging from 150 mg / day to 450 mg / day, administered on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor, administered daily during the 28-day cycle.

[0181] Further aspects of this disclosure relate to ribociclib for use in a method of improving one or more of the overall survival (OS), distant disease-free survival (DDFS), or recurrence-free survival (RFS) in adult patients diagnosed with HR+ / HER2-stage II or stage III early breast cancer, the method comprising administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg / day to 450 mg / day administered on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle.

[0182] The methods described herein may prevent local and / or regional invasive recurrence of early breast cancer.

[0183] Accordingly, certain aspects of the present disclosure relate to a method for reducing the risk of local or regional invasive recurrence of early breast cancer in adult patients diagnosed with HR+ / HER2- stage II or stage III early breast cancer, comprising administering to the patient an adjuvant therapy comprising (i) ribociclib in doses ranging from 150 mg / day to 450 mg / day, administered on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor, administered daily during the 28-day cycle.

[0184] Certain aspects of this disclosure relate to ribociclib for use in a method for reducing the risk of local or regional invasive recurrence of early breast cancer in adult patients diagnosed with HR+ / HER2- stage II or stage III early breast cancer, comprising administering to the patient an adjuvant therapy comprising (i) ribociclib at doses ranging from 150 mg / day to 450 mg / day administered on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle.

[0185] The methods described herein may prevent cancer recurrence in extramammary tissues such as bone, liver, and lungs or pleura.

[0186] Thus, further aspects of the present disclosure relate to a method for reducing the risk of invasive recurrence of early breast cancer in one or more of the bone, liver, lungs, or pleura in adult patients diagnosed with HR+ / HER2-stage II or III early breast cancer, comprising administering to the patient an adjuvant therapy comprising (i) ribociclib at a dose ranging from 150 mg / day to 450 mg / day on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle.

[0187] Further aspects of this disclosure relate to ribociclib for use in a method for reducing the risk of invasive recurrence of early breast cancer in one or more of the bone, liver, lungs, or pleura in adult patients diagnosed with HR+ / HER2-stage II or stage III early breast cancer, comprising administering to the patient an adjuvant therapy comprising (i) ribociclib in doses ranging from 150 mg / day to 450 mg / day administered on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle.

[0188] Treatment can be administered regardless of the lymph node status of the breast cancer.

[0189] Another aspect of this disclosure relates to a method for reducing the risk of early breast cancer recurrence in adult patients diagnosed with HR+ / HER2- stage II or stage III early breast cancer, comprising administering an adjuvant therapy comprising (i) ribociclib at a dose ranging from 150 mg / day to 450 mg / day on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle, wherein the therapy is administered regardless of the lymph node status of the breast cancer.

[0190] Aspects of this disclosure relate to ribociclib for use in a method for reducing the risk of early breast cancer recurrence in adult patients diagnosed with HR+ / HER2- stage II or stage III early breast cancer, comprising administering to the patient an adjuvant therapy comprising (i) a dose ranging from 150 mg / day to 450 mg / day administered on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle, wherein the therapy is administered regardless of the lymph node status of the breast cancer.

[0191] For example, breast cancer may have lymph node status N0, N1, N2, or N3. Breast cancer may have lymph node status N0.

[0192] In some embodiments, early breast cancer is stage II, for example, stage IIA. In some embodiments, early breast cancer is stage III, for example, stage IIIB or IIIC.

[0193] In certain embodiments, breast cancer is a subtype of ductal carcinoma.

[0194] In some embodiments, the patient is Asian.

[0195] Adjuvant therapy may be necessary after a patient has received at least one prior treatment for breast cancer. In some embodiments, the methods described herein are adjuvant therapies because the patient has received at least one prior treatment for breast cancer selected from the group consisting of surgery, chemotherapy, and radiotherapy.

[0196] In some embodiments, the patient has never undergone a mastectomy.

[0197] In some embodiments, the dose of ribociclib is 400 mg / day. Ribociclib may be administered in salt form, preferably as ribociclib succinate.

[0198] In some embodiments, the aromatase inhibitor is letrozole or anastrozole. For example, the aromatase inhibitor may be letrozole administered at a dose of preferably 2.5 mg / day. The aromatase inhibitor may be anastrozole administered at a dose of preferably 1 mg / day.

[0199] In some embodiments, the dose of ribociclib is 400 mg / day, ribociclib is administered in the form of ribociclib succinate, and the aromatase inhibitor is letrozole or anastrozole, preferably 2.5 mg / day of letrozole or 1 mg / day of anastrozole.

[0200] In some embodiments, improvements in OS, DDFS, and / or RFS, or a reduction in the risk of breast cancer recurrence, are achieved in the patient for at least 36 months.

[0201] In some embodiments, the patient has never previously received a CDK4 / 6 inhibitor.

[0202] In some embodiments, the patient has not received tamoxifen, raloxifene, or an aromatase inhibitor for the reduction of breast cancer risk ("chemoprevention") and / or treatment of osteoporosis within the two years prior to performing this procedure.

[0203] In some embodiments, the patient receives 450 mg / m² of doxorubicin before undergoing this procedure. 2 The above, or 900 mg / m² of epirubicin. 2I have never received treatment with anthracycline drugs at a cumulative dose exceeding the above amount.

[0204] In some embodiments, the patient does not have a known hypersensitivity to any of the excipients of ribociclib and / or ET (for example, the patient does not have rare genetic problems such as galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption, or soy allergy).

[0205] In some embodiments, the patient has not received any other antineoplasm therapy other than the adjuvant ET described herein.

[0206] In some embodiments, patients have not undergone major surgery, chemotherapy, or radiotherapy within 14 days of receiving this procedure.

[0207] In some embodiments, patients have not recovered to NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) Version 4.03 Grade ≤ 1 from clinical and laboratory acute toxicity related to prior anticancer therapy on the randomization date. However, as an exception, patients with any grade of alopecia, amenorrhea, grade 2 neuropathy, or other toxicity are not considered a safety risk to the patient.

[0208] In some embodiments, patients do not have concomitant invasive malignancies or a history of invasive malignancies that have been treated within two years prior to randomization. Patients may have been adequately treated for basal cell carcinoma or squamous cell carcinoma, or may have had a curatively resected cervical intraepithelial neoplasia.

[0209] In some embodiments, the patient has no known history of human immunodeficiency virus (HIV) infection.

[0210] In some embodiments, the patient does not have a known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (testing is not required unless required by the regulations of each facility).

[0211] In some embodiments, the patient does not have clinically significant poorly controlled cardiac disease and / or cardiac repolarization abnormalities, including any of the following: • A documented history of myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft within the six months prior to performing this procedure. • Documented cardiomyopathy Left ventricular ejection fraction (LVEF) < 50% as determined by multi-gate acquisition (MUGA) scan or echocardiography (ECHO). • Family history of long QT syndrome, sudden idiopathic death, or congenital long QT syndrome, or any of the following: Risk factors for torsades de pointe (TdP), including uncorrected hypocalcemia, hypokalemia, or hypomagnesemia, a history of heart failure, or a history of clinically significant / symptomatic bradycardia. • One or more combination therapies known to have a risk of prolonging the QT interval and / or causing TdP, which cannot be discontinued or replaced by a safe alternative therapy (e.g., within 5 half-lives or 7 days prior to performing this procedure). • The QTcF interval is undeterminable. Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, and / or high-grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II, and third-degree AV block). • Poorly controlled arterial hypertension with systolic blood pressure > 160 mmHg.

[0212] In some embodiments, the patient has not received any of the following substances within 7 days prior to performing this procedure: • Concomitant drug therapies, herbal supplements, and / or fruits (e.g., grapefruit, pomelo, star fruit, bitter orange) and their juices known to be potent inhibitors or inducers of CYP3A4 / 5. • Drug therapies with a narrow therapeutic window, predominantly metabolized via CYP3A4 / 5.

[0213] In some embodiments, the patient does not ingest grapefruit (or grapefruit juice). In some embodiments, the patient does not ingest pomelo, star fruit, and bitter orange (and their juices). In certain embodiments, the patient does not concomitantly use any of the following: boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir, ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, and voriconazole.

[0214] In some embodiments, the patient is not currently receiving systemic corticosteroids, has not received them within the two weeks prior to performing this method, or has not fully recovered from the side effects of such treatment. In some embodiments, the patient may use corticosteroids for the following: short-term (less than 5 days) systemic corticosteroids; topical application for any duration (e.g., for skin rashes), inhaled spray (e.g., for obstructive airway diseases), eye drops, or local injection (e.g., intra-articular).

[0215] In some embodiments, the patient does not have a GI function disorder or GI disease (e.g., poorly controlled ulcerative disease, poorly controlled nausea, vomiting or diarrhea, malabsorption syndrome, or small bowel resection) that could significantly alter the absorption of the oral test treatment.

[0216] In some embodiments, the patient does not have any co-occurring severe and / or poorly controlled medical conditions (e.g., chronic pancreatitis, chronic active hepatitis, cirrhosis or any other serious liver disease, active untreated or poorly controlled fungal, bacterial or viral infection, active infection requiring systemic antibacterial therapy, etc.) that could cause unacceptable safety risks, contraindicate the patient's treatment, impair compliance with the method, or limit life expectancy to less than 5 years.

[0217] In some embodiments, the patient has not been involved in the treatment related to one or more investigational drugs within 30 days before performing this method or within 5 half-lives of one or more investigational drugs (whichever is longer).

[0218] IX. Additional Criteria In some embodiments, the patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

[0219] In some embodiments, the patient has bone marrow and organ functions as defined by the following values: · Absolute neutrophil count (ANC) ≥ 1.5 × 10 9 / L. · Platelets ≥ 100 × 10 9 / L. · Hemoglobin ≥ 9.0 g / dL. · Estimated glomerular filtration rate (eGFR) ≥ 30 mL / min / 1.73 m when following the Modification of Diet in Renal Disease (MDRD) equation 2 . · Alanine transaminase (ALT) < 2.5 × upper limit of normal (ULN). · Aspartate transaminase (AST) < 2.5 × ULN. · In patients with well-documented Gilbert's syndrome, serum total bilirubin < ULN; or total bilirubin ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN. · International normalized ratio (INR) ≤ 1.5 (except when the patient is receiving anticoagulant therapy and the INR is within the therapeutic range for the purpose of using that anticoagulant within 7 days before randomization). · For the following items, clinical test values are within the normal range or corrected to within the normal range with supplements (clinical test values at each facility must be documented to be within the normal range after correction): · Potassium · Magnesium · Total calcium (serum albumin corrected value)

[0220] In some embodiments, the patient has a standard 12-lead ECG value of the QTcF interval (QT interval using Fridericia correction) < 450 msec at screening and a resting heart rate of 50 to 90 beats per minute (determined from the ECG).

[0221] X. Region and Race / Ethnicity In some embodiments, the patient lives in North America. The patient may live in Europe, for example, Western Europe. The patient may live in Oceania, for example, Australia. In some embodiments, the patient lives in Asia. In some embodiments, the patient lives in Africa. In some embodiments, the patient lives in Latin America.

[0222] In some embodiments, the patient may be an American Indian. In some embodiments, the patient may be an Alaska Native. In some embodiments, the patient may be Asian. In some embodiments, the patient may be Black or African American. In some embodiments, the patient may be a Native Hawaiian or other Pacific Islander. In some embodiments, the patient may be White. In some embodiments, the patient may be multi-racial. In some embodiments, the patient may be non-Asian. In some embodiments, the patient may be Hispanic or Latino. In some embodiments, the patient is not Hispanic or Latino.

[0223] E. Effective Lead Out Certain aspects of the present disclosure relate to a method of treating early breast cancer in adult patients who require treatment for early breast cancer, the method comprising administering to the patient a treatment comprising a cyclin - dependent kinase (CDK) inhibitor in combination with endocrine therapy (ET), the treatment being characterized by an improvement in the patient's condition when compared to a patient who has not received treatment or when compared to the patient prior to treatment. In some embodiments, the selection of a treatment regimen, e.g., the dosage of ribociclib and / or an aromatase inhibitor, is selected such that a certain improvement in the patient's condition is achieved when compared to a patient who has not received treatment or when compared to the patient prior to treatment.

[0224] In some embodiments, a patient who has not received the treatment described herein may include a patient who has not received administration of ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate). In some embodiments, a patient who has not received the treatment described herein may include a patient who has not received administration of a combination of ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate) and endocrine therapy. For example, a patient may receive only administration of endocrine therapy alone without ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate). A patient may receive only administration of letrozole alone without ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate). A patient may receive only administration of anastrozole alone without ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate). In some embodiments, a patient who has not received the treatment described herein may have received another cancer treatment, where the other cancer treatment is a combination of ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate) and endocrine therapy. In some embodiments, a patient who has not received the treatment described herein may be a patient who has not received any cancer treatment.

[0225] Improvement in the patient's condition may relate to a reduction in the signs and / or symptoms of breast cancer. For example, improvement may include a reduction in breast cancer progression and / or recurrence. Improvement may include prevention of breast cancer progression, early breast cancer recurrence, and / or death from breast cancer. Improvement may include a reduction in the risk of cancer progression, the risk of cancer recurrence, and / or the risk of death from cancer (or avoidance of death from cancer).

[0226] In some embodiments, improvement in the patient's condition is the maintenance of the pre-existing signs and / or symptoms of breast cancer. For example, after treatment, the breast cancer may have almost the same characteristics as before treatment, but without further progression or worsening of its characteristics.

[0227] In some embodiments, the improvement in the patient's condition is an improvement compared to a patient who has not received treatment. In some embodiments, the patient who has not received treatment receives another treatment for early-stage breast cancer. In some embodiments, the patient who has not received treatment receives endocrine therapy alone.

[0228] In some embodiments, improvement in the patient's condition may include one or more of the following: reduction in tumor size, prevention of tumor spread, prevention or reduction of breast cancer recurrence, prevention of secondary primary malignancies, and increased survival.

[0229] For example, improvement in the patient's condition may include the absence (or reduction) of local relapses, distant relapses, ipsilateral and contralateral invasive breast cancer, and secondary primary non-breast cancer invasive cancer.

[0230] In some embodiments, improvement in the patient's condition relates to measurements 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 recurrence-free survival (LLRFS).

[0231] Disease-free survival (DFS) may refer to the length of time a patient survives without local recurrence, contralateral recurrence, distant disease, secondary cancer, or new primary cancer. DFS may be defined as the time from day one (e.g., the day cancer treatment is initiated, or instead, the day cancer treatment is completed) to the day the patient shows cancer recurrence or death.

[0232] Invasive disease-free survival (iDFS) is defined as DFS, but ductal carcinoma in situ is excluded as a recurrent event.

[0233] Overall survival (OS) may refer to the length of time a patient is alive, including death from any cause, regardless of whether breast cancer has recurred or spread. OS may be defined as the time from day one (for example, the day cancer treatment began, or instead, the day cancer treatment ended) to the day of death from any cause.

[0234] Distant disease-free survival (DDFS) may refer to the length of time a patient remains disease-free, for example, from cancer recurrence in a distant site other than the original breast. DDFS may be defined as the time from day one (e.g., the day cancer treatment was initiated, or instead, the day cancer treatment was completed) to the day of the first event of distant recurrence, death (of any cause), or secondary primary non-breast invasive cancer (excluding cutaneous basal cell and squamous cell carcinoma).

[0235] Recurrence-free survival (RFS) may include any recurrence (local, regional, or distant) of the original breast cancer, but not one or more new cancers. RFS may be defined as the time from day one (e.g., the day cancer treatment was initiated, or instead, the day cancer treatment was terminated) to the day of the first event of locally invasive breast recurrence, regional invasive recurrence, distant recurrence, or death (of any cause).

[0236] Local recurrence-free survival (LRRFS) may be defined as the time from day one (e.g., the day cancer treatment was initiated, or instead, the day cancer treatment was completed) to the day of the first occurrence of local (ipsilateral) invasive breast recurrence, regional invasive recurrence, or death from any cause.

[0237] Therefore, in some embodiments, the method improves one or more of the following in patients receiving treatment compared to untreated patients: DFS, iDFS, OS, DDFS, RFS, and LLRFS. For example, the improvement in the patient's condition may be an extension of the period between the first day (e.g., the day cancer treatment began, or alternatively, the day cancer treatment ended) and the day on which an event occurred as defined by DFS, iDFS, OS, DDFS, RFS, and LLRFS.

[0238] In some embodiments, the improvement in the patient's condition is a reduction in the incidence (or time to occurrence) of one or more of the following: recurrence of invasive ipsilateral breast tumor (IBTR), localized invasive recurrence, distant recurrence (e.g., presence of metastasis), death from breast cancer, death from causes other than breast cancer, death from unknown causes, presence of invasive contralateral breast cancer, and presence of secondary primary invasive cancer.

[0239] For example, treatment may reduce the incidence (or time to occurrence) of deaths from breast cancer, deaths from causes other than breast cancer, and deaths from unknown causes.

[0240] In some embodiments, improvements in the patient's condition include a reduced incidence (or shorter time to occurrence) of distant recurrence (e.g., presence of metastasis), death from breast cancer, death from causes other than breast cancer, death from unknown causes, and the presence of secondary primary invasive cancer.

[0241] In some embodiments, improvements in the patient's condition include a reduction in the incidence (or time to occurrence) of invasive ipsilateral breast tumor (IBTR) recurrence, localized invasive recurrence, distant recurrence (e.g., presence of metastasis), death from breast cancer, death from causes other than breast cancer, and death from unknown causes.

[0242] In some embodiments, improvement in the patient's condition is a reduction in the incidence (or time to occurrence) of one or more of the following: invasive ipsilateral breast tumor (IBTR) recurrence, locally invasive recurrence, death from breast cancer, death from causes other than breast cancer, and death from unknown causes.

[0243] If the improvement in the patient's condition is a reduction in the risk of other events related to an invasive disease or cancer, the risk may be determined using different scales. In some embodiments, the treatment reduces the risk of invasive disease and corresponds to a hazard ratio of less than about 1 when the risk is calculated compared to patients not receiving 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 of iDFS can be calculated using a model such as an unstratified and unadjusted for covariates Cox model or a stratified and adjusted for covariates Cox model as described in Appendix A.

[0244] In some embodiments, the hazard ratio can be about 0.78 or less. The hazard ratio can be about 0.72 or less.

[0245] In some embodiments, the patient has HR+ / HER2− early stage III breast cancer and the treatment reduces the risk of invasive disease and corresponds to a hazard ratio of about 0.74 or less when the risk is calculated compared to patients not receiving the treatment. The hazard ratio can be about 0.76 or less. In some embodiments, the treatment results in at least a 25% reduction in the risk of invasive disease and corresponds to a hazard ratio of 0.75 when the risk is calculated compared to patients not receiving the treatment.

[0246] In some embodiments, the treatment reduces the risk of invasive disease to a level similar to that of a patient subgroup including patients with early stage II breast cancer, patients with early stage III breast cancer, premenopausal women or men, and postmenopausal women.

[0247] In some embodiments, the treatment as disclosed herein can achieve the following hazard ratios for detailed patients with HR+ / HER2− early breast cancer.

[0248] In some embodiments, the patient is female, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.76 when the risk is calculated compared to an untreated patient.

[0249] In some embodiments, the patient is a premenopausal woman or man, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.72 when the risk is calculated compared to a patient who does not receive treatment.

[0250] In some embodiments, the patient is a postmenopausal woman, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.78 when the risk is calculated compared to an untreated patient.

[0251] In some embodiments, patients may have previously received neo / adjuvant chemotherapy, and the treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.73 when the risk is calculated compared to untreated patients.

[0252] In some embodiments, patients reside in North America, Western Europe, or Oceania, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.76 when the risk is calculated compared to untreated patients.

[0253] In some embodiments, the patient does not reside in North America, Western Europe, or Oceania, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.76 when the risk is calculated compared to untreated patients.

[0254] In some embodiments, the patient has stage II cancer, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.76 when the risk is calculated compared to an untreated patient.

[0255] In some embodiments, the patient has stage III cancer, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.74 when the risk is calculated compared to a patient who has not received treatment.

[0256] In some embodiments, the patient has stage IIA cancer, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.5 when the risk is calculated compared to an untreated patient.

[0257] In some embodiments, the patient has stage IIB cancer, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.93 when the risk is calculated compared to an untreated patient.

[0258] In some embodiments, the patient has stage IIIA cancer, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.79 when the risk is calculated compared to a patient who has not received treatment.

[0259] In some embodiments, the patient has stage IIIB cancer, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.68 when the risk is calculated compared to an untreated patient.

[0260] In some embodiments, the patient has stage IIIC cancer, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.69 when the risk is calculated compared to an untreated patient.

[0261] In some embodiments, patients may have previously received adjuvant chemotherapy, and the treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.67 when the risk is calculated compared to patients who have not received treatment.

[0262] In some embodiments, the patient has not previously received adjuvant chemotherapy, and the treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.81 when the risk is calculated compared to a patient who has not received treatment.

[0263] In some embodiments, patients may have previously received neoadjuvant chemotherapy, and the treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.79 when the risk is calculated compared to patients who have not received treatment.

[0264] In some embodiments, the patient has not previously received neoadjuvant chemotherapy, and the treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.72 when the risk is calculated compared to untreated patients.

[0265] In some embodiments, the patient may have previously received radiotherapy, and the treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.74 when the risk is calculated compared to a patient who has not received treatment.

[0266] In some embodiments, the patient has never received radiotherapy before, and the treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.98 when the risk is calculated compared to a patient who has not received treatment.

[0267] In some embodiments, patients may have previously received endocrine therapy, and the treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.76 when the risk is calculated compared to patients who have not received treatment.

[0268] In some embodiments, the patient has never received endocrine therapy, and the treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.77 when the risk is calculated compared to a patient who has not received treatment.

[0269] In some embodiments, the patient may have previously undergone a mastectomy, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.85 when the risk is calculated compared to a patient who has not received treatment.

[0270] In some embodiments, the patient has never undergone a mastectomy, and the treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.55 when the risk is calculated compared to a patient who has not received treatment.

[0271] In some embodiments, the patient is Asian, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.52 when the risk is calculated compared to an untreated patient.

[0272] In some embodiments, the patient may not be Asian, and the risk of invasive disease may be reduced by treatment, corresponding to a hazard ratio of less than approximately 0.81 when the risk is calculated compared to an untreated patient.

[0273] In some embodiments, the patient lives in Europe, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.88 when the risk is calculated compared to an untreated patient.

[0274] In some embodiments, the patient resides in North America or Australia, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.70 when the risk is calculated compared to an untreated patient.

[0275] In some embodiments, the patient lives in Asia, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.34 when the risk is calculated compared to an untreated patient.

[0276] In some embodiments, the patient resides in Latin America, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.69 when the risk is calculated compared to an untreated patient.

[0277] In some embodiments, the patient is under 45 years of age, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.68 when the risk is calculated compared to untreated patients.

[0278] In some embodiments, the patient is 45–54 years old, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.75 when the risk is calculated compared to untreated patients.

[0279] In some embodiments, the patient population is 55–64, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.84 when the risk is calculated compared to untreated patients.

[0280] In some embodiments, the patient is 65 years of age or older, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.72 when the risk is calculated compared to untreated patients.

[0281] In some embodiments, patients may receive letrozole, and the treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.79 when the risk is calculated compared to patients who do not receive treatment.

[0282] In some embodiments, patients may receive anastrozole, and the treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.70 when the risk is calculated compared to patients who do not receive treatment.

[0283] In some embodiments, the patient has ER+ / PR+ cancer, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.73 when the risk is calculated compared to an untreated patient.

[0284] In some embodiments, the patient has ER+ / PR- cancer, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.91 when the risk is calculated compared to an untreated patient.

[0285] In some embodiments, the patient has a tumor with lymph node status 0, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.63 when the risk is calculated compared to an untreated patient.

[0286] In some embodiments, the patient has a tumor with lymph node status N1-N3, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.77 when the risk is calculated compared to an untreated patient.

[0287] In some embodiments, the patient has a tumor of classification T1 to T3, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.74 when the risk is calculated compared to an untreated patient.

[0288] In some embodiments, patients have tumors of a higher stage than T3 (e.g., T4), and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.83 when the risk is calculated compared to untreated patients.

[0289] In some embodiments, the patient has a histological grade 1 tumor, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.78 when the risk is calculated compared to an untreated patient.

[0290] In some embodiments, the patient has a histological grade 1 tumor, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.78 when the risk is calculated compared to an untreated patient.

[0291] In some embodiments, the patient has a histological grade 2 tumor, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.75 when the risk is calculated compared to an untreated patient.

[0292] In some embodiments, the patient has a histological grade 3 tumor, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.78 when the risk is calculated compared to an untreated patient.

[0293] In some embodiments, patients have tumors with a Ki67 status of 20% or less, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.80 when the risk is calculated compared to untreated patients.

[0294] In some embodiments, patients have tumors with a Ki67 status higher than 20%, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.75 when the risk is calculated compared to untreated patients.

[0295] In some embodiments, the patient has a ductal carcinoma subtype tumor, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.68 when the risk is calculated compared to an untreated patient.

[0296] In some embodiments, the patient has a tumor that is not a ductal carcinoma subtype or lobular carcinoma subtype, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.89 when the risk is calculated compared to an untreated patient.

[0297] In some embodiments, the patient has a BMI of 25 or higher, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.85 when the risk is calculated compared to an untreated patient.

[0298] In some embodiments, patients have a BMI of less than 25, and treatment may reduce the risk of invasive disease, corresponding to a hazard ratio of less than approximately 0.64 when the risk is calculated compared to untreated patients.

[0299] Regarding overall survival, treatment does not necessarily have to worsen overall survival, and when the risk is calculated compared to patients who do not receive treatment, it corresponds to a hazard ratio of 0.76.

[0300] In some embodiments, the treatment does not cause or exacerbate events such as pneumonia, pulmonary embolism, dyspnea, increased alanine aminotransferase, increased aspartate aminotransferase, arthralgia, fatigue, neutropenia, decreased neutropenia, and / or nausea.

[0301] In some embodiments, the treatment does not induce or exacerbate any hepatobiliary toxicity-related conditions, as measured, for example, by increases in alanine aminotransferase, aspartate aminotransferase, γ-glutamyltransferase, serum alkaline phosphatase, and / or serum bilirubin.

[0302] In some embodiments, the treatment does not cause or worsen conditions related to bone marrow suppression (e.g., anemia and / or leukopenia). For example, the treatment does not cause or worsen leukopenia, nor does it lead to a decrease in white blood cell count, lymphopenia, or a decrease in lymphocyte count.

[0303] In some embodiments, the treatment does not cause or worsen conditions related to myelosuppression (e.g., neutropenia, decreased neutropenia, thrombocytopenia, decreased platelet count).

[0304] In some embodiments, the treatment does not lengthen the QT interval on the electrocardiogram.

[0305] In some embodiments, the treatment does not cause or exacerbate nephrotoxicity-related conditions (e.g., increased serum creatinine, decreased glomerular filtration rate, increased serum urea).

[0306] In some embodiments, the treatment does not cause or worsen conditions related to reproductive toxicity, such as mastitis.

[0307] Treatment methods for F.HR+ / HER2- early-stage breast cancer One aspect of the present disclosure is a method for treating cancer in an adult patient requiring treatment for HR+ / HER2-stage II or III early breast cancer, comprising administering to the patient a treatment comprising ribociclib (or ribociclib succinate, or a pharmaceutically acceptable salt thereof) in doses ranging from 150 mg / day to 450 mg / day on days 1 to 21 of a 28-day cycle, in combination with an endocrine therapy (an aromatase inhibitor, preferably letrozole or anastrozole) administered daily (e.g., on days 1 to 28) of a 28-day cycle.

[0308] A further aspect of the present disclosure relates to a method for preventing early breast cancer or reducing its signs or symptoms, comprising administering to a patient a treatment comprising ribociclib in a dose ranging from 150 mg / day to 450 mg / day on days 1 to 21 of a 28-day cycle, in combination with an aromatase inhibitor, preferably letrozole or anastrozole, administered daily for the duration of the 28-day cycle.

[0309] Another aspect of the present disclosure is a method for maintaining remission in an adult patient previously diagnosed with HR+ / HER2-stage II or stage III early breast cancer, comprising administering to the patient a treatment comprising ribociclib, in the free base form thereof or a pharmaceutically acceptable salt thereof, in doses ranging from 150 mg / day to 450 mg / day on days 1 to 21 of a 28-day cycle, in combination with an aromatase inhibitor, preferably letrozole or anastrozole, administered daily for the duration of the 28-day cycle.

[0310] Another aspect of this disclosure relates to a method for preventing breast cancer recurrence in adult patients, comprising providing adjuvant therapy to patients who have previously received treatment for HR+ / HER2-stage II or III early breast cancer, wherein the adjuvant therapy comprises administering to the patient 400 mg 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 described in any one of embodiments 23 to 28, administered daily during the 28-day cycle.

[0311] In some embodiments, the treatment involves administering to the patient a treatment comprising a combination of endocrine therapy including a dose of approximately 400 mg / day (or approximately 200 mg / day) of ribociclib or ribociclib succinate, or a pharmaceutically acceptable salt thereof, on days 1 to 21 of a 28-day cycle over a period of 36 months, and an endocrine therapy comprising a dose of letrozole ranging from approximately 1 mg / day to approximately 4 mg / day or anastrozole ranging from approximately 0.5 mg / day to approximately 1.5 mg / day, administered daily (e.g., on days 1 to 28) of a 28-day cycle.

[0312] In some embodiments, the treatment involves administering to the patient a pharmaceutically acceptable salt thereof, such as ribociclib or ribociclib succinate, at a dose of approximately 400 mg / day (or approximately 200 mg / day) on days 1 to 21 of a 28-day cycle over a period of 36 months, in combination with an endocrine therapy comprising a dose of approximately 2.5 mg / day of letrozole or an approximately 1 mg / day of anastrozole administered on days 1 to 28 of a 28-day cycle.

[0313] In some embodiments, treatment reduces one or more of the following: recurrence of ipsilateral invasive breast tumor (IBTR), localized invasive recurrence, distant recurrence (e.g., presence of metastasis), death from breast cancer, death from causes other than breast cancer, death from unknown causes, presence of invasive contralateral breast cancer, and presence of secondary primary invasive cancer.

[0314] In some embodiments, treatment reduces the risk of invasive disease, corresponding to a hazard ratio of less than approximately 1 when the risk is calculated compared to untreated patients. For example, the hazard ratio for iDFS can be calculated using a model, such as an unstratified and unadjusted Cox model or a stratified and adjusted Cox model, as described in Appendix A.

[0315] In some embodiments, the hazard ratio may be about 0.78 or less. The hazard ratio may be about 0.72 or less.

[0316] In some embodiments, patients have HR+ / HER2-stage III early breast cancer, and treatment reduces the risk of invasive disease, corresponding to a hazard ratio of approximately 0.74 or less when the risk is calculated compared to untreated patients. The hazard ratio may be approximately 0.76 or less. In some embodiments, treatment results in at least a 25% reduction in the risk of invasive disease, corresponding to a hazard ratio of 0.75 when the risk is calculated compared to untreated patients.

[0317] In some embodiments, the treatment reduces the risk of invasive disease to a level similar to that of patient subgroups including patients with stage II early breast cancer, stage III early breast cancer, premenopausal women or men, and postmenopausal women.

[0318] Regarding overall survival, treatment does not necessarily have to worsen overall survival, and when the risk is calculated compared to patients who do not receive treatment, it corresponds to a hazard ratio of 0.76.

[0319] In some embodiments, the patient is a postmenopausal woman. In some embodiments, the patient is a premenopausal woman or man.

[0320] In some embodiments, early breast cancer includes a stage II tumor. In some embodiments, the tumor may have anatomical stage IIA. In some embodiments, the tumor may have anatomical stage IIB. In some embodiments, early breast cancer includes a stage III tumor. In some embodiments, the tumor may have anatomical stage IIIA. In some embodiments, the tumor may have anatomical stage IIIB. In some embodiments, the tumor may have anatomical stage IIIC.

[0321] In some embodiments, the patient has previously received neoadjuvant chemotherapy. In some embodiments, the patient has previously received adjuvant chemotherapy.

[0322] In some embodiments, the patient has a history of receiving radiation therapy.

[0323] In some embodiments, the patient has undergone a mastectomy. In some embodiments, the patient has not undergone a mastectomy.

[0324] In some embodiments, the patient lives in North America. In some embodiments, the patient lives in Europe, for example, Western Europe. In some embodiments, the patient lives in Oceania, for example, Australia. In some embodiments, the patient lives in Latin America. In some embodiments, the patient lives in Asia.

[0325] In some embodiments, the patient is Asian. In some embodiments, the patient is non-Asian.

[0326] In some embodiments, the patient may be an American Indian. In some embodiments, the patient may be an Alaskan Native. In some embodiments, the patient may be Black or African American. In some embodiments, the patient may be a Hawaiian Native or a resident of another Pacific Island. In some embodiments, the patient may be White. In some embodiments, the patient may be of mixed race. In some embodiments, the patient may be non-Asian. In some embodiments, the patient may be Hispanic or Latino. In some embodiments, the patient may not be Hispanic or Latino.

[0327] In some embodiments, the patient is 18 years of age or older. The patient may be 18 to 44 years of age. The patient may be 45 to 54 years of age. The patient may be 55 to 64 years of age. The patient may be 65 years of age or older.

[0328] In some embodiments, the endocrine therapy is a nonsteroidal aromatase inhibitor (NSAID). In some embodiments, the NSAID may be letrozole. In some embodiments, the NSAID may be anastrozole.

[0329] In some embodiments, early-stage breast cancer is selected from ER+ / PR+, ER- / PR+, and ER+ / PR- breast cancer.

[0330] In some embodiments, the treatment is administered regardless of the lymph node status of the breast cancer.

[0331] In some embodiments, early breast cancer has a lymph node status of N0, N1, N2, or N3.

[0332] In some embodiments, early breast cancer includes tumors of classification T0, T1, T2, T3, or T3.

[0333] In some embodiments, early-stage breast cancer has a histological grade of G1, G2, or G3 at the time of surgery.

[0334] In some embodiments, early-stage breast cancer may have a Ki67 status of 20 or less (e.g., from an archived tumor). Alternatively, early-stage breast cancer may have a Ki67 status of 20 or higher.

[0335] In some embodiments, early breast cancer has a histological subtype of ductal carcinoma or a histological subtype of lobular carcinoma.

[0336] Aspects of the present disclosure relate to a method for preventing breast cancer recurrence in adult patients who have previously received treatment for HR+ / HER2-stage II or stage III early breast cancer, comprising administering to the patient (i) a certain dose of ribociclib, its free base form, or a pharmaceutically acceptable salt thereof, and (ii) a certain dose of an aromatase inhibitor, preferably letrozole or anastrozole.

[0337] Further aspects of the present disclosure relate to a method for treating an adult patient in remission from HR+ / HER2- stage II or stage III early breast cancer, comprising administering to the patient (i) a certain dose of ribociclib, its free base form, or a pharmaceutically acceptable salt thereof, and (ii) a certain dose of an aromatase inhibitor, preferably letrozole or anastrozole.

[0338] Another aspect of the present disclosure relates to a method for treating cancer in adult patients requiring treatment for HR+ / HER2-stage II or stage III early breast cancer, comprising administering to the patient (i) ribociclib, its free base form, or a pharmaceutically acceptable salt thereof in doses ranging from 150 mg / day to 450 mg / day, administered on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor, preferably letrozole or anastrozole, administered daily during the 28-day cycle.

[0339] One aspect of the present disclosure is a method for treating breast cancer recurrence in an adult patient who has received at least one prior treatment for HR+ / HER2- stage II or III early breast cancer and who does not have any detectable signs or symptoms of breast cancer, comprising administering to the patient an adjuvant treatment comprising (i) ribociclib succinate in a dose that results in a total dose of 400 mg / day of ribociclib administered on days 1 to 21 of a 28-day cycle, and (ii) either a dose of letrozole or a dose of anastrozole of 2.5 mg / day administered daily during the 28-day cycle.

[0340] Additional aspects of the present disclosure relate to a method for treating an adult patient in remission from HR+ / HER2- stage II or stage III early breast cancer who requires adjuvant therapy, comprising administering to the patient an adjuvant therapy comprising (i) a dose of ribociclib succinate to a total dose of 400 mg / day of ribociclib administered on days 1 to 21 of a 28-day cycle, and (ii) a dose of either 2.5 mg / day of letrozole or 1 mg / day of anastrozole administered daily during the 28-day cycle.

[0341] In some embodiments, the patient has a BMI of 25 or higher. In some embodiments, the patient has a BMI of less than 25.

[0342] Further embodiments of this disclosure relate to a method for preventing early breast cancer or reducing its signs or symptoms, comprising administering to a patient a treatment comprising ribociclib, its free base form or a pharmaceutically acceptable salt thereof in combination with an aromatase inhibitor, preferably letrozole or anastrozole. In some embodiments, ribociclib is its free base form or a pharmaceutically acceptable salt thereof, administered to the patient in doses ranging from 150 mg / day to 450 mg / day on days 1 to 21 of a 28-day cycle. In some embodiments, the aromatase inhibitor is administered daily during the 28-day cycle.

[0343] G. Patients in remission One aspect of the present disclosure relates to a method for treating HR+ / HER2- stage II or stage III early breast cancer in adult patients in remission, comprising administering ribociclib in combination with an aromatase inhibitor to the adult patient, thereby maintaining remission in the adult patient for at least about three months.

[0344] A further embodiment relates to a method for treating HR+ / HER2- stage II or stage III early breast cancer in adult patients, comprising providing adjuvant therapy by administering ribociclib in combination with an aromatase inhibitor, wherein the patient is in complete remission at the start of adjuvant therapy, and complete remission in the adult patient is maintained for at least about 3 months by administering ribociclib in combination with the aromatase inhibitor.

[0345] Administering ribociclib in combination with an aromatase inhibitor can maintain remission (e.g., complete remission) in adult patients for at least approximately 3 months. In some embodiments, administration maintains remission in adult patients for at least approximately 6 months. In some embodiments, administration maintains remission in adult patients for at least approximately 9 months. In some embodiments, administration maintains remission in adult patients for at least approximately 12 months. In some embodiments, administration maintains remission in adult patients for at least approximately 15 months. In some embodiments, administration maintains remission in adult patients for at least approximately 18 months. In some embodiments, administration maintains remission in adult patients for at least approximately 21 months. In some embodiments, administration maintains remission in adult patients for at least approximately 24 months. In some embodiments, administration maintains remission in adult patients for at least approximately 27 months. In some embodiments, administration maintains remission in adult patients for at least approximately 30 months. In some embodiments, administration maintains remission in adult patients for at least approximately 33 months. In some embodiments, administration sustains remission in adult patients for at least approximately 36 months.

[0346] In certain embodiments, ribociclib and an aromatase inhibitor are administered for the duration of treatment, and the administration maintains remission in adult patients for at least the duration of treatment.

[0347] For the methods described herein, the dosage and treatment schedule of the combination of ribociclib and an aromatase inhibitor may follow the exemplary embodiments described below. In some embodiments, a dose of 400 mg of ribociclib is administered orally once daily on days 1 to 21 of a 28-day cycle, and the aromatase inhibitor is administered once daily every day during the 28-day cycle.

[0348] Ribociclib at a dose of 400 mg is administered orally once daily on days 1 to 21 of a 28-day cycle for a maximum treatment period of 3 years, while the aromatase inhibitor is administered once daily every day of the 28-day cycle for a maximum treatment period of 3 years. For example, ribociclib at a dose of 400 mg may be administered orally once daily on days 1 to 21 of a 28-day cycle for a maximum treatment period of 5 years, while the aromatase inhibitor is administered once daily every day of the 28-day cycle for a maximum treatment period of 5 years.

[0349] 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 may be ribociclib succinate.

[0350] In some embodiments, adult patients were never treated with a 600 mg dose of ribociclib.

[0351] In some embodiments, adult patients had never been diagnosed with HR+ / HER2- advanced or metastatic breast cancer.

[0352] Ribociclib and aromatase inhibitors may be administered as adjuvant therapy. In some embodiments, ribociclib is not administered at a dose of 600 mg / day.

[0353] The dose of ribociclib may be administered in tablet form. For example, two tablets may be administered orally to an adult patient once daily on days 1 to 21 of a 28-day cycle, repeated for the duration of treatment, with each tablet containing a pharmaceutically acceptable amount of ribociclib salt equivalent to 200 mg of ribociclib. In some embodiments, the ribociclib salt is ribociclib succinate. In some embodiments, the aromatase inhibitor is letrozole. In some embodiments, the aromatase inhibitor is anastrozole.

[0354] In some embodiments, the aromatase inhibitor is letrozole, and letrozole is administered once daily at a dose ranging from 1 mg to 4 mg. For example, the aromatase inhibitor may be letrozole, and letrozole may be administered once daily at a dose of 2.5 mg.

[0355] In some embodiments, the aromatase inhibitor is anastrozole, which is administered in doses ranging from 0.5 mg once daily to 1.5 mg once daily. For example, anastrozole may be administered at a dose of 1 mg once daily. The method according to any one of embodiments 117 to 148, where the patient is a postmenopausal woman.

[0356] In some embodiments, the patient is a premenopausal woman or man.

[0357] The patient may be a premenopausal woman or man. Some embodiments further include administering a gonadotropin-releasing hormone agonist to an adult patient, for example, when the patient is a premenopausal woman or man. In some embodiments, the gonadotropin-releasing hormone agonist is goserelin. In some embodiments, goserelin is administered in doses ranging from 2 mg to 5 mg. For example, the dose of goserelin may be 3.6 mg. In some embodiments, goserelin is administered subcutaneously. In some embodiments, goserelin is administered once every four weeks.

[0358] In some embodiments, breast cancer has a histological subtype that is ductal carcinoma or lobular carcinoma.

[0359] In some embodiments, breast cancer is stage IIA or stage IIB. For example, breast cancer may be stage IIA. Breast cancer may be stage IIB.

[0360] In some embodiments, breast cancer is stage IIIA, stage IIIB, or stage IIIC. For example, breast cancer may be stage IIIA. Breast cancer may be stage IIIB. Breast cancer may be stage IIIC.

[0361] In some embodiments, the treatment is administered regardless of the lymph node status of the breast cancer. In some embodiments, the treatment with ribociclib and aromatase inhibitors is not adjusted based on the lymph node status of the early breast cancer.

[0362] In some embodiments, breast cancer has a lymph node state selected from N0, N1, N2, and N3. For example, breast cancer may have a lymph node state of N0. Breast cancer may have lymph node states of N1 to N3. Breast cancer may have a lymph node state of N1. Breast cancer may have a lymph node state of N2. Breast cancer may have a lymph node state of N3.

[0363] In some embodiments, breast cancer comprises one or more cells having a histological grade selected from G1, G2, or G3. For example, breast cancer may comprise one or more cells having histological grade G1. Breast cancer may comprise one or more cells having histological grade G2. Breast cancer may comprise one or more cells having histological grade G3.

[0364] In some embodiments, breast cancer includes tumors of classification T0, T1, T2, T3, or T4. For example, breast cancer may include tumors of classification T1, T2, or T3. Breast cancer may include tumors of classification T0. Breast cancer may include tumors of classification T1. Breast cancer may include tumors of classification T2. ​​Breast cancer may include tumors of classification T3. Breast cancer may include tumors of classification T4.

[0365] In some embodiments, breast cancer has a Ki67 status of 20 or less. In some embodiments, breast cancer has a Ki67 status of 20 or higher.

[0366] In some embodiments, prior to administering ribociclib and an aromatase inhibitor to adult patients, the patients had undergone surgery for early-stage breast cancer.

[0367] In some embodiments, prior to administering ribociclib and an aromatase inhibitor to adult patients, the patients underwent (1) surgery for early-stage breast cancer, followed by (2) chemotherapy.

[0368] In some embodiments, prior to administering ribociclib and aromatase inhibitors to adult patients, the patients underwent (1) surgery for early-stage breast cancer, followed by (2) chemotherapy and / or endocrine therapy.

[0369] In some embodiments, endocrine therapy was a therapy using past aromatase inhibitors. These past aromatase inhibitors may have been letrozole or anastrozole.

[0370] In some embodiments, immediately before administering ribociclib and an aromatase inhibitor to adult patients, the patients underwent surgery for early-stage breast cancer. In some embodiments, the surgery included complete surgical removal of the cancer. In some embodiments, the surgery was a mastectomy.

[0371] In some embodiments, patients received neoadjuvant therapy. For example, neoadjuvant therapy could be chemotherapy.

[0372] In some embodiments, adult patients reside in a geographical area selected from North America, Western Europe, or Oceania.

[0373] In some embodiments, the patient is Asian.

[0374] In some embodiments, the patient is between 18 and 45 years old. In some embodiments, the patient is between 45 and 54 years old. In some embodiments, the patient is between 54 and 64 years old. In some embodiments, the patient is over 64 years old.

[0375] In some embodiments, the patient has a BMI of 25 or higher. In some embodiments, the patient has a BMI of less than 25.

[0376] In some embodiments, the treatment improves the patient's condition compared to patients who have not received treatment and / or compared to the patient's condition before treatment.

[0377] In some embodiments, treatment reduces the risk of invasive disease. For example, treatment may reduce the risk of invasive disease in adult patients, corresponding to a hazard ratio of less than 1 when the risk is calculated compared to other patients who received the same treatment as the adult patients, except that they did not receive ribociclib.

[0378] In some embodiments, the treatment reduces the risk of invasive disease in adult patients, corresponding to a hazard ratio of 0.78 or less when the risk is calculated compared to other patients who received the same treatment as the adult patients, except that they did not receive ribociclib.

[0379] In some embodiments, the adult patients are premenopausal women or men, and the treatment reduces the risk of invasive disease, corresponding to a hazard ratio of 0.72 or less when the risk is calculated compared to other premenopausal women or men who received the same treatment, except that they did not receive ribociclib.

[0380] In some embodiments, adult patients are diagnosed with HR+ / HER2-stage III early breast cancer, and treatment reduces the risk of invasive disease in these adult patients, corresponding to a hazard ratio of 0.74 or less when the risk is calculated compared to other patients who received the same treatment as the adult patients, except that they did not receive ribociclib.

[0381] In some embodiments, adult patients are diagnosed with HR+ / HER2-stage II early breast cancer, and treatment reduces the risk of invasive disease, corresponding to a hazard ratio of 0.76 or less when the risk is calculated compared to other patients who received the same treatment as the adult patients, except that they did not receive ribociclib.

[0382] In some embodiments, adult patients were diagnosed with HR+ / HER2-stage III early breast cancer, and treatment resulted in at least a 25% reduction in the risk of invasive disease, corresponding to a hazard ratio of 0.75 when the risk was calculated compared to other patients who received the same treatment as the adult patients, except that they did not receive ribociclib.

[0383] In some embodiments, the treatment reduces the risk of invasive disease to a level similar to that of patient subgroups including patients with stage II early breast cancer, stage III early breast cancer, premenopausal women or men, and postmenopausal women.

[0384] In some embodiments, the treatment does not result in a deterioration of overall survival, and the risk corresponds to a hazard ratio of 0.76 when the other patients receive the same treatment as adult patients, except that they do not receive ribociclib.

[0385] In some embodiments, the treatment reduces and / or prevents one or more of the risks of cancer recurrence, cancer spread, development and / or proliferation of additional cancers, and death from cancer.

[0386] In some embodiments, the treatment reduces cancer recurrence, where recurrence is one or more of invasive ipsilateral breast tumor (IBTR) recurrence, locally invasive recurrence, and distant recurrence.

[0387] In some embodiments, the treatment reduces the spread of cancer, where the spread of cancer is invasive contralateral breast cancer or additional primary invasive cancer.

[0388] Further aspects of this disclosure relate to 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 breast cancer in adult patients, wherein the method is any one of the methods described herein.

[0389] Another aspect of this disclosure relates to the use of ribociclib or a pharmaceutically acceptable salt thereof and an aromatase inhibitor in the manufacture of a drug for the treatment of HR+ / HER2- stage II or III early breast cancer in adult patients, wherein the drug is administered by any one of the methods described herein.

[0390] Another aspect of this disclosure relates to a kit for carrying out a method for treating HR+ / HER2- stage II or stage III early breast cancer in adult patients by any one of the methods described herein.

[0391] H. Kit for use and instructions One aspect of this disclosure provides a kit for carrying out the methods disclosed herein, for example, a kit for carrying out a method for treating HR+ / HER2-stage II or stage III early breast cancer in adult patients. The kit may be promoted, distributed, or sold as a unit for carrying out the methods of the present invention.

[0392] In some embodiments, the kit comprises a certain dose of ribicilib, its free base form or a pharmaceutically acceptable salt thereof, and a certain dose of an aromatase inhibitor, such as letrozole or anastrozole. The kit may include instructions and / or a manual, such as a dosing schedule for ribicilib and / or the aromatase inhibitor.

[0393] In some embodiments, the kit includes ribociclib in doses ranging from about 150 mg / day to 450 mg / day, and instructions and / or information on administering ribociclib on days 1 to 21 of a 28-day cycle. The kit may further include a dose of an aromatase inhibitor, such as letrozole or anastrozole, for example, letrozole in doses of about 2.5 mg / day or anastrozole in doses of about 1 mg / day, and may further include instructions and / or information on administering the aromatase inhibitor daily during a 28-day cycle.

[0394] In some embodiments, the kit comprises a dose of ribociclib succinate resulting in a total dose of 400 mg / day of ribociclib, and either a dose of 2.5 mg / day of letrozole or a dose of 1 mg / day of anastrozole. The kit may further include instructions and / or instructions for administering the dose of ribociclib succinate on days 1 to 21 of a 28-day cycle, and the dose of letrozole or anastrozole administered daily throughout the 28-day cycle.

[0395] An exemplary kit may contain more than one daily dose; for example, a kit may contain 21 doses of ribociclib, or its free base form or a pharmaceutically acceptable salt thereof, and 28 doses of an aromatase inhibitor (e.g., letrozole or anastrozole) for administration over a total of 28-day cycles. Other exemplary kits may contain some dose of ribociclib, or its free base form or a pharmaceutically acceptable salt thereof, and multiple aromatase inhibitors (letrozole or anastrozole) for 28-day cycles.

[0396] I. Exemplary Embodiments The therapeutic methods and medical uses of this disclosure are provided in the following embodiments.

[0397] 1. A method for treating cancer in adult patients requiring treatment for HR+ / HER2-stage II or stage III early breast cancer, comprising administering to the patient a treatment comprising ribociclib, in the range of 150 mg / day to 450 mg / day, in the free base form thereof or a pharmaceutically acceptable salt thereof, in combination with an aromatase inhibitor, preferably letrozole or anastrozole, administered daily during the 28-day cycle, on days 1 to 21 of a 28-day cycle.

[0398] 2. A method for preventing early breast cancer or reducing its signs or symptoms, comprising administering to a patient a treatment comprising ribociclib, its free base form or a pharmaceutically acceptable salt thereof in combination with an aromatase inhibitor, preferably letrozole or anastrozole.

[0399] 3. The method according to Embodiment 2, wherein ribociclib, its free base form, or a pharmaceutically acceptable salt thereof is administered to the patient in doses ranging from 150 mg / day to 450 mg / day on days 1 to 21 of a 28-day cycle.

[0400] 4. The method according to Embodiment 2 or 3, wherein the aromatase inhibitor is administered daily during a 28-day cycle.

[0401] 5. A method for preventing early breast cancer or reducing its signs or symptoms, comprising administering to a patient a treatment comprising ribociclib, in the range of 150 mg / day to 450 mg / day, in doses ranging from 150 mg / day to 450 mg / day, on days 1 to 21 of a 28-day cycle, in combination with an aromatase inhibitor, preferably letrozole or anastrozole, administered daily during the 28-day cycle.

[0402] 6. The method according to any one of Embodiments 1 to 5, wherein the patient is in remission from HR+ / HER2- stage II or stage III early breast cancer.

[0403] 7. A method for maintaining remission in an adult patient previously diagnosed with HR+ / HER2-stage II or stage III early breast cancer, comprising administering to the patient a treatment comprising a certain dose of ribociclib, its free base form or a pharmaceutically acceptable salt thereof, in combination with an aromatase inhibitor, preferably letrozole or anastrozole.

[0404] 8. The method according to Embodiment 6 or 7, wherein the remission is complete remission.

[0405] 9. The method according to Embodiment 6 or 7, wherein the remission is partial remission.

[0406] 10. The method according to any one of Embodiments 1 to 9, wherein the treatment reduces the recurrence of HR+ / HER2-stage II or stage III early breast cancer.

[0407] 11. The method according to Embodiment 10, wherein the treatment prevents recurrence for at least three months.

[0408] 12. The method according to Embodiment 11, wherein the treatment prevents recurrence for at least 6 months.

[0409] 13. The method according to Embodiment 12, wherein the treatment prevents recurrence for at least one year.

[0410] 14. The method according to any one of Embodiments 1 to 13, wherein the patient does not have any signs or symptoms of cancer prior to treatment.

[0411] 15. The method according to any one of Embodiments 1 to 14, wherein the treatment prevents the proliferation of HR+ / HER2- breast cancer cells.

[0412] 16. The method according to any one of Embodiments 1 to 15, wherein the treatment is adjuvant therapy.

[0413] 17. The method according to any one of Embodiments 1 to 16, wherein ribociclib is a pharmaceutically acceptable ribociclib salt.

[0414] 18. The method according to Embodiment 17, wherein the ribociclib salt is ribociclib succinate.

[0415] 19. The method according to any one of Embodiments 1 to 18, wherein the dose of ribociclib is 200 mg / day or 400 mg / day.

[0416] 20. The method according to any one of Embodiments 1 to 18, wherein ribociclib is not administered at a dose of 600 mg / day.

[0417] 21. The method according to any one of Embodiments 1 to 19, wherein ribociclib is administered as ribociclib succinate, and the total dose of ribociclib is 200 mg / day.

[0418] 22. The method according to any one of Embodiments 1 to 19, wherein ribociclib is administered as ribociclib succinate, and the total dose of ribociclib is 400 mg / day.

[0419] 23. The method according to any one of Embodiments 1 to 19, wherein ribociclib is administered at a dose of 400 mg / day for a period of time, and then ribociclib is administered at a dose of 200 mg / day thereafter.

[0420] 24. The method according to any one of Embodiments 1 to 23, wherein the dose of ribociclib is administered orally.

[0421] 25. The method according to any one of Embodiments 1 to 24, wherein the dose of ribociclib is administered in tablet form.

[0422] 26. The method according to any one of Embodiments 1 to 24, wherein the aromatase inhibitor is letrozole or anastrozole.

[0423] 27. The method according to any one of Embodiments 1 to 26, wherein the aromatase inhibitor is administered orally.

[0424] 28. The method according to Embodiment 26 or 27, wherein letrozole is administered in a dose ranging from 1 mg / day to 4 mg / day.

[0425] 29. The method according to Embodiment 28, wherein letrozole is administered at a dose of 2.5 mg / day.

[0426] 30. The method according to Embodiment 26 or 27, wherein anastrozole is administered in a dose ranging from 0.5 mg / day to 1.5 mg / day.

[0427] 31. The method according to Embodiment 30, wherein anastrozole is administered at a dose of 1 mg / day.

[0428] 32. The method according to any one of Embodiments 1 to 31, wherein the treatment comprises a gonadotropin-releasing hormone agonist.

[0429] 33. The method according to Embodiment 32, wherein the gonadotropin-releasing hormone agonist is goserelin.

[0430] 34. The method according to Embodiment 33, wherein goserelin is administered in a dose ranging from 2 mg to 5 mg.

[0431] 35. The method according to Embodiment 34, wherein the dose of goserelin is 3.6 mg.

[0432] 36. The method according to any one of embodiments 33 to 35, wherein goserelin is administered subcutaneously.

[0433] 37. The method according to any one of embodiments 33 to 36, wherein goserelin is administered once every four weeks.

[0434] 38. The method according to any one of Embodiments 1 to 31, wherein the patient is a postmenopausal woman.

[0435] 39. The method according to any one of Embodiments 1 to 37, wherein the patient is a premenopausal woman or a man.

[0436] 40. The method according to any one of Embodiments 1 to 39, wherein the treatment is administered to the patient for at least 12 months.

[0437] 41. The method according to Embodiment 40, wherein the treatment is administered to the patient for at least 24 months.

[0438] 42. The method according to Embodiment 40 or 41, wherein the treatment is administered to the patient for at least 36 months.

[0439] 43. The method according to Embodiment 40 or 41, wherein the treatment is administered to the patient for at least 48 months.

[0440] 44. The method according to Embodiment 40 or 41, wherein the treatment is administered to the patient for at least 60 months.

[0441] 45. The method according to any one of Embodiments 1 to 44, wherein the treatment is continued until there is no detectable cancer in the patient.

[0442] 46. ​​The method according to any one of Embodiments 1 to 45, wherein the breast cancer is ER+ and PR+.

[0443] 47. The method according to any one of Embodiments 1 to 45, wherein the breast cancer is ER- and PR-+.

[0444] 48. The method according to any one of Embodiments 1 to 45, wherein the breast cancer is ER+ and PR-.

[0445] 49. The method according to any one of Embodiments 1 to 48, wherein the breast cancer has a histological subtype that is ductal carcinoma or lobular carcinoma.

[0446] 50. The method according to any one of Embodiments 1 to 49, wherein the breast cancer is stage IIA or stage IIB.

[0447] 51. The method according to Embodiment 50, wherein the breast cancer is stage IIA cancer.

[0448] 52. The method according to Embodiment 50, wherein the breast cancer is stage IIB cancer.

[0449] 53. The method according to any one of Embodiments 1 to 49, wherein the breast cancer is stage IIIA, stage IIIB, or stage IIIC.

[0450] 54. The method according to Embodiment 53, wherein the breast cancer is stage IIIA cancer.

[0451] 55. The method according to Embodiment 53, wherein the breast cancer is stage IIIB cancer.

[0452] 56. The method according to Embodiment 53, wherein the breast cancer is stage IIIC cancer.

[0453] 57. The method according to any one of Embodiments 1 to 56, wherein the treatment is administered regardless of the lymph node status of the breast cancer.

[0454] 58. The method according to any one of Embodiments 1 to 57, wherein the breast cancer has a lymph node state selected from N0, N1, N2, and N3.

[0455] 59. The method according to Embodiment 57 or 58, wherein the breast cancer has an N0 lymph node state.

[0456] 60. The method according to Embodiment 57 or 58, wherein the breast cancer has a lymph node state of N1-N3.

[0457] 61. The method according to Embodiment 57 or 58, wherein the breast cancer has an N1 lymph node state.

[0458] 62. The method according to Embodiment 57 or 58, wherein the breast cancer has an N2 lymph node state.

[0459] 63. The method according to Embodiment 57 or 58, wherein the breast cancer has an N3 lymph node state.

[0460] 64. The method according to any one of Embodiments 1 to 63, wherein the breast cancer comprises one or more cells having a histological grade selected from G1, G2, or G3.

[0461] 65. The method according to Embodiment 64, wherein the breast cancer comprises one or more cells having histological grade G1.

[0462] 66. The method according to Embodiment 64, wherein the breast cancer comprises one or more cells having histological grade G2.

[0463] 67. The method according to Embodiment 64, wherein the breast cancer comprises one or more cells having histological grade G3.

[0464] 68. The method according to any one of Embodiments 1 to 67, wherein the breast cancer includes tumors of classification T0, T1, T2, T3, or T4.

[0465] 69. The method according to Embodiment 68, wherein the breast cancer includes tumors of classification T1, T2, or T3.

[0466] 70. The method according to Embodiment 68, wherein the breast cancer includes a tumor of classification T0.

[0467] 71. The method according to Embodiment 68 or 69, wherein the breast cancer includes a tumor of classification T1.

[0468] 72. The method according to Embodiment 68 or 69, wherein the breast cancer includes a tumor of classification T2.

[0469] 73. The method according to Embodiment 68 or 69, wherein the breast cancer includes a tumor of classification T3.

[0470] 74. The method according to Embodiment 68, wherein the breast cancer includes a tumor of classification T4.

[0471] 75. The method according to any one of Embodiments 1 to 74, wherein the breast cancer has a Ki67 status of 20 or less.

[0472] 76. The method according to any one of Embodiments 1 to 74, wherein the breast cancer has a Ki67 status higher than 20.

[0473] 77. The method according to any one of Embodiments 1 to 76, wherein the patient had received a loading dose of (i) ribociclib and / or (ii) endocrine therapy prior to administration.

[0474] 78. The method according to any one of Embodiments 1 to 77, wherein the patient has received at least one prior treatment for cancer.

[0475] 79. The method according to embodiment 78, wherein the prior treatment is an adjuvant treatment following another prior treatment.

[0476] 80. The method according to embodiment 78 or 79, wherein the prior treatment is surgical.

[0477] 81. The method according to embodiment 80, wherein the surgical procedure includes complete surgical resection of the cancer.

[0478] 82. The method according to embodiment 80 or 81, wherein the surgical procedure is a mastectomy.

[0479] 83. The method according to Embodiment 80 or 81, wherein the prior treatment is chemotherapy.

[0480] 84. The method according to embodiment 83, wherein the prior treatment is adjuvant chemotherapy.

[0481] 85. The method according to embodiment 83, wherein the prior treatment is neoadjuvant chemotherapy.

[0482] 86. The method according to Embodiment 78 or 79, wherein the prior treatment is endocrine therapy.

[0483] 87. The method according to Embodiment 78 or 79, wherein the prior treatment is radiotherapy.

[0484] 88. The method according to any one of embodiments 78 to 87, wherein the patient did not respond to prior treatment.

[0485] 89. The method according to any one of Embodiments 1 to 88, wherein the patient resides in a geographical area selected from North America, Western Europe, or Oceania.

[0486] 90. The method according to any one of Embodiments 1 to 89, wherein the patient is of Asian descent.

[0487] 91. The method according to any one of Embodiments 1 to 90, wherein the patient is between 18 and 45 years of age.

[0488] 92. The method according to any one of Embodiments 1 to 90, wherein the patient is 45 to 54 years old.

[0489] 93. The method according to any one of Embodiments 1 to 90, wherein the patient is between 54 and 64 years old.

[0490] 94. The method according to any one of Embodiments 1 to 90, wherein the patient is over 64 years of age.

[0491] 95. The method according to any one of Embodiments 1 to 94, wherein the patient has a BMI of 25 or higher.

[0492] 96. The method according to any one of Embodiments 1 to 94, wherein the patient has a BMI of less than 25.

[0493] 97. The method according to any one of Embodiments 1 to 96, wherein the treatment improves the patient's condition compared to a patient who has not received treatment and / or compared to the patient's condition before treatment.

[0494] 98. The method according to any one of Embodiments 1 to 97, wherein the treatment reduces the risk of invasive disease.

[0495] 99. The method according to Embodiment 98, wherein treatment reduces the risk of invasive disease, and when the risk is calculated compared to untreated patients, it corresponds to a hazard ratio of less than 1.

[0496] 100. The method according to Embodiment 99, wherein the treatment reduces the risk of invasive disease, and when the risk is calculated compared to a patient who has not received treatment, the hazard ratio corresponds to 0.78 or less.

[0497] 101. The method according to any one of Embodiments 1 to 37 and 39 to 100, wherein the patient is a premenopausal woman or man, the treatment reduces the risk of invasive disease, and the hazard ratio when the risk is calculated compared to a patient receiving treatment is 0.72 or less.

[0498] 102. The method according to any one of embodiments 98 to 100, wherein the patient has HR+ / HER2-stage III early breast cancer, and treatment reduces the risk of invasive disease, corresponding to a hazard ratio of 0.74 or less when the risk is calculated compared to a patient who has not received treatment.

[0499] 103. The method according to any one of Embodiments 98 to 100, wherein the patient has HR+ / HER2-stage II early breast cancer, and the risk of invasive disease is reduced by treatment, corresponding to a hazard ratio of 0.76 or less when the risk is calculated compared to a patient who has not received treatment.

[0500] 104. The method according to any one of Embodiments 98 to 100, wherein the patient has HR+ / HER2-stage III early breast cancer, and treatment results in at least a 25% reduction in the risk of invasive disease, corresponding to a hazard ratio of 0.75 when the risk is calculated compared to a patient who has not received treatment.

[0501] 105. The method according to any one of Embodiments 1 to 104, wherein the treatment reduces the risk of invasive disease to a level similar to that of a patient subgroup including patients with stage II early breast cancer, stage III early breast cancer, premenopausal women or men, and postmenopausal women.

[0502] 106. The method according to any one of Embodiments 1 to 105, wherein the treatment does not result in a deterioration of overall survival and corresponds to a hazard ratio of 0.76 when the risk is calculated compared to patients who do not receive treatment.

[0503] 107. The method according to any one of Embodiments 1 to 106, wherein the treatment reduces and / or prevents one or more risks of cancer recurrence, cancer spread, development and / or proliferation of additional cancers, and death from cancer.

[0504] 108. The method according to Embodiment 107, wherein treatment reduces cancer recurrence, and the recurrences are one or more of invasive ipsilateral breast tumor (IBTR) recurrence, locally invasive recurrence, and distant recurrence.

[0505] 109. The method according to Embodiment 107 or 108, wherein the treatment reduces the extent of cancer, and the extent of cancer is invasive contralateral breast cancer or additional primary invasive cancer.

[0506] 110. The method according to any one of Embodiments 1 to 109, wherein the treatment prevents death from cancer.

[0507] 111. A method for maintaining remission in an adult patient previously diagnosed with HR+ / HER2-stage II or stage III early breast cancer, comprising administering to the patient a treatment comprising administering to the patient a treatment comprising ribociclib, in the range of 150 mg / day to 450 mg / day on days 1 to 21 of a 28-day cycle, in combination with an aromatase inhibitor, preferably letrozole or anastrozole, administered daily during the 28-day cycle.

[0508] 112. A method for preventing recurrence of breast cancer in adult patients, comprising providing adjuvant therapy to patients who have previously received treatment for HR+ / HER2-stage II or III early breast cancer, wherein the adjuvant therapy comprises administering to the patient 400 mg 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 described in any one of embodiments 26 to 31, administered daily during the 28-day cycle.

[0509] 113. The method according to embodiment 112, wherein the prior treatment is surgical resection of cancer.

[0510] 114. Ribociclib or a pharmaceutically acceptable salt thereof and an aromatase inhibitor for use in a method for treating HR+ / HER2- stage II or III early breast cancer in adult patients, according to any one of Embodiments 1 to 112.

[0511] 115. Use of ribociclib or a pharmaceutically acceptable salt thereof and an aromatase inhibitor in the manufacture of a pharmaceutical product for the treatment of HR+ / HER2- stage II or III early breast cancer in adult patients, wherein the pharmaceutical product is administered by the method described in any one of Embodiments 1 to 112.

[0512] 116. A kit for carrying out a method for treating HR+ / HER2- stage II or stage III early breast cancer in adult patients as described in any one of Embodiments 1 to 112.

[0513] 117. A method for treating HR+ / HER2- stage II or stage III early breast cancer in an adult patient in remission, comprising administering ribociclib in combination with an aromatase inhibitor to the adult patient, wherein the administration maintains remission in the adult patient for at least three months.

[0514] 118. A method for treating HR+ / HER2- stage II or stage III early breast cancer in adult patients, comprising providing adjuvant therapy by administering ribociclib in combination with an aromatase inhibitor, wherein the patient is in complete remission at the start of adjuvant therapy, and the administration of ribociclib in combination with an aromatase inhibitor maintains complete remission in adult patients for at least 3 months.

[0515] 119. The method according to Embodiment 117 or 118, wherein administration maintains remission (e.g., complete remission) in adult patients for at least 6 months.

[0516] 120. The method according to Embodiment 117 or 118, wherein administration maintains remission (e.g., complete remission) in adult patients for at least 9 months.

[0517] 121. The method according to Embodiment 117 or 118, wherein administration maintains remission (e.g., complete remission) in adult patients for at least 12 months.

[0518] 122. The method according to Embodiment 117 or 118, wherein administration maintains remission (e.g., complete remission) in adult patients for at least 15 months.

[0519] 123. The method according to Embodiment 117 or 118, wherein administration maintains remission (e.g., complete remission) in adult patients for at least 18 months.

[0520] 124. The method according to Embodiment 117 or 118, wherein administration maintains remission (e.g., complete remission) in adult patients for at least 21 months.

[0521] 125. The method according to Embodiment 117 or 118, wherein administration maintains remission (e.g., complete remission) in adult patients for at least 24 months.

[0522] 126. The method according to Embodiment 117 or 118, wherein administration maintains remission (e.g., complete remission) in adult patients for at least 27 months.

[0523] 127. The method according to Embodiment 117 or 118, wherein administration maintains remission (e.g., complete remission) in adult patients for at least 30 months.

[0524] 128. The method according to Embodiment 117 or 118, wherein administration maintains remission (e.g., complete remission) in adult patients for at least 33 months.

[0525] 129. The method according to Embodiment 117 or 118, wherein administration maintains remission (e.g., complete remission) in adult patients for at least 36 months.

[0526] 130. The method according to any one of Embodiments 117 to 129, wherein ribociclib and an aromatase inhibitor are administered over the duration of treatment, and the administration maintains remission (e.g., complete remission) in adult patients for at least the duration of treatment.

[0527] The method according to any one of embodiments 117 to 129, wherein a dose of 131,400 mg of ribociclib is administered orally once daily on days 1 to 21 of a 28-day cycle, and an aromatase inhibitor is administered once daily every day during the 28-day cycle.

[0528] The method according to any one of Embodiments 117 to 129, wherein 132,400 mg of ribociclib is administered orally once daily on days 1 to 21 of a 28-day cycle for a maximum treatment period of 3 years, and an aromatase inhibitor is administered once daily every day of a 28-day cycle for a maximum period of 3 years.

[0529] The method according to any one of embodiments 117 to 129, wherein a dose of 133,400 mg of ribociclib is administered orally once daily on days 1 to 21 of a 28-day cycle for a maximum treatment period of 5 years, and an aromatase inhibitor is administered once daily every day during a 28-day cycle for a maximum period of 5 years.

[0530] 134. The method according to 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.

[0531] 135. The method according to Embodiment 134, wherein the pharmaceutically acceptable salt is ribociclib succinate.

[0532] 136. The method according to any one of Embodiments 117 to 135, wherein the adult patient had never been treated with a 600 mg dose of ribociclib.

[0533] 137. The method according to any one of Embodiments 117 to 136, wherein the adult patient had never been diagnosed with HR+ / HER2- advanced or metastatic breast cancer.

[0534] 138. The method according to any one of Embodiments 117 to 137, wherein ribociclib and an aromatase inhibitor are administered as adjuvant therapy.

[0535] 139. The method according to any one of embodiments 117 to 138, wherein ribociclib is not administered at a dose of 600 mg / day.

[0536] 140. The method according to any one of Embodiments 117 to 139, wherein the dose of ribociclib is administered in tablet form.

[0537] 141. The method according to any one of Embodiments 117 to 139, wherein two tablets are orally administered to an adult patient once daily on days 1 to 21 of a 28-day cycle, for the duration of treatment, and each tablet contains a pharmaceutically acceptable ribociclib salt in an amount equivalent to 200 mg of ribociclib.

[0538] 142. The method according to Embodiment 141, wherein the ribociclib salt is ribociclib succinate.

[0539] 143. The method according to any one of embodiments 117 to 142, wherein the aromatase inhibitor is letrozole.

[0540] 144. The method according to any one of embodiments 117 to 142, wherein the aromatase inhibitor is anastrozole.

[0541] 145. The method according to any one of Embodiments 117 to 144, wherein the aromatase inhibitor is letrozole, and letrozole is administered once daily in a dose ranging from 1 mg to 4 mg.

[0542] 146. The method according to any one of Embodiments 117 to 144, wherein the aromatase inhibitor is letrozole, and letrozole is administered once daily at a dose of 2.5 mg.

[0543] 147. The method according to any one of Embodiments 117 to 144, wherein the aromatase inhibitor is anastrozole, and anastrozole is administered in a dose ranging from 0.5 mg once daily to 1.5 mg once daily.

[0544] 148. The method according to any one of Embodiments 117 to 144, wherein the aromatase inhibitor is anastrozole, and anastrozole is administered once daily at a dose of 1 mg.

[0545] 149. The method according to any one of embodiments 114 to 148, further comprising administering a gonadotropin-releasing hormone agonist to an adult patient.

[0546] 150. The method according to Embodiment 149, wherein the gonadotropin-releasing hormone agonist is goserelin.

[0547] 151. The method according to Embodiment 150, wherein goserelin is administered in a dose ranging from 2 mg to 5 mg.

[0548] 152. The method according to Embodiment 151, wherein the dose of goserelin is 3.6 mg.

[0549] 153. The method according to any one of embodiments 150 to 152, wherein goserelin is administered subcutaneously.

[0550] 154. The method according to any one of embodiments 150 to 153, wherein goserelin is administered once every four weeks.

[0551] 155. The method according to any one of embodiments 117 to 148, wherein the patient is a postmenopausal woman.

[0552] 156. The method according to any one of embodiments 117 to 154, wherein the patient is a premenopausal woman or a man.

[0553] 157. The method according to any one of embodiments 117 to 156, wherein the breast cancer has a histological subtype that is ductal carcinoma or lobular carcinoma.

[0554] 158. The method according to any one of embodiments 117 to 156, wherein the breast cancer is stage IIA or stage IIB.

[0555] 159. The method according to any one of embodiments 117 to 156, wherein the breast cancer is stage IIA cancer.

[0556] 160. The method according to any one of embodiments 117 to 156, wherein the breast cancer is stage IIB cancer.

[0557] 161. The method according to any one of embodiments 117 to 156, wherein the breast cancer is stage IIIA, stage IIIB, or stage IIIC.

[0558] 162. The method according to any one of embodiments 117 to 156, wherein the breast cancer is stage IIIA cancer.

[0559] 163. The method according to any one of embodiments 117 to 156, wherein the breast cancer is stage IIIB cancer.

[0560] 164. The method according to any one of embodiments 117 to 156, wherein the breast cancer is stage IIIC cancer.

[0561] 165. The method according to any one of embodiments 117 to 156, wherein the treatment is administered regardless of the lymph node status of the breast cancer.

[0562] 166. The method according to any one of embodiments 117 to 156, wherein treatment with ribociclib and an aromatase inhibitor is not adjusted based on the lymph node status of early breast cancer.

[0563] 167. The method according to any one of embodiments 117 to 156, wherein the breast cancer has a lymph node state selected from N0, N1, N2, and N3.

[0564] 168. The method according to any one of embodiments 117 to 156, wherein the breast cancer has an N0 lymph node state.

[0565] 169. The method according to any one of embodiments 117 to 156, wherein the breast cancer has a lymph node status of N1 to N3.

[0566] 170. The method according to any one of embodiments 117 to 156, wherein the breast cancer has an N1 lymph node state.

[0567] 171. The method according to any one of embodiments 117 to 156, wherein the breast cancer has an N2 lymph node state.

[0568] 172. The method according to any one of embodiments 117 to 156, wherein the breast cancer has an N3 lymph node state.

[0569] 173. The method according to any one of Embodiments 117 to 156, wherein the breast cancer comprises one or more cells having a histological grade selected from G1, G2, or G3.

[0570] 174. The method according to any one of embodiments 117 to 156, wherein the breast cancer comprises one or more cells having histological grade G1.

[0571] 175. The method according to any one of embodiments 117 to 156, wherein the breast cancer comprises one or more cells having histological grade G2.

[0572] 176. The method according to any one of embodiments 117 to 156, wherein the breast cancer comprises one or more cells having histological grade G3.

[0573] 177. The method according to any one of Embodiments 117 to 156, wherein the breast cancer includes tumors of classification T0, T1, T2, T3, or T4.

[0574] 178. The method according to any one of embodiments 117 to 156, wherein the breast cancer includes a tumor of classification T1, T2, or T3.

[0575] 179. The method according to any one of embodiments 117 to 156, wherein the breast cancer includes a tumor of classification T0.

[0576] 180. The method according to any one of embodiments 117 to 156, wherein the breast cancer includes a tumor of classification T1.

[0577] 181. The method according to any one of embodiments 117 to 156, wherein the breast cancer includes a tumor of classification T2.

[0578] 182. The method according to any one of embodiments 117 to 156, wherein the breast cancer includes a tumor of classification T3.

[0579] 183. The method according to any one of embodiments 117 to 156, wherein the breast cancer includes a tumor of classification T4.

[0580] 184. The method according to any one of embodiments 117 to 156, wherein the breast cancer has a Ki67 status of 20 or less.

[0581] 185. The method according to any one of embodiments 117 to 156, wherein the breast cancer has a Ki67 status higher than 20.

[0582] 186. The method according to any one of Embodiments 117 to 185, wherein the adult patient underwent surgery for early-stage breast cancer before being administered ribociclib and an aromatase inhibitor.

[0583] 187. The method according to any one of Embodiments 117 to 185, wherein, before administering ribociclib and an aromatase inhibitor to an adult patient, the patient underwent (1) surgery for early-stage breast cancer followed by (2) chemotherapy.

[0584] 188. The method according to any one of Embodiments 117 to 185, wherein, prior to administration of ribociclib and an aromatase inhibitor to an adult patient, the patient underwent (1) surgery for early-stage breast cancer, followed by (2) chemotherapy and / or endocrine therapy.

[0585] 189. The method according to Embodiment 188, wherein the endocrine therapy was a past therapy using aromatase inhibitors.

[0586] 190. The method according to Embodiment 188, wherein the aromatase inhibitor used in the past was letrozole or anastrozole.

[0587] 191. The method according to any one of Embodiments 117 to 185, wherein the adult patient underwent surgery for early-stage breast cancer immediately before being administered ribociclib and an aromatase inhibitor.

[0588] 192. The method according to any one of embodiments 186 to 191, wherein the surgical procedure includes the complete surgical resection of the cancer.

[0589] 193. The method according to any one of embodiments 186 to 191, wherein the surgical procedure was a mastectomy.

[0590] 194. The method according to any one of embodiments 186 to 191, wherein the patient receives neoadjuvant therapy.

[0591] 195. The method according to Embodiment 194, wherein the neoadjuvant therapy was chemotherapy.

[0592] 196. The method according to any one of Embodiments 117-195, wherein the adult patient resides in a geographical area selected from North America, Western Europe, or Oceania.

[0593] 197. The method according to any one of embodiments 117 to 195, wherein the patient is of Asian descent.

[0594] 198. The method according to any one of embodiments 117 to 195, wherein the patient is between 18 and 45 years of age.

[0595] 199. The method according to any one of embodiments 117 to 195, wherein the patient is 45 to 54 years old.

[0596] 200. The method according to any one of embodiments 117 to 195, wherein the patient is 54 to 64 years old.

[0597] 201. The method according to any one of embodiments 117 to 195, wherein the patient is over 64 years of age.

[0598] 202. The method according to any one of embodiments 117 to 195, wherein the patient has a BMI of 25 or greater.

[0599] 203. The method according to any one of embodiments 117 to 195, wherein the patient has a BMI of less than 25.

[0600] 204. The method according to any one of Embodiments 117 to 203, wherein the treatment improves the patient's condition compared to a patient who has not received treatment and / or compared to the patient's condition before treatment.

[0601] 205. The method according to any one of embodiments 117 to 203, wherein the treatment reduces the risk of invasive disease.

[0602] 206. The method according to any one of Embodiments 117 to 203, wherein the treatment reduces the risk of invasive disease in adult patients, and when the risk is calculated compared to other patients who received the same treatment as the adult patients except that other patients did not receive ribociclib, the hazard ratio corresponds to less than 1.

[0603] 207. The method according to any one of Embodiments 117 to 203, wherein the treatment reduces the risk of invasive disease in adult patients, and when the risk is calculated compared to other patients who received the same treatment as the adult patients except that other patients did not receive ribociclib, the hazard ratio corresponds to 0.78 or less.

[0604] 208. The method according to any one of Embodiments 117 to 203, wherein the adult patient is a premenopausal woman or man, and the treatment reduces the risk of invasive disease, and the hazard ratio is 0.72 or less when the risk is calculated compared to other premenopausal women or men who received the same treatment, except that other premenopausal women or men did not receive ribociclib.

[0605] 209. The method according to any one of Embodiments 117 to 203, wherein an adult patient is diagnosed with HR+ / HER2-stage III early breast cancer, and the treatment reduces the adult patient's risk of invasive disease, corresponding to a hazard ratio of 0.74 or less when the risk is calculated compared to other patients who received the same treatment as the adult patient, except that the other patients did not receive ribociclib.

[0606] 210. The method according to any one of Embodiments 117 to 203, wherein an adult patient is diagnosed with HR+ / HER2- Stage II early breast cancer, and the treatment reduces the risk of invasive disease, corresponding to a hazard ratio of 0.76 or less when the risk is calculated compared to other patients who received the same treatment as the adult patient, except that other patients did not receive ribociclib.

[0607] 211. The method according to any one of Embodiments 117 to 203, wherein an adult patient is diagnosed with HR+ / HER2-stage III early breast cancer, and treatment results in at least a 25% reduction in the risk of invasive disease, corresponding to a hazard ratio of 0.75 when the risk is calculated compared to other patients who received the same treatment as the adult patient, except that other patients did not receive ribociclib.

[0608] 212. The method according to any one of Embodiments 117 to 203, wherein the treatment reduces the risk of invasive disease to a level similar to that of patient subgroups including patients with stage II early breast cancer, stage III early breast cancer, patients who are premenopausal women or men, and patients who are postmenopausal women.

[0609] 213. The method according to any one of Embodiments 117 to 203, wherein the treatment does not result in a deterioration of overall survival and corresponds to a hazard ratio of 0.76 when the risk is calculated compared to other patients who received the same treatment as the adult patient, except that the other patients did not receive ribociclib.

[0610] 214. The method according to any one of Embodiments 117 to 203, wherein the treatment reduces and / or prevents one or more of the risks of cancer recurrence, cancer spread, development and / or proliferation of additional cancers, and death from cancer.

[0611] 215. The method according to any one of Embodiments 117 to 203, wherein treatment reduces cancer recurrence, and the recurrences are one or more of invasive ipsilateral breast tumor (IBTR) recurrence, locally invasive recurrence, and distant recurrence.

[0612] 216. The method according to any one of Embodiments 117 to 203, wherein the treatment reduces the extent of the cancer, and the extent of the cancer is invasive contralateral breast cancer or additional primary invasive cancer.

[0613] 217. Ribociclib or a pharmaceutically acceptable salt thereof and an aromatase inhibitor for use in a method for treating HR+ / HER2- stage II or III early breast cancer in adult patients, according to any one of embodiments 117 to 216.

[0614] 218. Use of ribociclib or a pharmaceutically acceptable salt thereof and an aromatase inhibitor in the manufacture of a pharmaceutical product for the treatment of HR+ / HER2- stage II or III early breast cancer in adult patients, wherein the pharmaceutical product is administered by any one of embodiments 117 to 216.

[0615] 219. A kit for carrying out a method for treating HR+ / HER2- stage II or stage III early breast cancer in adult patients as described in any one of embodiments 117 to 216.

[0616] 220. A method for treating an adult patient diagnosed with HER+ / HER2-stage II or stage III early breast cancer, comprising administering to the patient an adjuvant therapy comprising (i) ribociclib in doses ranging from 150 mg / day to 450 mg / day administered on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle, wherein the method results in an improvement in one or more of the patient's overall survival (OS), distant disease-free survival (DDFS), or recurrence-free survival (RFS).

[0617] 221. A method for improving one or more of the overall survival (OS), distant disease-free survival (DDFS), or recurrence-free survival (RFS) of a patient diagnosed with HR+ / HER2-stage II or stage III early breast cancer, comprising administering to the patient an adjuvant therapy comprising (i) ribociclib in a dose ranging from 150 mg / day to 450 mg / day administered on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle.

[0618] 222. A method for reducing the risk of local or regional invasive recurrence of early breast cancer in adult patients diagnosed with HR+ / HER2- stage II or stage III early breast cancer, comprising administering to the patient an adjuvant therapy comprising (i) ribociclib in doses ranging from 150 mg / day to 450 mg / day, administered on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor, administered daily during the 28-day cycle.

[0619] 223. A method for reducing the risk of invasive recurrence of early breast cancer in one or more of the bone, liver, lungs, or pleura in adult patients diagnosed with HR+ / HER2-stage II or III early breast cancer, comprising administering to the patient an adjuvant therapy comprising (i) ribociclib at a dose ranging from 150 mg / day to 450 mg / day on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle.

[0620] 224. The method according to any one of embodiments 220 to 223, wherein the treatment is administered regardless of the lymph node status of the breast cancer.

[0621] 225. A method for reducing the risk of early breast cancer recurrence in adult patients diagnosed with HR+ / HER2- stage II or stage III early breast cancer, comprising administering to the patient an adjuvant therapy comprising (i) ribociclib at a dose ranging from 150 mg / day to 450 mg / day on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle, wherein the therapy is administered regardless of the lymph node status of the breast cancer.

[0622] 226. The method according to any one of embodiments 220 to 225, wherein the breast cancer has a lymph node status of N0, N1, N2, or N3.

[0623] 227. The method according to Embodiment 226, wherein the breast cancer has an N0 lymph node state.

[0624] 228. The method according to any one of embodiments 220 to 227, wherein the early-stage breast cancer is stage II, for example, stage IIA.

[0625] 229. The method according to any one of embodiments 220 to 227, wherein the early-stage breast cancer is stage III, for example, stage IIIB or IIIC.

[0626] 230. The method according to any one of embodiments 220 to 229, wherein the breast cancer is a ductal carcinoma subtype.

[0627] 231. The method according to any one of embodiments 220 to 230, wherein the patient is of Asian descent.

[0628] 232. The method according to any one of embodiments 220 to 231, which is an 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.

[0629] 233. The method according to embodiment 232, wherein the patient has never undergone a mastectomy.

[0630] 234. The method according to any one of Embodiments 220 to 233, wherein the dose of ribociclib is 400 mg / day.

[0631] 235. The method according to any one of Embodiments 220 to 234, wherein ribociclib is administered in the form of a salt, preferably as ribociclib succinate.

[0632] 236. The method according to any one of embodiments 220 to 235, wherein the aromatase inhibitor is letrozole or anastrozole.

[0633] 237. The method according to Embodiment 236, wherein the aromatase inhibitor is letrozole, preferably administered at a dose of 2.5 mg / day.

[0634] 238. The method according to Embodiment 236, wherein the aromatase inhibitor is anastrozole, preferably administered at a dose of 1 mg / day.

[0635] 239. The method according to any one of Embodiments 220 to 238, wherein the dose of ribociclib is 400 mg / day, ribociclib is administered in the form of ribociclib succinate, and the aromatase inhibitor is letrozole or anastrozole, preferably 2.5 mg / day of letrozole or 1 mg / day of anastrozole.

[0636] 240. The method according to any one of embodiments 220 to 239, wherein improvement in OS, DDFS and / or RFS, or reduction in the risk of breast cancer recurrence, is achieved in the patient for at least 36 months.

[0637] 241. Ribociclib for use in a method to improve one or more of the overall survival (OS), distant disease-free survival (DDFS), or recurrence-free survival (RFS) in adult patients diagnosed with HR+ / HER2-stage II or stage III early breast cancer, wherein the method comprises administering to the patient an adjuvant therapy comprising (i) a dose of ribociclib ranging from 150 mg / day to 450 mg / day administered on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle.

[0638] 242. Ribociclib for use in a method for reducing the risk of local or regional invasive recurrence of early breast cancer in adult patients diagnosed with HR+ / HER2-stage II or III early breast cancer, comprising administering to the patient an adjuvant therapy comprising (i) ribociclib in doses ranging from 150 mg / day to 450 mg / day administered on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during a 28-day cycle.

[0639] 243. Ribociclib for use in a method for reducing the risk of invasive recurrence of early breast cancer in one or more of the bone, liver, lungs, or pleura in adult patients diagnosed with HR+ / HER2-stage II or III early breast cancer, comprising administering to the patient an adjuvant therapy comprising (i) ribociclib in doses ranging from 150 mg / day to 450 mg / day administered on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during a 28-day cycle.

[0640] 244. Ribociclib for use according to any one of embodiments 241 to 243, wherein the treatment is administered regardless of the lymph node status of the breast cancer.

[0641] 245. Ribociclib for use in a method for reducing the risk of early breast cancer recurrence in adult patients diagnosed with HR+ / HER2- stage II or III early breast cancer, comprising administering to the patient an adjuvant therapy comprising (i) a dose of ribociclib ranging from 150 mg / day to 450 mg / day administered on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle, wherein the therapy is administered regardless of the lymph node status of the breast cancer.

[0642] 246. Ribociclib for use according to any one of Embodiments 241 to 245, wherein the breast cancer has a lymph node status of N0, N1, N2, or N3.

[0643] 247. Ribociclib for use according to Embodiment 246 in a breast cancer patient having an N0 lymph node state.

[0644] 248. Ribociclib for use according to any one of Embodiments 241 to 247, for early breast cancer which is stage II, such as stage IIA.

[0645] 249. Ribociclib for use according to any one of Embodiments 241 to 247, wherein the early-stage breast cancer is stage III, such as stage IIIB or IIIC.

[0646] 250. Ribociclib for use according to any one of Embodiments 241 to 249, wherein the breast cancer is a ductal carcinoma subtype.

[0647] 251. Ribociclib for use according to any one of Embodiments 241-250, wherein the patient is of Asian descent.

[0648] 252. Ribociclib for use according to any one of Embodiments 241-251, 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.

[0649] 253. Ribociclib for use as described in Embodiment 252, in a patient who has never undergone mastectomy.

[0650] 254. Ribociclib for use according to any one of Embodiments 241 to 253, wherein the dose of ribociclib is 400 mg / day.

[0651] 255. Ribociclib for use according to any one of Embodiments 241 to 254, wherein ribociclib is administered in the form of a salt, preferably as ribociclib succinate.

[0652] 256. Ribociclib for use according to any one of Embodiments 241 to 255, wherein the aromatase inhibitor is letrozole or anastrozole.

[0653] 257. Ribociclib for use according to Embodiment 256, wherein the aromatase inhibitor is letrozole, preferably administered at a dose of 2.5 mg / day.

[0654] 258. Ribociclib for use according to Embodiment 256, wherein the aromatase inhibitor is anastrozole, preferably administered at a dose of 1 mg / day.

[0655] 259. Ribociclib for use according to any one of Embodiments 241 to 258, wherein the dose of ribociclib is 400 mg / day, ribociclib is administered in the form of ribociclib succinate, and the aromatase inhibitor is letrozole or anastrozole, preferably 2.5 mg / day of letrozole or 1 mg / day of anastrozole.

[0656] 260. Ribociclib for use according to any one of Embodiments 241 to 259, wherein improvement in OS, DDFS and / or RFS, or reduction in the risk of breast cancer recurrence is achieved in the patient for at least 36 months.

[0657] 261. Ribociclib succinate for use in a method for treating HR+ / HER2- stage II or stage III early breast cancer in adult patients who have received at least one prior treatment for early breast cancer and who do not have signs or symptoms of cancer, comprising administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib succinate resulting in a total dose of 400 mg / day of ribociclib administered on days 1 to 21 of a 28-day cycle, and (ii) a dose of either 2.5 mg / day of letrozole or 1 mg / day of anastrozole administered daily during a 28-day cycle.

[0658] 262. Ribociclib succinate for use according to Embodiment 261, wherein adjuvant therapy comprises a dose of 2.5 mg / day of letrozole.

[0659] 263. Ribociclib succinate for use according to Embodiment 261, wherein adjuvant therapy comprises a dose of 1 mg / day anastrozole.

[0660] 264. Ribociclib succinate for use according to any one of embodiments 261 to 263, wherein the breast cancer has a lymph node status of N0, N1, N2, or N3.

[0661] 265. Ribociclib succinate for use according to Embodiment 264 in a breast cancer having an N0 lymph node state.

[0662] 266. Ribociclib succinate for use according to any one of embodiments 261 to 265, for early breast cancer which is stage II, such as stage IIA.

[0663] 267. Ribociclib succinate for use according to any one of embodiments 261 to 265, for early breast cancer which is stage III, such as stage IIIB.

[0664] 268. Ribociclib succinate for use according to any one of embodiments 261 to 265, for early breast cancer which is stage III, such as stage IIIC.

[0665] 269. Ribociclib succinate for use according to any one of embodiments 261 to 268, wherein the breast cancer is a ductal carcinoma subtype.

[0666] 270. Ribociclib succinate for use according to any one of embodiments 261 to 269, wherein the patient is of Asian descent.

[0667] 271. Ribociclib succinate for use according to any one of embodiments 261 to 270, for which 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 radiotherapy.

[0668] 272. Ribociclib succinate for use according to Embodiment 271, for patients who have never undergone mastectomy.

[0669] 273. Ribociclib succinate for use according to any one of Embodiments 261 to 272, wherein the method improves the patient's overall survival (OS), distant disease-free survival (DDFS), and / or recurrence-free survival (RFS) for breast cancer over a period of at least 36 months; or the method reduces the patient's risk of breast cancer recurrence over a period of at least 36 months.

[0670] 274. A method for preventing breast cancer recurrence in adult patients who have previously received treatment for HR+ / HER2-stage II or stage III early breast cancer, comprising administering to the patient (i) a certain dose of ribociclib, its free base form, or a pharmaceutically acceptable salt thereof, and (ii) a certain dose of an aromatase inhibitor, preferably letrozole or anastrozole.

[0671] 275. A method for treating an adult patient in remission from HR+ / HER2- stage II or stage III early breast cancer, comprising administering to the patient (i) a certain dose of ribociclib, its free base form, or a pharmaceutically acceptable salt thereof, and (ii) a certain dose of an aromatase inhibitor, preferably letrozole or anastrozole.

[0672] 276. A method for treating cancer in adult patients requiring treatment for HR+ / HER2-stage II or stage III early breast cancer, comprising administering to the patient (i) ribociclib, its free base form, or a pharmaceutically acceptable salt thereof in doses ranging from 150 mg / day to 450 mg / day, administered on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor, preferably letrozole or anastrozole, administered daily during the 28-day cycle.

[0673] 277. The method according to any one of embodiments 274 to 276, wherein ribociclib is a pharmaceutically acceptable ribociclib salt.

[0674] 278. The method according to Embodiment 277, wherein the ribociclib salt is ribociclib succinate.

[0675] 279. The method according to any one of embodiments 274, 275, 277, and 278, wherein the dose of ribociclib is not 600 mg / day.

[0676] 280. The method according to any one of Embodiments 274 to 278, wherein the dose of ribociclib is 200 mg / day or 400 mg / day.

[0677] 281. The method according to Embodiment 280, wherein ribociclib is administered as ribociclib succinate, and the total dose of ribociclib is 200 mg / day.

[0678] 282. The method according to Embodiment 280, wherein ribociclib is administered as ribociclib succinate, and the total dose of ribociclib is 400 mg / day.

[0679] 283. The method according to Embodiment 280, wherein ribociclib is administered at a dose of 400 mg / day for a period of time, and then at a dose of 200 mg / day thereafter.

[0680] 284. The method according to any one of embodiments 274 to 283, wherein the dose of ribociclib is administered orally.

[0681] 285. The method according to any one of embodiments 274 to 284, wherein the dose of ribociclib is administered in tablet form.

[0682] 286. The method according to any one of embodiments 274 to 285, wherein the aromatase inhibitor is letrozole or anastrozole.

[0683] 287. The method according to any one of embodiments 274 to 286, wherein the aromatase inhibitor is administered orally.

[0684] 288. The method according to Embodiment 286 or 287, wherein letrozole is administered in a dose ranging from 1 mg / day to 4 mg / day.

[0685] 289. The method according to Embodiment 288, wherein letrozole is administered at a dose of 2.5 mg / day.

[0686] 290. The method according to Embodiment 286 or 287, wherein anastrozole is administered in a dose ranging from 0.5 mg / day to 1.5 mg / day.

[0687] 291. The method according to Embodiment 290, wherein anastrozole is administered at a dose of 1 mg / day.

[0688] 292. A method for treating recurrent breast cancer in an adult patient who has received at least one prior treatment for HR+ / HER2-stage II or III early breast cancer and who does not have any detectable signs or symptoms of breast cancer, comprising administering to the patient an adjuvant therapy comprising (i) a dose of ribociclib succinate to a total dose of 400 mg / day of ribociclib administered on days 1 to 21 of a 28-day cycle, and (ii) a dose of either 2.5 mg / day of letrozole or 1 mg / day of anastrozole administered daily during a 28-day cycle.

[0689] 293. A method for treating an adult patient in remission from HR+ / HER2- stage II or stage III early breast cancer who requires adjuvant therapy, comprising administering to the patient an adjuvant therapy comprising (i) a dose of ribociclib succinate to a total dose of 400 mg / day of ribociclib administered on days 1 to 21 of a 28-day cycle, and (ii) a dose of either 2.5 mg / day of letrozole or 1 mg / day of anastrozole administered daily during a 28-day cycle.

[0690] 294. The method according to any one of embodiments 274 to 293, further comprising administering a gonadotropin-releasing hormone agonist as part of the treatment.

[0691] 295. The method according to Embodiment 294, wherein the gonadotropin-releasing hormone agonist is goserelin.

[0692] 296. The method according to Embodiment 295, wherein goserelin is administered in a dose ranging from 2 mg to 5 mg.

[0693] 297. The method according to Embodiment 296, wherein the dose of goserelin is 3.6 mg.

[0694] 298. The method according to any one of embodiments 294 to 297, wherein goserelin is administered subcutaneously.

[0695] 299. The method according to any one of embodiments 294 to 298, wherein goserelin is administered once every four weeks.

[0696] 300. The method according to any one of embodiments 274 to 299, wherein the patient is a postmenopausal woman.

[0697] 301. The method according to any one of embodiments 274 to 293, wherein the patient is a premenopausal woman or a man.

[0698] 302. The method according to any one of embodiments 274 to 301, wherein the treatment is administered to the patient for at least 12 months.

[0699] 303. The method according to Embodiment 302, wherein the treatment is administered to the patient for at least 24 months.

[0700] 304. The method according to Embodiment 302 or 303, wherein the treatment is administered to the patient for at least 36 months.

[0701] 305. The method according to any one of embodiments 302 to 304, wherein the treatment is administered to the patient for at least 48 months.

[0702] 306. The method according to any one of embodiments 302 to 305, wherein the treatment is administered to the patient for at least 60 months.

[0703] 307. The method according to any one of embodiments 274 to 306, wherein the breast cancer is ER+ and PR+.

[0704] 308. The method according to any one of embodiments 274 to 306, wherein the breast cancer is ER- and PR-+.

[0705] 309. The method according to any one of embodiments 274 to 306, wherein the breast cancer is ER+ and PR-.

[0706] 310. The method according to any one of embodiments 274 to 309, wherein the breast cancer has a histological subtype of ductal carcinoma.

[0707] 311. The method according to any one of embodiments 274 to 310, wherein the breast cancer has a histological subtype of lobular carcinoma.

[0708] 312. The method according to any one of embodiments 274 to 311, wherein the breast cancer is stage IIA or stage IIB.

[0709] 313. The method according to embodiment 312, wherein the breast cancer is stage IIA cancer.

[0710] 314. The method according to embodiment 312, wherein the breast cancer is stage IIB cancer.

[0711] 315. The method according to any one of embodiments 274 to 311, wherein the breast cancer is stage IIIA, stage IIIB, or stage IIIC.

[0712] 316. The method according to Embodiment 315, wherein the breast cancer is stage IIIA cancer.

[0713] 317. The method according to embodiment 315, wherein the breast cancer is stage IIIB cancer.

[0714] 318. The method according to Embodiment 315, wherein the breast cancer is stage IIIC cancer.

[0715] 319. The method according to any one of embodiments 274 to 318, wherein the treatment is administered regardless of the lymph node status of the breast cancer.

[0716] 320. The method according to any one of embodiments 274 to 319, wherein the breast cancer has a lymph node state selected from N0, N1, N2, and N3.

[0717] 321. The method according to Embodiment 319 or 320, wherein the breast cancer has an N0 lymph node state.

[0718] 322. The method according to Embodiment 319 or 320, wherein the breast cancer has a lymph node status of N1 to N3.

[0719] 323. The method according to Embodiment 319 or 320, wherein the breast cancer has an N1 lymph node state.

[0720] 324. The method according to Embodiment 319 or 320, wherein the breast cancer has an N2 lymph node state.

[0721] 325. The method according to Embodiment 319 or 320, wherein the breast cancer has an N3 lymph node state.

[0722] 326. The method according to any one of embodiments 274 to 325, wherein the breast cancer comprises one or more cells having a histological grade selected from G1, G2, or G3.

[0723] 327. The method according to Embodiment 326, wherein the breast cancer comprises one or more cells having histological grade G1.

[0724] 328. The method according to Embodiment 326, wherein the breast cancer comprises one or more cells having histological grade G2.

[0725] 329. The method according to Embodiment 326, wherein the breast cancer comprises one or more cells having histological grade G3.

[0726] 330. The method according to any one of Embodiments 274 to 329, wherein the breast cancer includes tumors of classification T0, T1, T2, T3, or T4.

[0727] 331. The method according to Embodiment 330, wherein the breast cancer includes tumors of classification T1, T2, or T3.

[0728] 332. The method according to Embodiment 330, wherein the breast cancer includes a tumor of classification T0.

[0729] 333. The method according to Embodiment 330 or 331, wherein the breast cancer includes a tumor of classification T1.

[0730] 334. The method according to Embodiment 330 or 331, wherein the breast cancer includes a tumor of classification T2.

[0731] 335. The method according to Embodiment 330 or 331, wherein the breast cancer includes a tumor of classification T3.

[0732] 336. The method according to Embodiment 330, wherein the breast cancer includes a tumor of classification T4.

[0733] 337. The method according to any one of embodiments 274 to 336, wherein the breast cancer has a Ki67 status of 20 or less.

[0734] 338. The method according to any one of embodiments 274 to 336, wherein the breast cancer has a Ki67 status higher than 20.

[0735] 339. The method according to any one of Embodiments 274 to 338, wherein the patient had received a loading dose of (i) ribociclib and / or (ii) endocrine therapy prior to administration.

[0736] 340. The method according to any one of embodiments 274-291 and 293-339, wherein the patient has received at least one prior treatment for cancer.

[0737] 341. The method according to any one of Embodiments 292 to 340, wherein the prior treatment is an adjuvant treatment following another prior treatment.

[0738] 342. The method according to embodiment 340 or 341, wherein the prior treatment is surgical.

[0739] 343. The method according to embodiment 342, wherein the surgical procedure includes complete surgical resection of the cancer.

[0740] 344. The method according to embodiment 342 or 343, wherein the surgical procedure is a mastectomy.

[0741] 345. The method according to embodiment 340 or 341, wherein the prior treatment is chemotherapy.

[0742] 346. The method according to embodiment 345, wherein the prior treatment is adjuvant chemotherapy.

[0743] 347. The method according to embodiment 345, wherein the prior treatment is neoadjuvant chemotherapy.

[0744] 348. The method according to Embodiment 340 or 341, wherein the prior treatment is endocrine therapy.

[0745] 349. The method according to Embodiment 340 or 341, wherein the prior treatment is radiotherapy.

[0746] 350. The method according to any one of Embodiments 292 and 340-349, wherein prior treatment was ineffective in the patient.

[0747] 351. The method according to any one of Embodiments 274 to 350, wherein the patient resides in a geographical area selected from North America, Western Europe, or Oceania.

[0748] 352. The method according to any one of embodiments 274 to 351, wherein the patient is of Asian descent.

[0749] 353. The method according to any one of embodiments 274 to 352, wherein the patient is between 18 and 45 years of age.

[0750] 354. The method according to any one of embodiments 274 to 352, wherein the patient is 45 to 54 years old.

[0751] 355. The method according to any one of embodiments 274 to 352, wherein the patient is 54 to 64 years old.

[0752] 356. The method according to any one of embodiments 274 to 352, wherein the patient is over 64 years of age.

[0753] 357. The method according to any one of embodiments 274 to 357, wherein the patient has a BMI of 25 or greater.

[0754] 358. The method according to any one of embodiments 274 to 357, wherein the patient has a BMI of less than 25.

[0755] 359. The method according to any one of embodiments 274 to 358, wherein the treatment improves the patient's condition compared to a patient who has not received treatment and / or compared to the patient's condition before treatment.

[0756] 360. The method according to any one of embodiments 274 to 359, wherein the treatment reduces the risk of invasive disease.

[0757] 361. The method according to Embodiment 360, wherein treatment reduces the risk of invasive disease, corresponding to a hazard ratio of less than 1 when the risk is calculated compared to patients who have not received treatment.

[0758] 362. The method according to Embodiment 361, wherein treatment reduces the risk of invasive disease, and when the risk is calculated compared to a patient who has not received treatment, the hazard ratio corresponds to 0.78 or less.

[0759] 363. The method according to any one of embodiments 274-299 and 301-362, wherein the patient is a premenopausal woman or man, the treatment reduces the risk of invasive disease, and the hazard ratio when the risk is calculated compared to a patient receiving treatment is 0.72 or less.

[0760] 364. The method according to any one of embodiments 360 to 362, wherein the cancer is HR+ / HER2-stage III early breast cancer, and the risk of invasive disease is reduced by treatment, corresponding to a hazard ratio of 0.74 or less when the risk is calculated compared to a patient who has not received treatment.

[0761] 365. The method according to any one of embodiments 360 to 362, wherein the cancer is HR+ / HER2-stage II early breast cancer, and the risk of invasive disease is reduced by treatment, corresponding to a hazard ratio of 0.76 or less when the risk is calculated compared to a patient who has not received treatment.

[0762] 366. The method according to any one of embodiments 360 to 362, wherein the cancer is HR+ / HER2-stage III early breast cancer, and treatment results in at least a 25% reduction in the risk of invasive disease, corresponding to a hazard ratio of 0.75 when the risk is calculated compared to an untreated patient.

[0763] 367. The method according to any one of embodiments 360 to 366, wherein the treatment reduces the risk of invasive disease to a level similar to that of a patient subgroup including patients with stage II early breast cancer, stage III early breast cancer, patients who are premenopausal women or men, and patients who are postmenopausal women.

[0764] 368. The method according to any one of embodiments 274 to 367, wherein the treatment does not result in a deterioration of overall survival and corresponds to a hazard ratio of 0.76 when the risk is calculated compared to patients who do not receive treatment.

[0765] 369. The method according to any one of embodiments 274 to 368, wherein the treatment reduces and / or prevents one or more of the risks of cancer recurrence, cancer spread, development and / or proliferation of additional cancers, and death from cancer.

[0766] 370. The method according to Embodiment 369, wherein treatment reduces cancer recurrence, and the recurrences are one or more of invasive ipsilateral breast tumor (IBTR) recurrence, locally invasive recurrence, and distant recurrence.

[0767] 371. The method according to Embodiment 369, wherein the treatment reduces the extent of cancer, and the extent of cancer is invasive contralateral breast cancer or additional primary invasive cancer.

[0768] 372. The method according to any one of embodiments 274 to 371, wherein the treatment prevents death from cancer.

[0769] J. Further Exemplary Embodiments The following embodiments provide further therapeutic methods and the use of ribociclib.

[0770] 1. A method for treating an adult patient diagnosed with HER+ / HER2- stage II or stage III early breast cancer, comprising administering to the patient an adjuvant therapy comprising (i) ribociclib in doses ranging from 150 mg / day to 450 mg / day administered on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle, wherein the method results in an improvement in one or more of the patient's overall survival (OS), distant disease-free survival (DDFS), or recurrence-free survival (RFS).

[0771] 2. A method for improving one or more of the overall survival (OS), distant disease-free survival (DDFS), or recurrence-free survival (RFS) of a patient diagnosed with HR+ / HER2-stage II or stage III early breast cancer, comprising administering to the patient an adjuvant therapy comprising (i) ribociclib in a dose ranging from 150 mg / day to 450 mg / day administered on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle.

[0772] 3. A method for reducing the risk of local or regional invasive recurrence of early breast cancer in adult patients diagnosed with HR+ / HER2- stage II or stage III early breast cancer, comprising administering to the patient an adjuvant therapy comprising (i) ribociclib in doses ranging from 150 mg / day to 450 mg / day administered on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle.

[0773] 4. A method for reducing the risk of invasive recurrence of early breast cancer in one or more of the bone, liver, lungs, or pleura in adult patients diagnosed with HR+ / HER2-stage II or stage III early breast cancer, comprising administering to the patient an adjuvant therapy comprising (i) ribociclib in a dose ranging from 150 mg / day to 450 mg / day on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle.

[0774] 5. The method according to any one of claims 1 to 4, wherein the treatment is administered regardless of the lymph node status of the breast cancer.

[0775] 6. A method for reducing the risk of early breast cancer recurrence in adult patients diagnosed with HR+ / HER2- stage II or stage III early breast cancer, comprising administering an adjuvant therapy comprising (i) ribociclib at a dose ranging from 150 mg / day to 450 mg / day on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle, wherein the therapy is administered regardless of the lymph node status of the breast cancer.

[0776] 7. The method according to any one of claims 1 to 6, wherein the breast cancer has a lymph node status of N0, N1, N2, or N3.

[0777] 8. The method according to claim 7, wherein the breast cancer has an N0 lymph node state.

[0778] 9. The method according to any one of claims 1 to 8, wherein the early-stage breast cancer is stage II, for example, stage IIA.

[0779] 10. The method according to any one of claims 1 to 8, wherein the early-stage breast cancer is stage III, for example, stage IIIB or IIIC.

[0780] 11. The method according to any one of claims 1 to 10, wherein the breast cancer is a ductal carcinoma subtype.

[0781] 12. The method according to any one of claims 1 to 11, wherein the patient is of Asian descent.

[0782] 13. The method according to any one of claims 1 to 12, wherein the patient has received at least one prior treatment for breast cancer selected from the group consisting of surgery, chemotherapy, and radiotherapy, which is an adjuvant treatment.

[0783] 14. The method according to claim 13, wherein the patient has never undergone a mastectomy.

[0784] 15. The method according to any one of claims 1 to 14, wherein the dose of ribociclib is 400 mg / day.

[0785] 16. The method according to any one of claims 1 to 15, wherein ribociclib is administered in the form of a salt, preferably as ribociclib succinate.

[0786] 17. The method according to any one of claims 1 to 16, wherein the aromatase inhibitor is letrozole or anastrozole.

[0787] 18. The method according to claim 17, wherein the aromatase inhibitor is letrozole, preferably administered at a dose of 2.5 mg / day.

[0788] 19. The method according to claim 17, wherein the aromatase inhibitor is anastrozole, preferably administered at a dose of 1 mg / day.

[0789] 20. The method according to any one of claims 1 to 19, wherein the dose of ribociclib is 400 mg / day, ribociclib is administered in the form of ribociclib succinate, and the aromatase inhibitor is letrozole or anastrozole, preferably 2.5 mg / day of letrozole or 1 mg / day of anastrozole.

[0790] 21. The method according to any one of claims 1 to 20, wherein improvement in OS, DDFS and / or RFS, or reduction in the risk of breast cancer recurrence is achieved in the patient for at least 36 months.

[0791] 22. Ribociclib for use in a method for improving one or more of the overall survival (OS), distant disease-free survival (DDFS), or recurrence-free survival (RFS) of an adult patient diagnosed with HR+ / HER2-stage II or stage III early breast cancer, comprising administering to the patient an adjuvant therapy comprising (i) ribociclib in doses ranging from 150 mg / day to 450 mg / day administered on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle.

[0792] 23. Ribociclib for use in a method for reducing the risk of local or regional invasive recurrence of early breast cancer in adult patients diagnosed with HR+ / HER2-stage II or III early breast cancer, comprising administering to the patient an adjuvant therapy comprising (i) ribociclib in doses ranging from 150 mg / day to 450 mg / day administered on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during a 28-day cycle.

[0793] 24. Ribociclib for use in an adjuvant therapy method for reducing the risk of invasive recurrence of early breast cancer in one or more of the bone, liver, lungs, or pleura in adult patients diagnosed with HR+ / HER2-stage II or III early breast cancer, comprising administering to the patient an adjuvant therapy comprising (i) a dose of ribociclib ranging from 150 mg / day to 450 mg / day administered on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during a 28-day cycle.

[0794] 25. Ribociclib for use according to any one of claims 22 to 24, wherein the treatment is administered regardless of the lymph node status of the breast cancer.

[0795] 26. Ribociclib for use in a method for reducing the risk of early breast cancer recurrence in adult patients diagnosed with HR+ / HER2- stage II or stage III early breast cancer, comprising administering to the patient an adjuvant therapy comprising (i) a dose of ribociclib ranging from 150 mg / day to 450 mg / day administered on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle, wherein the therapy is administered regardless of the lymph node status of the breast cancer.

[0796] 27. Ribociclib for use according to any one of claims 22 to 26, wherein the breast cancer has a lymph node status of N0, N1, N2, or N3.

[0797] 28. Ribociclib for use according to claim 27, wherein breast cancer has an N0 lymph node status.

[0798] 29. Ribociclib for use according to any one of claims 22 to 28, wherein the early breast cancer is stage II, such as stage IIA.

[0799] 30. Ribociclib for use according to any one of claims 22 to 28, wherein the early-stage breast cancer is stage III, such as stage IIIB or IIIC.

[0800] 31. Ribociclib for use according to any one of claims 22 to 30, wherein the breast cancer is a ductal carcinoma subtype.

[0801] 32. Ribociclib for use according to any one of claims 22 to 31, wherein the patient is of Asian descent.

[0802] 33. Ribociclib for use according to any one of claims 22 to 32, wherein the method is an 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.

[0803] 34. Ribociclib for use according to claim 33, wherein the patient has never undergone a mastectomy.

[0804] 35. Ribociclib for use according to any one of claims 22 to 34, wherein the dose of ribociclib is 400 mg / day.

[0805] 36. Ribociclib for use according to any one of claims 22 to 35, wherein ribociclib is administered in the form of a salt, preferably as ribociclib succinate.

[0806] 37. Ribociclib for use according to any one of claims 22 to 36, wherein the aromatase inhibitor is letrozole or anastrozole.

[0807] 38. Ribociclib for use according to claim 37, wherein the aromatase inhibitor is letrozole, preferably administered at a dose of 2.5 mg / day.

[0808] 39. Ribociclib for use according to claim 37, wherein the aromatase inhibitor is anastrozole, preferably administered at a dose of 1 mg / day.

[0809] 40. Ribociclib for use according to any one of claims 22 to 39, wherein the dose of ribociclib is 400 mg / day, ribociclib is administered in the form of ribociclib succinate, and the aromatase inhibitor is letrozole or anastrozole, preferably 2.5 mg / day of letrozole or 1 mg / day of anastrozole.

[0810] 41. Ribociclib for use according to any one of claims 22 to 40, wherein improvement in OS, DDFS and / or RFS, or reduction in the risk of breast cancer recurrence is achieved in the patient for at least 36 months.

[0811] K. More Exemplary Embodiments The following embodiments provide more treatment methods and uses of ribociclib.

[0812] 1. Ribociclib succinate for use in a method for treating HR+ / HER2- stage II or stage III early breast cancer in adult patients who have received at least one prior treatment for early breast cancer and who do not have signs or symptoms of cancer, comprising administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib succinate resulting in a total dose of 400 mg / day of ribociclib administered on days 1 to 21 of a 28-day cycle, and (ii) a dose of either 2.5 mg / day of letrozole or 1 mg / day of anastrozole administered daily during a 28-day cycle.

[0813] 2. Ribociclib succinate for use according to Embodiment 1, wherein adjuvant therapy comprises a dose of 2.5 mg / day of letrozole.

[0814] 3. Ribociclib succinate for use according to Embodiment 1, wherein adjuvant therapy comprises a dose of 1 mg / day anastrozole.

[0815] 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.

[0816] 5. Ribociclib succinate for use according to Embodiment 4 in a breast cancer patient having an N0 lymph node state.

[0817] 6. Ribociclib succinate for use according to any one of Embodiments 1 to 5, for early breast cancer that is stage II, such as stage IIA.

[0818] 7. Ribociclib succinate for use according to any one of Embodiments 1 to 5, for early breast cancer which is stage III, such as stage IIIB.

[0819] 8. Ribociclib succinate for use according to any one of Embodiments 1 to 5, for early breast cancer which is stage III, such as stage IIIC.

[0820] 9. Ribociclib succinate for use according to any one of Embodiments 1 to 8, wherein the breast cancer is a ductal carcinoma subtype.

[0821] 10. Ribociclib succinate for use according to any one of Embodiments 1 to 9, wherein the patient is of Asian descent.

[0822] 11. Ribociclib succinate for use 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 radiotherapy.

[0823] 12. Ribociclib succinate for use as described in Embodiment 11, for patients who have never undergone mastectomy.

[0824] 13. Ribociclib succinate for use according to any one of Embodiments 1 to 12, wherein the method improves the patient's overall survival (OS), distant disease-free survival (DDFS), and / or recurrence-free survival (RFS) for at least 36 months; or the method reduces the patient's risk of breast cancer recurrence for at least 36 months.

[0825] L. Additional exemplary embodiments The following embodiments provide additional therapeutic methods and the use of ribociclib.

[0826] 1. A method for preventing breast cancer recurrence in adult patients who have previously received treatment for HR+ / HER2-stage II or stage III early breast cancer, comprising administering to the patient (i) a certain dose of ribociclib, its free base form, or a pharmaceutically acceptable salt thereof, and (ii) a certain dose of an aromatase inhibitor, preferably letrozole or anastrozole.

[0827] 2. A method for treating an adult patient in remission from HR+ / HER2- stage II or stage III early breast cancer, comprising administering to the patient (i) a certain dose of ribociclib, its free base form, or a pharmaceutically acceptable salt thereof, and (ii) a certain dose of an aromatase inhibitor, preferably letrozole or anastrozole.

[0828] 3. A method for treating cancer in adult patients requiring treatment for HR+ / HER2-stage II or stage III early breast cancer, comprising administering to the patient (i) ribociclib, its free base form, or a pharmaceutically acceptable salt thereof in doses ranging from 150 mg / day to 450 mg / day, administered on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor, preferably letrozole or anastrozole, administered daily during the 28-day cycle.

[0829] 4. The method according to any one of Embodiments 1 to 3, wherein ribociclib is a pharmaceutically acceptable ribociclib salt.

[0830] 5. The method according to Embodiment 4, wherein the ribociclib salt is ribociclib succinate.

[0831] 6. The method according to any one of Embodiments 1, 2, 4, and 5, wherein the dose of ribociclib is not 600 mg / day.

[0832] 7. The method according to any one of Embodiments 1 to 5, wherein the dose of ribociclib is 200 mg / day or 400 mg / day.

[0833] 8. The method according to Embodiment 7, wherein ribociclib is administered as ribociclib succinate, and the total dose of ribociclib is 200 mg / day.

[0834] 9. The method according to Embodiment 7, wherein ribociclib is administered as ribociclib succinate, and the total dose of ribociclib is 400 mg / day.

[0835] 10. The method according to Embodiment 7, wherein ribociclib is administered at a dose of 400 mg / day for a period of time, and then at a dose of 200 mg / day thereafter.

[0836] 11. The method according to any one of Embodiments 1 to 10, wherein the dose of ribociclib is administered orally.

[0837] 12. The method according to any one of Embodiments 1 to 11, wherein the dose of ribociclib is administered in tablet form.

[0838] 13. The method according to any one of Embodiments 1 to 12, wherein the aromatase inhibitor is letrozole or anastrozole.

[0839] 14. The method according to any one of Embodiments 1 to 13, wherein an aromatase inhibitor is administered orally.

[0840] 15. The method according to Embodiment 13 or 14, wherein letrozole is administered in a dose ranging from 1 mg / day to 4 mg / day.

[0841] 16. The method according to Embodiment 15, wherein letrozole is administered at a dose of 2.5 mg / day.

[0842] 17. The method according to Embodiment 13 or 14, wherein anastrozole is administered in a dose ranging from 0.5 mg / day to 1.5 mg / day.

[0843] 18. The method according to Embodiment 17, wherein anastrozole is administered at a dose of 1 mg / day.

[0844] 19. A method for treating recurrent breast cancer in an adult patient who has received at least one prior treatment for HR+ / HER2-stage II or III early breast cancer and who does not have any detectable signs or symptoms of breast cancer, comprising administering to the patient an adjuvant therapy comprising (i) a dose of ribociclib succinate to a total dose of 400 mg / day of ribociclib administered on days 1 to 21 of a 28-day cycle, and (ii) a dose of either letrozole at a dose of 2.5 mg / day or anastrozole at a dose of 1 mg / day administered daily during a 28-day cycle.

[0845] 20. A method for treating an adult patient in remission from HR+ / HER2- stage II or stage III early breast cancer who requires adjuvant therapy, comprising administering to the patient an adjuvant therapy comprising (i) a dose of ribociclib succinate to a total dose of 400 mg / day of ribociclib administered on days 1 to 21 of a 28-day cycle, and (ii) a dose of either 2.5 mg / day of letrozole or 1 mg / day of anastrozole administered daily during a 28-day cycle.

[0846] 21. The method according to any one of Embodiments 1 to 20, wherein the treatment comprises administering a gonadotropin-releasing hormone agonist.

[0847] 22. The method according to Embodiment 21, wherein the gonadotropin-releasing hormone agonist is goserelin.

[0848] 23. The method according to Embodiment 22, wherein goserelin is administered in a dose ranging from 2 mg to 5 mg.

[0849] 24. The method according to Embodiment 23, wherein the dose of goserelin is 3.6 mg.

[0850] 25. The method according to any one of embodiments 22 to 24, wherein goserelin is administered subcutaneously.

[0851] 26. The method according to any one of embodiments 22 to 25, wherein goserelin is administered once every four weeks.

[0852] 27. The method according to any one of Embodiments 1 to 20, wherein the patient is a postmenopausal woman.

[0853] 28. The method according to any one of Embodiments 1 to 26, wherein the patient is a premenopausal woman or a man.

[0854] 29. The method according to any one of Embodiments 1 to 28, wherein the treatment is administered to the patient for at least 12 months.

[0855] 30. The method according to Embodiment 29, wherein the treatment is administered to the patient for at least 24 months.

[0856] 31. The method according to Embodiment 29 or 30, wherein the treatment is administered to the patient for at least 36 months.

[0857] 32. The method according to any one of embodiments 29 to 31, wherein the treatment is administered to the patient for at least 48 months.

[0858] 33. The method according to any one of embodiments 29 to 32, wherein the treatment is administered to the patient for at least 60 months.

[0859] 34. The method according to any one of Embodiments 1 to 33, wherein the breast cancer is ER+ and PR+.

[0860] 35. The method according to any one of Embodiments 1 to 33, wherein the breast cancer is ER- and PR-+.

[0861] 36. The method according to any one of Embodiments 1 to 33, wherein the breast cancer is ER+ and PR-.

[0862] 37. The method according to any one of Embodiments 1 to 36, wherein the breast cancer has a histological subtype of ductal carcinoma.

[0863] 38. The method according to any one of Embodiments 1 to 37, wherein the breast cancer has a histological subtype of lobular carcinoma.

[0864] 39. The method according to any one of Embodiments 1 to 38, wherein the breast cancer is stage IIA or stage IIB.

[0865] 40. The method according to Embodiment 39, wherein the breast cancer is stage IIA cancer.

[0866] 41. The method according to Embodiment 39, wherein the breast cancer is stage IIB cancer.

[0867] 42. The method according to any one of Embodiments 1 to 38, wherein the breast cancer is stage IIIA, stage IIIB, or stage IIIC.

[0868] 43. The method according to Embodiment 42, wherein the breast cancer is stage IIIA cancer.

[0869] 44. The method according to Embodiment 42, wherein the breast cancer is stage IIIB cancer.

[0870] 45. The method according to Embodiment 42, wherein the breast cancer is stage IIIC cancer.

[0871] 46. ​​The method according to any one of Embodiments 1 to 45, wherein the treatment is administered regardless of the lymph node status of the breast cancer.

[0872] 47. The method according to any one of Embodiments 1 to 46, wherein the breast cancer has a lymph node state selected from N0, N1, N2, and N3.

[0873] 48. The method according to Embodiment 46 or 47, wherein the breast cancer has an N0 lymph node state.

[0874] 49. The method according to Embodiment 46 or 47, wherein the breast cancer has a lymph node state of N1-N3.

[0875] 50. The method according to Embodiment 46 or 47, wherein the breast cancer has an N1 lymph node state.

[0876] 51. The method according to Embodiment 46 or 47, wherein the breast cancer has an N2 lymph node state.

[0877] 52. The method according to Embodiment 46 or 47, wherein the breast cancer has an N3 lymph node state.

[0878] 53. The method according to 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.

[0879] 54. The method according to Embodiment 53, wherein the breast cancer comprises one or more cells having histological grade G1.

[0880] 55. The method according to Embodiment 53, wherein the breast cancer comprises one or more cells having histological grade G2.

[0881] 56. The method according to Embodiment 53, wherein the breast cancer comprises one or more cells having histological grade G3.

[0882] 57. The method according to any one of Embodiments 1 to 56, wherein the breast cancer includes tumors of classification T0, T1, T2, T3, or T4.

[0883] 58. The method according to Embodiment 57, wherein the breast cancer includes tumors of classification T1, T2, or T3.

[0884] 59. The method according to Embodiment 57, wherein the breast cancer includes a tumor of classification T0.

[0885] 60. The method according to Embodiment 57 or 58, wherein the breast cancer includes a tumor of classification T1.

[0886] 61. The method according to Embodiment 57 or 58, wherein the breast cancer includes a tumor of classification T2.

[0887] 62. The method according to Embodiment 57 or 58, wherein the breast cancer includes a tumor of classification T3.

[0888] 63. The method according to Embodiment 57, wherein the breast cancer includes a tumor of classification T4.

[0889] 64. The method according to any one of Embodiments 1 to 63, wherein the breast cancer has a Ki67 status of 20 or less.

[0890] 65. The method according to any one of Embodiments 1 to 63, wherein the breast cancer has a Ki67 status higher than 20.

[0891] 66. The method according to any one of Embodiments 1 to 65, wherein the patient had received a loading dose of (i) ribociclib and / or (ii) endocrine therapy prior to administration.

[0892] 67. The method according to any one of embodiments 1 to 18 and 20 to 66, wherein the patient has received at least one prior treatment for cancer.

[0893] 68. The method according to any one of embodiments 19 to 67, wherein the prior treatment is an adjuvant treatment following another prior treatment.

[0894] 69. The method according to embodiment 67 or 68, wherein the prior treatment is surgical.

[0895] 70. The method according to embodiment 69, wherein the surgical procedure includes complete surgical resection of the cancer.

[0896] 71. The method according to embodiment 69 or 70, wherein the surgical procedure is a mastectomy.

[0897] 72. The method according to embodiment 67 or 68, wherein the prior treatment is chemotherapy.

[0898] 73. The method according to embodiment 72, wherein the prior treatment is adjuvant chemotherapy.

[0899] 74. The method according to embodiment 72, wherein the prior treatment is neoadjuvant chemotherapy.

[0900] 75. The method according to embodiment 67 or 68, wherein the prior treatment is endocrine therapy.

[0901] 76. The method according to embodiment 67 or 68, wherein the prior treatment is radiotherapy.

[0902] 77. The method according to any one of Embodiments 19 and 67-76, in which the patient did not respond to prior treatment.

[0903] 78. The method according to any one of Embodiments 1 to 77, wherein the patient resides in a geographical area selected from North America, Western Europe, or Oceania.

[0904] 79. The method according to any one of Embodiments 1 to 78, wherein the patient is of Asian descent.

[0905] 80. The method according to any one of Embodiments 1 to 79, wherein the patient is between 18 and 45 years of age.

[0906] 81. The method according to any one of Embodiments 1 to 79, wherein the patient is 45 to 54 years old.

[0907] 82. The method according to any one of Embodiments 1 to 79, wherein the patient is 54 to 64 years old.

[0908] 83. The method according to any one of Embodiments 1 to 79, wherein the patient is over 64 years of age.

[0909] 84. The method according to any one of Embodiments 1 to 83, wherein the patient has a BMI of 25 or higher.

[0910] 85. The method according to any one of Embodiments 1 to 83, wherein the patient has a BMI of less than 25.

[0911] 86. The method according to any one of Embodiments 1 to 85, wherein the treatment improves the patient's condition compared to a patient who has not received treatment and / or compared to the patient's condition before treatment.

[0912] 87. The method according to any one of Embodiments 1 to 86, wherein the treatment reduces the risk of invasive disease.

[0913] 88. The method according to Embodiment 87, wherein treatment reduces the risk of invasive disease, corresponding to a hazard ratio of less than 1 when the risk is calculated compared to patients who have not received treatment.

[0914] 89. The method according to Embodiment 88, wherein the treatment reduces the risk of invasive disease, and when the risk is calculated compared to a patient who has not received treatment, the hazard ratio corresponds to 0.78 or less.

[0915] 90. The method according to any one of Embodiments 1 to 26 and 28 to 89, wherein the patient is a premenopausal woman or man, the treatment reduces the risk of invasive disease, and the hazard ratio when the risk is calculated compared to a patient receiving treatment is 0.72 or less.

[0916] 91. The method according to any one of embodiments 87 to 89, wherein the cancer is HR+ / HER2-stage III early breast cancer, and the risk of invasive disease is reduced by treatment, corresponding to a hazard ratio of 0.74 or less when the risk is calculated compared to a patient who has not received treatment.

[0917] 92. The method according to any one of embodiments 87 to 89, wherein the cancer is HR+ / HER2-stage II early breast cancer, and the risk of invasive disease is reduced by treatment, corresponding to a hazard ratio of 0.76 or less when the risk is calculated compared to a patient who has not received treatment.

[0918] 93. The method according to any one of embodiments 87 to 89, wherein the cancer is HR+ / HER2-stage III early breast cancer, and treatment results in at least a 25% reduction in the risk of invasive disease, corresponding to a hazard ratio of 0.75 when the risk is calculated compared to an untreated patient.

[0919] 94. The method according to any one of Embodiments 1 to 93, wherein the treatment reduces the risk of invasive disease to a level similar to that of a patient subgroup including patients with stage II early breast cancer, stage III early breast cancer, premenopausal women or men, and postmenopausal women.

[0920] 95. The method according to any one of Embodiments 1 to 94, wherein the treatment does not result in a deterioration of overall survival and corresponds to a hazard ratio of 0.76 when the risk is calculated compared to patients who do not receive treatment.

[0921] 96. The method according to any one of Embodiments 1 to 95, wherein the treatment reduces and / or prevents one or more risks of cancer recurrence, cancer spread, development and / or proliferation of additional cancers, and death from cancer.

[0922] 97. The method according to Embodiment 96, wherein treatment reduces cancer recurrence, and the recurrences are one or more of invasive ipsilateral breast tumor (IBTR) recurrence, locally invasive recurrence, and distant recurrence.

[0923] 98. The method according to Embodiment 96, wherein the treatment reduces the extent of cancer, and the extent of cancer is invasive contralateral breast cancer or additional primary invasive cancer.

[0924] 99. The method according to any one of Embodiments 1 to 98, wherein the treatment prevents death from cancer.

[0925] XI.Definitions Except as provided herein, or unless otherwise indicated, all numerical values ​​used herein to represent quantities, dosages, or reaction conditions of ingredients should be understood to be modified by the term “approximately,” as a person skilled in the art would interpret the term in that way. As used herein, “approximately” is equivalent to ±10% of a given numerical value, unless otherwise specified.

[0926] "Adjuvant therapy" (or adjuvant treatment) refers to treatment given after primary treatment, for example, to reduce the risk of disease recurrence. In cancer, adjuvant therapy may, among other things, be administered to reduce the risk of cancer recurrence, for example, by destroying cancer cells remaining after primary treatment. For example, a treatment containing a certain dose of ribociclib in combination with an aromatase inhibitor may be administered as an adjuvant after primary treatment, including, for example, surgery, radiotherapy, and / or chemotherapy.

[0927] "Neoadjuvant therapy" (or neoadjuvant treatment) refers to treatment delivered before primary treatment. In cancer, neoadjuvant therapy may, among other things, reduce the size of the tumor or kill spread cancer cells.

[0928] Terms such as "co-administration," "co-dosing," or "combined administration" encompass the administration of selected therapeutic drugs to a single patient, and include treatment regimens in which those drugs are not necessarily administered via the same route or at the same time.

[0929] The term "combination" refers to either a fixed combination of two or more drugs (also referred to as co-drugs or combination partners) in a single dosage unit form, or a non-fixed combination for a combination administration (or kit of parts) in which the first drug (also referred to as the first therapeutic agent) and the second drug (also referred to as the second therapeutic agent) may be administered independently at the same time, or individually within a time interval that allows the combination partners to provide a synergistic effect, for example. When used herein, the terms "combination administration," etc., are intended to encompass the administration of a selection of combination partners to a single subject (e.g., a patient) who requires it, and include treatment regimens in which the drugs are not necessarily administered via the same route of administration or at the same time. The term "fixed combination" means that both active ingredients, for example, the combination partners, are administered simultaneously to the patient in a single dosage form. The term “non-fixed combination” or “kit of parts” means that the active ingredients, for example, the combination partners, are provided individually, for example, within a kit, and / or both are administered to the patient simultaneously as separate forms of medication, or sequentially without any particular time constraint, and such administration provides the patient with therapeutically effective levels of the two compounds.

[0930] The "dose range" refers to the upper and lower limits of the acceptable variation in the amount of a specified therapeutic agent. Typically, a patient receiving treatment may be administered any dose of the agent within the specified range.

[0931] A “loading dose” can be an initial dose of a drug that may be given at the beginning or before the course of treatment until it is reduced to another, typically lower dose (e.g., therapeutic or maintenance dose). A loading dose can be a single dose or a short-term regimen compound administered to a subject to rapidly raise the blood drug concentration level. Preferably, the short-term regimens used herein are 1 to 14 days; e.g., 1 to 7 days; e.g., 1 to 3 days; e.g., 3 days; e.g., 2 days; e.g., 1 day. In some embodiments, a “loading dose” can raise the blood drug concentration to a therapeutically effective level. In some embodiments, a “loading dose” can raise the blood drug concentration to a therapeutically effective level in combination with a therapeutic dose of the drug. A “loading dose” can be administered once daily or more frequently (e.g., up to four times daily). In some embodiments, loading doses may be used for drug molecules that exhibit a long half-life or slow elimination in vivo.

[0932] "Pharmaceutical preparation" or "pharmaceutical composition" refers to a mixture or solution containing at least one therapeutic agent suitable for administration to warm-blooded animals, such as humans.

[0933] "Pharmacologically acceptable" means a compound, material, composition, and / or dosage form that is suitable for contact with mammalian tissue, particularly human tissue, within reasonable medical judgment, in proportion to a reasonable risk-benefit ratio, without excessive toxicity, irritation, allergic reactions, and other problematic complications.

[0934] The terms “subject,” “patient,” or “warm-blooded animal” are intended to include animals. Examples of subjects include mammals, such as humans, dogs, cattle, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In certain embodiments, the subject is a human.

[0935] "Therapeutically effective" preferably refers to a quantity of a therapeutic agent that is capable of providing a therapeutic response to a subject or is prophylactically effective against the progression of cancer. The therapeutically effective treatment or quantity does not need to completely cure the subject, but may partially or completely delay, improve, counteract, or reduce at least one or more signs, symptoms, or symptom onset of the disease.

[0936] "Treatment" or "treating" can be preventive and / or therapeutic (including, but not limited to, symptomatic, symptom-relieving, and symptom-suppressive) and delay the progression of a disease or disorder, such as cancer. The term "preventive" means the prevention or delay of the onset or recurrence of a disease, such as cancer. The term "delay of progression," as used herein, means the administration of a combination of treatments to patients in whom the cancer to be treated is in a stage prior to or early in the disease, in whom a pre-cancerous form of the corresponding cancer is diagnosed, and / or in patients in whom conditions are diagnosed that are likely to develop the corresponding cancer.

[0937] A "tumor" refers to an abnormal mass of tissue. Tumors may contain cancer cells. A tumor can be described as benign if it has not spread to or invaded adjacent tissues or other parts of the body. A tumor can be described as malignant if it has spread to other tissues or parts of the body.

[0938] [Table 3]

[0939] [Table 4]

[0940] [Table 5]

[0941] [Table 6]

[0942] [Table 7]

[0943] [Table 8]

[0944] [Table 9]

[0945] XIII. See references All publications, patents, and patent applications referenced herein are referred to by reference in the same manner as each individual publication, patent, or patent application is specifically and individually indicated as being referred to by reference in whole. [Examples]

[0946] XIV. Examples The present invention will be described in more detail and specifically below with reference to this example, however, this is not intended to limit the invention.

[0947] a. Example 1. Overview of the clinical trial The Phase III clinical trial, protocol name "A Phase III, multicenter, randomized, open-label study to evaluate the efficacy and safety of ribociclib in combination with endocrine therapy as an adjuvant in patients with hormone receptor-positive, HER2-negative early-stage breast cancer," is listed on ClinicalTrials.gov under identification number: NCT03701334 (the entire disclosure on this webpage is incorporated herein by reference). The trial is conducted and will be conducted in accordance with the protocol described below.

[0948] Study design: See Figure 1.

[0949] Summary of the clinical protocol for the NATALEE trial (a novel adjuvant trial using ribociclib [LEE011]).

[0950] [Table 10]

[0951] [Table 11]

[0952] [Table 12]

[0953] [Table 13]

[0954] [Table 14]

[0955] [Table 15]

[0956] [Table 16]

[0957] [Table 17]

[0958] [Table 18]

[0959] [Table 19]

[0960] Table 20

[0961] Table 21

[0962] Table 22

[0963] Table 23

[0964] Table 24

[0965] Table 25

[0966] Table 26

[0967] Table 27

[0968] Table 28

[0969] Table 29

[0970] result Summary of Results Interim analysis results of the NATALEE trial:

[0971] Kisqali plus endocrine therapy (ET) significantly reduced the risk of disease recurrence compared to standard ET alone in an adjuvant setting.

[0972] NATALEE is the first and only positive Phase III study of a CDK4 / 6 inhibitor to demonstrate consistent benefits in a broad population of patients with stage II and III HR+ / HER2- early breast cancer (EBC) at risk of recurrence, including patients without lymph node lesions.

[0973] The primary endpoint of invasive disease-free survival (iDFS) was met. Kisqali+ET significantly reduced the risk of disease recurrence compared to standard adjuvant ET alone, and the benefit was consistent in patients with stage II and stage III EBC, regardless of lymph node involvement. • This study met its primary iDFS endpoint at the time of interim analysis 3 (426 / 500 events). A one-sided p-value of 0.0014 satisfies the initial effectiveness termination boundary (p<0.0128). • Approximately 25% reduction in iDFS risk (HR: 0.748, 95% CI (0.619~0.906)) • 3-year iDFS rate: RIB+ET: 90.4% vs. ET alone: ​​87.1%; Δ: 3.3% • Overall consistent iDFS effect in key subgroups • Stage III - HR: 0.74 (0.59-0.92); Stage II - HR: 0.76 (0.52-1.1) • Premenopausal and male: HR 0.72 (0.53-0.98); Postmenopausal: HR: 0.78 (0.613-0.997) • Positive trends were observed for all secondary efficacy endpoints: RFS, DDFS, and OS. • Can prevent any deterioration in overall survival (OS): HR 0.76 (0.54~1.07), p-value: 0.0559

[0974] In terms of safety, this study demonstrated a well-tolerated safety profile. Furthermore, the 400 mg ribociclib dose demonstrated an improved profile with fewer overall toxicity, particularly dose-dependent adverse events (cardiac QT interval and neutropenia). No novel safety findings were observed compared to the known and established safety profile of ribociclib therapy. The discontinuation rate due to adverse events during the 3-year period was similar in early-stage breast cancer patients to that of patients with metastatic breast cancer. Compared to the preceding "monarch-E" trial, diarrhea was not a high-frequency (≥5%) grade 3 or 4 adverse reaction, and no patients discontinued treatment or reduced their ribociclib dose due to diarrhea.

[0975] In summary, patients in the RIB+ET arm demonstrated significantly longer iDFS compared to ET alone (HR 0.748, p=0.0014), with a 3-year iDFS rate increasing to 90.4% (vs. 87.1%). The iDFS benefit was consistent across stratification factors and other subgroups. Secondary endpoints of overall survival, recurrence-free survival, and distant disease-free survival were consistently favorable in the RIB+ET arm. Furthermore, the addition of RIB resulted in a favorable safety profile with no novel signals. Overall, the addition of RIB to standard-care ET demonstrated a statistically significant and clinically meaningful improvement in iDFS, with a well-tolerated safety profile. Therefore, this combination therapy appears suitable for use in a broad population of patients with stage II or stage III HR+ / HRE2- early breast cancer, including N0 patients whose cancer has not spread to adjacent lymph nodes. This is unexpected based on the results of other parallel studies.

[0976] Assessment of health-related quality of life (HRQOL) in NATALEE Quality of life (QoL) was analyzed after a median follow-up of 34 months. Approximately 20% of patients had completed 3 years of ribociclib plus endocrine therapy.

[0977] The pre-specified HRQOL analysis was based on patient-reported outcomes using several survey instruments: the EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire) for function (physical, social, and emotional) and overall health; the EORTC QLQ-BR23 for breast cancer symptoms; the EQ-VAS (Euro-QoL Visual Analog Scale) for EQ-5D-5L; and the Hamilton Anxiety and Depression Rating Scale (see also Figures 5-8 for illustrative questionnaires). HRQOL in patients with HR+ / HER2- EBC was maintained by adding ribociclib to standard-care adjuvant NSAI compared to NSAI alone. Physical function and overall health scores were maintained over time in both the ribociclib + NSAI arm and the NSAI alone arm.

[0978] XV. Example 2. Test Protocol The NATALEE trial is conducted and will be conducted in accordance with the protocol described in Appendix A.

[0979] XVI. Example 3. Initial Interpretable Results and Latest Analysis The first interpretable results are described in Appendix B.

[0980] With an additional 5.6 months of follow-up (median follow-up of 33.3 months), 78.3% of patients had completed treatment with Kisqali® (ribociclib), and the latest analysis demonstrates sustained iDFS benefit and stability of secondary endpoints, including overall survival (OS).

[0981] The iDFS benefit was consistently maintained among key patient subgroups; among patients with stage II and stage III tumors, Kisqali reduced risk by 30% and 24.5%, respectively.

[0982] The results reinforce the benefits seen in the preceding interim analysis, showing that patients with stage II and III hormone receptor-positive / human epidermal growth factor receptor 2-negative (HR+ / HER2-) early breast cancer (EBC) treated with adjuvant Kisqali plus a nonsteroidal aromatase inhibitor as standard endocrine therapy (ET) had a 25.1% reduced risk of disease recurrence (HR=0.749; 95% CI:0.628, 0.892; p=0.0006) compared to ET alone.

[0983] Kisqali iDFS benefits between pre-specified subgroups:

[0984] [Table 30]

[0985] Kisqali data across all secondary efficacy endpoints were also consistent, including distant disease-free survival (DDFS) (25.1% risk reduction) and recurrence-free survival (RFS) (27.3% risk reduction). Events occurred in less than 4% of both treatment groups (3.3% in the Kisqali-ET arm and 3.4% in the ET-only arm), and overall survival (OS) outcomes continued to improve over longer periods.

[0986] The safety profile of Kisqali at a 400 mg dose consistently maintained previously reported results, with generally low grade adverse events (AEs), excluding abnormal laboratory findings. Particularly noteworthy AEs (grade 3 or higher) were neutropenia (44.3%), liver-related AEs (e.g., elevated transaminases) (8.6%), and QT interval prolongation (1.0%).1,2 No novel safety signals were identified.

[0987] XVII. Appendix A - Clinical Trial Protocols Approximately 425 sites worldwide will participate in this trial. The list of principal investigators participating in this trial will be managed by Translational Research in Oncology (TRIO).

[0988] Table 31

[0989] Table 32

[0990] Table 33

[0991] Table 34

[0992] Table 35

[0993] Table 36

[0994] Table 37

[0995] Table 38

[0996] Table 39

[0997] Table 40

[0998] Table 41

[0999] Table 42

[1000] Table 43

[1001] Table 44

[1002] Table 45

[1003] Table 46

[1004] Table 47

[1005] Table 48

[1006] Table 49

[1007] Table 50

[1008] Table 51

[1009] [Table 52]

[1010] [Table 53]

[1011] [Table 54]

[1012] [Table 55]

[1013] [Table 56]

[1014] [Table 57]

[1015] [Table 58]

[1016] 1. Background and theoretical basis 1.1. Disease Overview 1.1.1. Epidemiology Breast cancer (BC) is the most frequently diagnosed cancer worldwide. In 2012, there were an estimated 1.7 million new cases of BC and 522,000 deaths from the disease worldwide. 1 The incidence of BC varies among different ethnic groups and across different geographical locations around the world, ranging from 27 cases per 100,000 people in Central Africa and East Asia to 92 cases per 100,000 people in North America. 2In the United States, cancer-blocking cancer (BC) was projected to be the most frequently diagnosed cancer in 2018, with an estimated incidence of 268,670 new cases and 41,400 deaths. 3 The estimated incidence of BC in European countries in 2012 was 458,337 cases. 4 Male BC is uncommon, accounting for about 1% of all BCs, but its incidence continues to rise. 5 .

[1017] The vast majority of newly diagnosed breast cancer (BC) cases are early-stage breast cancer (EBC) localized in breast tissue and regional lymphatic vessels, which are potentially curable with localized treatment modalities such as surgery and radiotherapy. Based on data from the Surveillance, Epidemiology and End Results (SEER) program collected between 1975 and 2012, 93% of diagnosed cases were EBC, 62% were confined to breast tissue, and 31% were localized within the breast tissue and regional lymph nodes. 6 .

[1018] 1.1.2. Treatment of EBC In addition to primary surgery, management of EBC typically includes radiotherapy and additional antineoplastic modalities such as adjuvant or neoadjuvant systemic therapy. While many EBC patients can become disease-free with surgical resection and radiotherapy, distant recurrence due to micrometastatic disease is common thereafter and is a leading cause of death in EBC patients. 7 According to a meta-analysis of approximately 150,000 women in 200 randomized clinical trials, the EBC Trialists' Collaborative Group (EBCTCG) found that approximately 36% and 20% of EBC patients without any adjuvant systemic therapy experienced relapse and BC-related death, respectively, during the 5-year follow-up period. 8 Furthermore, relapses and BC-related deaths continued to occur in hormone receptor (HR)-positive EBC patients even 5 years after surgery, and only 45% of patients were reported to be relapse-free after 15 years of follow-up.

[1019] Adjuvant systemic therapy, including cytotoxic, biological, and endocrine therapies, reduces local and regional recurrence, decreases BC-specific mortality, and improves overall survival (OS) in EBC patients. 8 The necessity and selection of systemic adjuvant therapy are guided by several clinical, pathological, and genomic predictive and prognostic factors of the tumor and patient, based on the individual's risk of recurrence, including tumor stage, histopathological grade, tumor HR status, human epidermal growth factor receptor 2 (HER2) status, multiple gene testing recurrence score, growth markers such as Ki67, menopausal status, patient comorbidities, and age. Using these factors, EBC can be classified as low-risk, moderate / moderate-risk, or high-risk for recurrence after surgery. 7 There is no consensus on the definition of these risk groups, but generally, patients with smaller tumors, no metastasis to regional lymph nodes, low tumor grade, HR-positive and HER2-negative status, and a low recurrence genomic score have a low risk of recurrence (i.e., a 5-year recurrence rate of 5-10%). For these patients, chemotherapy-free ET is usually considered because the clinical benefit of chemotherapy is lower than that of adjuvant endocrine therapy (ET). On the other hand, patients with metastasis to multiple regional lymph nodes, high tumor grade, HER2-positive status, or a high recurrence genomic score have a high risk of recurrence. For these patients, adjuvant chemotherapy (and HER2-targeted drugs in HER2-positive BC patients) is usually considered, and if the tumor expresses HR, adjuvant ET (usually delivered after completion of chemotherapy) is also considered.

[1020] It is estimated that 75% of BCs express receptors for steroid hormones (estrogen receptor [ER] and / or progesterone receptor [PgR]), and therefore these patients may benefit from adjuvant ET with tamoxifen or aromatase inhibitors (AIs) (letrozole, anastrozole, or exemestane). 9 ET reduces the risk of relapse and BC mortality in HR-positive EBC, independently of chemotherapy. 8 .

[1021] The current clinical guideline recommendations for adjuvant ET in HR-positive EBC are as follows: 10、11: • About premenopausal women: • Tamoxifen with or without ovarian suppression for 5-10 years, AI with ovarian suppression for 5 years 12 . • About postmenopausal women: • Initial AI will be based on results from the MA.17R trial for 5 years (or up to 10 years). 13 ), or • Either tamoxifen for 2-3 years followed by AI for a total of up to 5 years, or AI treatment for up to 5 years. • Tamoxifen for approximately 5 years, followed by 5 years of AI, or • Tamoxifen for up to 10 years 10、11 . In men: Limited data suggests that tamoxifen or AI in combination with a gonadotropin-releasing hormone (GnRH) agonist should be the ET of choice for HR-positive HER2-negative EBC. 14 .

[1022] Despite extensive research and recent advances in the multimodality management of EBC, recurrence remains common, particularly in patients with adverse clinical, pathological, and genomic features. Approximately 25%–30% of HR-positive, HER2-negative EBC patients with multiple (four or more) metastatic regional lymph nodes (roughly corresponding to anatomical stage III in the AJCC 8th edition breast cancer staging classification) will experience recurrence within 5 years with ET, including AI. 8 Only 48% of these patients will achieve distant recurrence-free survival within 20 years, and nearly half of the patients will die from BC within 20 years despite a 5-year ET (extension therapy). 15Patients with 1-3 metastatic regional lymph nodes (generally corresponding to anatomical stage II in the AJCC 8th edition breast cancer staging classification) may have a lower risk of recurrence than patients with anatomical stage III, but despite ET, distant recurrence is still observed in 31% of patients within 20 years, and 28% die from BC. 15 .

[1023] Therefore, novel therapeutic strategies are needed to improve the clinical outcomes of HR-positive, HER2-negative EBC patients.

[1024] 1.1.3. The Role of the CDK4 / 6 Pathway in BC Dysregulation of the CDK4 / 6-Rb-E2F pathway is a significant contributing factor to ET resistance in BC. Luminal A and B subtypes of BC (85% of which are ER-positive and HER2-negative) have a high rate of cyclin D / CDK activation; cyclin D1 (CCND1) amplification was observed in 29% and 58% of luminal A and B subtypes, respectively, and CDK4 amplification was observed in 14% and 25%. 16、17 Luminal A subtype tumors also have the CDK inhibitor p16 INK4A There is also the loss of CDKN2A, which codes for CDKN2A. 18 The luminal subtype also maintains Rb expression, which is critically important for the benefits of treatment with CDK4 / 6 inhibitors. 19 .

[1025] Dysregulation of cell cycle checkpoints can have clinical and therapeutic implications. For example, HR-positive BC patients exhibiting a gene expression signature of Rb loss had shorter relapse-free survival (RFS) after adjuvant tamoxifen treatment. 20 The oncogene expression signature for E2F activation is also associated with a high rate of residual tumor cell proliferation after neoadjuvant AI therapy. Therefore, activation of the CDK4 / 6-Rb-E2F pathway promotes endocrine resistance, and treatment with CDK4 / 6 inhibitors or knockdown of CDK4 expression leads to Rb reactivation, restoring E2F binding and subsequently causing cell cycle arrest, thus suppressing the proliferation of endocrine-resistant cells.

[1026] Selective CDK4 / 6 inhibitors, such as palbociclib, abemaciclib, and ribociclib, have demonstrated synergistic effects with ET in preclinical studies, demonstrated efficacy in clinical trials, and are approved as initial therapy (in combination with AI) or as prior treatment ET (in combination with fulvestrant) in patients with HR-positive, HER2-negative advanced BC. 21~26 (For further information on the efficacy of ribociclib, please refer to the latest Ribociclib Investigational Brochure (IB).)

[1027] Given the demonstrated efficacy of CDK4 / 6 inhibitors in HR-positive, HER2-negative, advanced BC, co-targeting the CDK4 / 6-Rb-E2F pathway with CDK4 / 6 inhibitors may be a viable strategy to enhance endocrine responsiveness and prevent or delay the development of acquired resistance, and should be explored in adjuvant settings.

[1028] New data from ongoing clinical trials (PALLAS and monarchE) investigating other CDK4 / 6 inhibitors in HR-positive, HER2-negative EBC suggest that adjuvant settings may increase therapeutic benefit in anatomical stage III patients compared to anatomical stage II patients. 27、28 The PALLAS trial, which investigated palbociclib in stage II (including a certain proportion of patients with low-risk stage IIA) and stage III EBC, recently reported negative outcomes, while monarchE, which investigated abemaciclib and appears to include stage III patients, reported positive outcomes. Although there are differences between the two study designs and differences in the biochemical properties of the two CDK4 / 6 inhibitors, the early signs of a greater therapeutic effect favorable to high-risk stage III EBC from CDK4 / 6 inhibition cannot be ignored.

[1029] 1.2. Overview of Investigational Drug Therapy and Other Investigational Therapies This study includes treatment with ribociclib (LEE011) and ET using a nonsteroidal aromatase inhibitor (NSAID; anastrozole or letrozole) ± goserelin.

[1030] 1.2.1. Overview of Ribociclib Ribociclib is an orally bioavailable, highly selective small molecule inhibitor with highly specific nanomolar inhibitory activity against the CDK4 / cyclin-D1 and CDK6 / cyclin-D3 enzyme complexes. As of the date of this document, ribociclib is approved by several regulatory authorities, including the U.S. Food and Drug Administration (FDA) and the European Commission. According to the FDA, it is approved in combination with: (1) as an initial endocrine-based therapy in combination with AI for the treatment of premenopausal / perimenopause or postmenopausal women with HR-positive HER2-negative advanced or metastatic BC; or (2) as an initial endocrine-based therapy or after disease progression during ET for the treatment of postmenopausal women with HR-positive HER2-negative advanced or metastatic BC in combination with fulvestrant. In Europe, ribociclib is indicated as an initial endocrine-based therapy in combination with an artificial antiprostate (AI) or fulvestrant for the treatment of women with HR-positive, HER2-negative locally advanced or metastatic BC, or for women who have previously received ET. In premenopausal or perimenopausal women, ET must be combined with a luteinizing hormone-releasing agonist.

[1031] 1.2.1.1. Non-clinical data For more details, please refer to the latest information on ribociclib IB.

[1032] 1.2.1.2. Clinical Experience Ribociclib is currently being investigated in multiple clinical trials at different development phases in patients with BC and other solid tumors. For more information on clinical trials, please refer to the latest Ribociclib IB report.

[1033] 1.2.1.2.1. Clinical safety of ribociclib The clinical safety of ribociclib in combination with endocrine agents such as letrozole, tamoxifen, exemestane, fulvestrant, and goserelin has been evaluated in several combination studies. The safety profile of ribociclib in combination with NSAI (± goserelin) was investigated in two Phase III trials (MONALEESA-2 and MONALEESA-7) in patients with advanced BC. 24、29 .

[1034] Based on the results from the MONALEESA-7 trial, the use of ribociclib in combination with tamoxifen is not recommended because it increases the risk of QT prolongation. 29 .

[1035] For a comprehensive review of the safety profile of ribociclib in combination with endocrine agents, see the latest ribociclib IB.

[1036] 1.2.1.2.2. Clinical efficacy of ribociclib The efficacy of ribociclib in combination with endocrine agents has been evaluated in three previously published Phase III combination trials in patients with advanced BC, two of which evaluated the combination of ribociclib with an NSA (+ / - goserelin). 24、29 .

[1037] For further details on the efficacy profile of ribociclib, please refer to the latest information on ribociclib IB.

[1038] 1.2.1.2.3. Clinical Pharmacokinetics of Ribociclib The clinical pharmacokinetics (PK) of ribociclib have been evaluated in a Phase I study in patients with advanced solid tumors or lymphoma (Study CLEE011X2101). After administration of a single oral dose of 400 mg of the capsule formulation, ribociclib was present for 4.00 hours. maxAbsorption occurs in a median time (range: 0.58-4.20 hours). After repeated daily oral administration, a steady state of ribociclib was achieved by approximately the 8th day. In the steady state, ribociclib plasma C max The geometric mean is 1040 ng / mL (geometric coefficient of variation [CV] 49.3%), and the AUC 0-24h The effective T of ribociclib was 11400 ng × h / mL (geometric CV 57.8%). 1 / 2 The geometric mean was 31.6 hours (geometric CV 33.2%), and the accumulation ratio was 2.46 (geometric CV 24.6%). LEQ803, the active metabolite of ribociclib, has similar PK characteristics to the parent drug. Neither ribociclib nor LEQ803 accumulates substantially after repeated daily administration.

[1039] Based on in vitro and in vivo studies, ribociclib undergoes extensive hepatic metabolism by CYP3A in humans. Ribociclib is primarily eliminated through hepatic clearance, with renal clearance playing a smaller role in humans. The majority of the administered dose was excreted in the feces (69.1%), with only a small amount excreted in the urine (22.6%). Ribociclib accounted for approximately 23% of the total radioactivity in plasma (CLEE011A2102). The most prominent metabolites in plasma were CCI284 (N-hydroxylated), LEQ803 (N-demethylated), and M1 (secondary glucuronide), each accounting for less than 10% of the total radioactivity. The clinical activity (pharmacological and safety) after ribociclib treatment is mainly attributable to the parent drug, with contributions from circulating metabolites being negligible.

[1040] Concomitant use of ribociclib with potent CYP3A4 inhibitors or potent CYP3A4 inducers should be avoided as it can significantly affect ribociclib exposure. Co-administration of a potent CYP3A4 inhibitor (ritonavir) can significantly alter the ribociclib AUC after a single oral dose of 400 mg of ribociclib. inf The AUC of ribociclib increased 3.2 times (CLEE011A2101). When a potent CYP3A4 inducer (rifampicin) was co-administered, the AUC of ribociclib increased after administration of a single oral dose of 600 mg of ribociclib. infIt decreased by 89% (CLEE011A2101).

[1041] Ribociclib is a moderate to potent inhibitor of CYP3A4 and had no substantial effect on CYP1A2 substrates in humans (CLEE011A2106). Co-administration of midazolam (CYP3A4 substrate) with multiple doses of ribociclib (400 mg) increased midazolam exposure 3.8 times. Co-administration of caffeine (CYP1A2 substrate) with multiple doses of ribociclib (400 mg) increased caffeine exposure by 20% (1.2 times). Co-administration of highly sensitive CYP3A4 substrates with a narrow therapeutic index should be avoided. Co-administration of CYP1A2 substrates does not appear to lead to clinically significant drug interactions (DDIs).

[1042] Food does not affect the pharmacokinetic activity (PK) of ribociclib administered as a capsule or tablet; therefore, ribociclib capsules or tablets can be taken without considering meals (CLEE011A2111, CLEE011A2103).

[1043] Based on PK data from the MONALEESA-2 and -7 trials, no clear drug-drug interactions (DDIs) were observed between ribociclib and its combination partners, letrozole or anastrozole. Population PK analysis showed that concomitant use of letrozole or anastrozole had no effect on ribociclib exposure.

[1044] For further details, please refer to the latest information on ribociclib IB.

[1045] 1.2.2. Overview of Adjuvant Endocrine Therapy In HR-positive EBC women, tamoxifen, NSAIs (i.e., letrozole, anastrozole), and steroid AIs (i.e., exemestane) are used as adjuvant ET. AIs can be used as upfront therapy or 2-3 years or 5 years after prior tamoxifen treatment (see Section 1.1.2). Both AI administration methods show similar long-term efficacy.30 Clinical treatment guidelines suggest that there is no compelling evidence to show meaningful differences in clinical efficacy or toxicity among letrozole, anastrozole, and exemestane; therefore, similar precautions for use and activity monitoring should be applied regardless of the type of AI administered. 11 GnRH agonists are used to achieve gonadal suppression in premenopausal women or men.

[1046] The following sections provide general information regarding NSAIs and goserelin. For comprehensive safety and efficacy information, as well as guidance for each drug therapy, please refer to current prescribing information and clinical guidelines at your institution.

[1047] 1.2.2.1. Overview of Letrozole Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system. Letrozole acts by highly selectively inhibiting the conversion of androgens (primarily from the adrenal glands, the main source of estrogen in postmenopausal women) to estrogen. Letrozole induces a 75%–95% reduction in estrogen levels after two weeks of treatment at a daily dose of 0.1–5 mg, without significant clinical or laboratory toxicity or changes in the levels of other endocrine hormones. 31、32 .

[1048] Letrozole is administered orally once daily at a dose of 2.5 mg. It is rapidly and completely absorbed from the gastrointestinal (GI) tract. Co-ingestion of food does not affect the degree of letrozole absorption. Letrozole is metabolized by CYP3A4 to pharmacologically inactive metabolites, and renal excretion of the glucuronide conjugate of these metabolites is the primary letrozole clearance pathway.

[1049] In the Phase Ib / II dose escalation / expansion study (CLEE011X2107), letrozole (2.5 mg daily) and ribociclib (600 mg daily, 3 weeks on / 1 week off) did not affect each other's metabolism.

[1050] In adjuvant and extended adjuvant clinical trials, the most frequently reported adverse events (AEs) for letrozole were hot flashes, arthralgia / arthritis, and myalgia. Generally, the observed adverse reactions were mild to moderate in severity. Adjuvant use of letrozole (or anastrozole) is associated with decreased bone mass density, which can lead to osteoporosis and associated fractures. Bone mass density monitoring should be considered.

[1051] Letrozole, and other artificial inhalants, should not be used for the above indications in women with intact ovarian function or in men who have not been castrated, due to their mechanism of action.

[1052] For further information regarding letrozole, please refer to the current prescription information at your facility.

[1053] 1.2.2.2. Overview of Anastrozole Anastrozoles, such as letrozole, are selective non-steroidal antimicrobial agents (NSAIDs). They significantly lower serum estradiol levels without any detectable effect on the formation of adrenal corticosteroids or aldosterone.

[1054] Anastrozole is administered orally once daily at a dose of 1 mg, and may be taken 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 total clearance. The major circulating metabolites of anastrozole lack pharmacological activity. Based on in vitro data, anastrozole metabolism is mainly carried out by CYP3A4 and UGT1A4. 33 Therefore, anastrozole metabolism may be potentially affected by co-administration with ribociclib. However, anastrozole has been studied at doses up to 10 mg / day (10 times the daily dose), and all evaluated doses were well tolerated, with no significant acute toxicity attributable to anastrozole. 34 .

[1055] For further information regarding anastrozole, please refer to the current prescription information at your facility.

[1056] 1.2.2.3. Overview of GnRH Agonists GnRH agonists are synthetic analogs of gonadotropin-releasing hormone that desensitize the pituitary gland to GnRH through continuous stimulation of GnRH receptors. GnRH agonists differ from naturally occurring GnRH in that they undergo decapeptide structural modifications that reduce molecular degradation (usually by amino acid substitutions at position 6, but also sometimes at positions 9 and 10).

[1057] Goserelin is the GnRH agonist that will be used in this study. The most common adverse events (AEs) in women treated with goserelin include hot flashes, headaches, sweating, acne, emotional liability, depression, decreased libido, vaginitis, breast atrophy, seborrhea, and peripheral edema. In men, goserelin may be associated with hot flashes, sexual dysfunction, erectile dysfunction, and lower urinary tract symptoms.

[1058] For further information regarding goserelin, please refer to current prescription information and / or clinical guidelines at your facility.

[1059] 1.3. Theoretical basis 1.3.1. Theoretical basis for conducting this examination Adjuvant ET for HR-positive EBC is effective in reducing the risk of relapse and improving survival, but relapses are still common, especially in patients with features indicating a moderate or high risk of relapse, such as anatomical stage II and III patients. These relapses are mostly in the form of distant metastases, are usually incurable, and ultimately lead to BC death. 15 .

[1060] Adding ribociclib to ET has demonstrated clinical efficacy with a tolerable toxicity profile in HR-positive, HER2-negative advanced BC; therefore, adding ribociclib in an adjuvant setting may extend invasive disease-free survival (iDFS) in HR-positive, HER2-negative EBC patients with moderate and high relapse risk by enhancing primary endocrine response and preventing or delaying the development of acquired resistance to ET.

[1061] The objective of this randomized, open-label trial is to evaluate the effect of adding ribociclib to standard adjuvant ET on iDFS in patients with EBC who are HR-positive, HER2-negative, and in anatomical stage III, IIB, or subgroup IIA (as defined in inclusion criterion 8).

[1062] 1.3.2. Theoretical basis for the study design This is a phase III, multicenter, randomized, open-label trial to evaluate the addition of ribociclib to standard adjuvant etiolates (ETs) in HR-positive, HER2-negative EBC women and men. The adjuvant ETs in this trial will be non-steroidal antimicrobial agents (NSAIs) (letrozole, anastrozole) for postmenopausal women and goserelin-based NSAs for premenopausal women and men.

[1063] The randomization, stratification, and multicenter design of this study minimize allocation bias and balance both known and unknown prognostic factors when allocating treatment.

[1064] The appropriate selection of outcomes, particularly the primary endpoint, is critically important to the validity of the results in this open-label trial. To reduce bias, the primary endpoint of selection will be objective (iDFS) and will use a standardized definition (according to the STEEP system for defining standardized efficacy endpoints in adjuvant breast cancer trials). 35Furthermore, iDFS events must be confirmed not only based on clinical or radiological evaluation, but also histologically or cytologically (unless there is an unacceptable risk to the patient due to the procedure), and therefore objective confirmation is required to consider a relapse as an iDFS event. In addition, if a patient discontinues the study treatment for reasons other than distant relapse, the assessment of relapse must continue until a distant relapse occurs according to the STEEP criteria. All of these factors support the validity and objectivity of the relapse assessment underlying the iDFS endpoint, and ensure that the results of the study are not influenced by the open-label design. Moreover, ribociclib is associated with a neutropenia rate of approximately 75%. 36 Therefore, concealing treatment allocations is unlikely to be effective.

[1065] This study will enroll premenopausal and postmenopausal women and men with HR-positive, HER2-negative EBC in anat...

Claims

1. A method for treating cancer in an adult patient requiring treatment for HR+ / HER2- stage II or stage III early breast cancer, comprising administering to the patient a treatment comprising ribociclib, in the range of 150 mg / day to 450 mg / day, in the range of 150 mg / day to 450 mg / day, on days 1 to 21 of a 28-day cycle, in combination with an aromatase inhibitor, preferably letrozole or anastrozole, administered daily during the 28-day cycle.

2. A method for preventing early breast cancer or reducing its signs or symptoms, comprising administering to the patient a treatment comprising ribociclib, its free base form or a pharmaceutically acceptable salt thereof in combination with an aromatase inhibitor, preferably letrozole or anastrozole.

3. The method according to claim 2, wherein ribociclib, its free base form, or a pharmaceutically acceptable salt thereof is administered to the patient in a dose ranging from 150 mg / day to 450 mg / day on days 1 to 21 of a 28-day cycle.

4. The method according to claim 2 or 3, wherein the aromatase inhibitor is administered daily during the 28-day cycle.

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

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

7. A method for maintaining remission in an adult patient who has previously been diagnosed with HR+ / HER2- stage II or stage III early breast cancer, comprising administering to the patient a treatment comprising a certain dose of ribociclib, in its free base form or a pharmaceutically acceptable salt thereof, in combination with an aromatase inhibitor, preferably letrozole or anastrozole.

8. The method according to claim 6 or 7, wherein the remission is complete remission.

9. The method according to claim 6 or 7, wherein the remission is partial remission.

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

11. The method according to claim 10, wherein the treatment prevents recurrence for at least three months.

12. The method according to claim 11, wherein the treatment prevents recurrence for at least six months.

13. The method according to claim 12, wherein the treatment prevents recurrence for at least one year.

14. The method according to any one of claims 1 to 13, wherein the patient does not have signs or symptoms of cancer prior to receiving the treatment.

15. The method according to any one of claims 1 to 14, wherein the treatment prevents the proliferation of HR+ / HER2- breast cancer cells.

16. The method according to any one of claims 1 to 15, wherein the treatment is adjuvant therapy.

17. The method according to any one of claims 1 to 16, wherein the ribociclib is a pharmaceutically acceptable ribociclib salt.

18. The method according to claim 17, wherein the ribociclib salt is ribociclib succinate.

19. The method according to any one of claims 1 to 18, wherein the dose of ribociclib is 200 mg / day or 400 mg / day.

20. The method according to any one of claims 1 to 18, wherein the ribociclib is not administered at a dose of 600 mg / day.

21. The method according to any one of claims 1 to 19, wherein ribociclib is administered as ribociclib succinate, and the total dose of ribociclib is 200 mg / day.

22. The method according to any one of claims 1 to 19, wherein ribociclib is administered as ribociclib succinate, and the total dose of ribociclib is 400 mg / day.

23. The method according to any one of claims 1 to 19, wherein the ribociclib is administered at a dose of 400 mg / day over a period of time, and thereafter at a dose of 200 mg / day of ribociclib.

24. The method according to any one of claims 1 to 23, wherein the aforementioned dose of ribociclib is administered orally.

25. The method according to any one of claims 1 to 24, wherein the dose of ribociclib is administered in tablet form.

26. The method according to any one of claims 1 to 24, wherein the aromatase inhibitor is letrozole or anastrozole.

27. The method according to any one of claims 1 to 26, wherein the aromatase inhibitor is administered orally.

28. The method according to claim 26 or 27, wherein the letrozole is administered in a dose ranging from 1 mg / day to 4 mg / day.

29. The method according to claim 28, wherein the letrozole is administered at a dose of 2.5 mg / day.

30. The method according to claim 26 or 27, wherein the anastrozole is administered in a dose ranging from 0.5 mg / day to 1.5 mg / day.

31. The method according to claim 30, wherein the anastrozole is administered at a dose of 1 mg / day.

32. The method according to any one of claims 1 to 31, wherein the treatment comprises a gonadotropin-releasing hormone agonist.

33. The method according to claim 32, wherein the gonadotropin-releasing hormone agonist is goserelin.

34. The method according to claim 33, wherein goserelin is administered in a dose in the range of 2 mg to 5 mg.

35. The method according to claim 34, wherein the dose of goserelin is 3.6 mg.

36. The method according to any one of claims 33 to 35, wherein goserelin is administered subcutaneously.

37. The method according to any one of claims 33 to 36, wherein goserelin is administered once every four weeks.

38. The method according to any one of claims 1 to 31, wherein the patient is a postmenopausal woman.

39. The method according to any one of claims 1 to 37, wherein the patient is a premenopausal woman or a man.

40. The method according to any one of claims 1 to 39, wherein the treatment is administered to the patient for at least 12 months.

41. The method according to claim 40, wherein the treatment is administered to the patient for at least 24 months.

42. The method according to claim 40 or 41, wherein the treatment is administered to the patient for at least 36 months.

43. The method according to claim 40 or 41, wherein the treatment is administered to the patient for at least 48 months.

44. The method according to claim 40 or 41, wherein the treatment is administered to the patient for at least 60 months.

45. The method according to any one of claims 1 to 44, wherein the treatment is continued until there is no detectable cancer in the patient.

46. The method according to any one of claims 1 to 45, wherein the breast cancer is ER+ and PR+.

47. The method according to any one of claims 1 to 45, wherein the breast cancer is ER- and PR-+.

48. The method according to any one of claims 1 to 45, wherein the breast cancer is ER+ and PR-.

49. The method according to any one of claims 1 to 48, wherein the breast cancer has a histological subtype that is ductal carcinoma or lobular carcinoma.

50. The method according to any one of claims 1 to 49, wherein the breast cancer is stage IIA cancer or stage IIB cancer.

51. The method according to claim 50, wherein the breast cancer is stage IIA cancer.

52. The method according to claim 50, wherein the breast cancer is stage IIB cancer.

53. The method according to any one of claims 1 to 49, wherein the breast cancer is stage IIIA cancer, stage IIIB cancer, or stage IIIC cancer.

54. The method according to claim 53, wherein the breast cancer is stage IIIA cancer.

55. The method according to claim 53, wherein the breast cancer is stage IIIB cancer.

56. The method according to claim 53, wherein the breast cancer is stage IIIC cancer.

57. The method according to any one of claims 1 to 56, wherein the treatment is administered regardless of the lymph node status of the breast cancer.

58. The method according to any one of claims 1 to 57, wherein the breast cancer has a lymph node state selected from N0, N1, N2, and N3.

59. The method according to claim 57 or 58, wherein the breast cancer has a lymph node state of N0.

60. The method according to claim 57 or 58, wherein the breast cancer has lymph node status N1 to N3.

61. The method according to claim 57 or 58, wherein the breast cancer has a lymph node state of N1.

62. The method according to claim 57 or 58, wherein the breast cancer has a lymph node state of N2.

63. The method according to claim 57 or 58, wherein the breast cancer has a lymph node state of N3.

64. The method according to 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 according to claim 64, wherein the breast cancer comprises one or more cells having the histological grade G1.

66. The method according to claim 64, wherein the breast cancer comprises one or more cells having the histological grade G2.

67. The method according to claim 64, wherein the breast cancer comprises one or more cells having the histological grade G3.

68. The method according to any one of claims 1 to 67, wherein the breast cancer includes tumors of classification T0, T1, T2, T3, or T4.

69. The method according to claim 68, wherein the breast cancer includes tumors of classification T1, T2, or T3.

70. The method according to claim 68, wherein the breast cancer includes a tumor of classification T0.

71. The method according to claim 68 or 69, wherein the breast cancer includes a tumor of classification T1.

72. The method according to claim 68 or 69, wherein the breast cancer includes a tumor of classification T2.

73. The method according to claim 68 or 69, wherein the breast cancer includes a tumor of classification T3.

74. The method according to claim 68, wherein the breast cancer includes a tumor of classification T4.

75. The method according to any one of claims 1 to 74, wherein the breast cancer has a Ki67 status of 20 or less.

76. The method according to any one of claims 1 to 74, wherein the breast cancer has a Ki67 status higher than 20.

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

78. The method according to any one of claims 1 to 77, wherein the patient has received at least one prior treatment for cancer.

79. The method according to claim 78, wherein the prior treatment is an adjuvant treatment after another prior treatment.

80. The method according to claim 78 or 79, wherein the prior treatment is a surgical procedure.

81. The method according to claim 80, wherein the surgical procedure includes complete surgical resection of the cancer.

82. The method according to claim 80 or 81, wherein the surgical procedure is a mastectomy.

83. The method according to claim 80 or 81, wherein the prior treatment is chemotherapy.

84. The method according to claim 83, wherein the prior treatment is adjuvant chemotherapy.

85. The method according to claim 83, wherein the prior treatment is neoadjuvant chemotherapy.

86. The method according to claim 78 or 79, wherein the prior treatment is endocrine therapy.

87. The method according to claim 78 or 79, wherein the prior treatment is radiotherapy.

88. The method according to any one of claims 78 to 87, wherein the prior treatment was ineffective for the patient.

89. The method according to any one of claims 1 to 88, wherein the patient resides in a geographical area selected from North America, Western Europe, or Oceania.

90. The method according to any one of claims 1 to 89, wherein the patient is of Asian descent.

91. The method according to any one of claims 1 to 90, wherein the patient is between 18 and 45 years of age.

92. The method according to any one of claims 1 to 90, wherein the patient is 45 to 54 years old.

93. The method according to any one of claims 1 to 90, wherein the patient is between 54 and 64 years of age.

94. The method according to any one of claims 1 to 90, wherein the patient is over 64 years of age.

95. The method according to any one of claims 1 to 94, wherein the patient has a BMI of 25 or more.

96. The method according to any one of claims 1 to 94, wherein the patient has a BMI of less than 25.

97. The method according to any one of claims 1 to 96, wherein the treatment improves the patient's condition compared to a patient who has not received the treatment and / or compared to the patient's condition before the treatment.

98. The method according to any one of claims 1 to 97, wherein the treatment reduces the risk of invasive disease.

99. The method according to claim 98, wherein the treatment reduces the risk of infiltrative disease, and when the risk is calculated compared to a patient who has not received the treatment, the hazard ratio corresponds to less than 1.

100. The method according to claim 99, wherein the treatment reduces the risk of invasive disease, and when the risk is calculated compared to a patient who has not received the treatment, the hazard ratio corresponds to 0.78 or less.

101. The method according to any one of claims 1 to 37 and 39 to 100, wherein the patient is a premenopausal woman or man, the treatment reduces the risk of invasive disease, and when the risk is calculated compared to a patient receiving the treatment, it corresponds to a hazard ratio of 0.72 or less.

102. The method according to any one of claims 98 to 100, wherein the patient has HR+ / HER2- stage III early breast cancer, the treatment reduces the risk of invasive disease, and when the risk is calculated compared to a patient who has not received the treatment, the hazard ratio corresponds to 0.74 or less.

103. The method according to any one of claims 98 to 100, wherein the patient has HR+ / HER2- stage II early breast cancer, the treatment reduces the risk of invasive disease, and when the risk is calculated compared to a patient who has not received the treatment, the hazard ratio corresponds to 0.76 or less.

104. The method according to any one of claims 98 to 100, wherein the patient has HR+ / HER2- stage III early breast cancer, the treatment results in at least a 25% reduction in the risk of invasive disease, and when the risk is calculated compared to a patient who has not received the treatment, it corresponds to a hazard ratio of 0.

75.

105. The method according to any one of claims 1 to 104, wherein the treatment reduces the risk of invasive disease to the same level as that of a subgroup of patients, including patients with stage II early breast cancer, stage III early breast cancer, patients who are premenopausal women or men, and patients who are postmenopausal women.

106. The method according to any one of claims 1 to 105, wherein the treatment does not result in a deterioration of overall survival, and the hazard ratio when the risk is calculated compared to a patient who does not receive the treatment corresponds to 0.

76.

107. The method according to any one of claims 1 to 106, wherein the treatment reduces and / or prevents one or more risks of cancer recurrence, cancer spread, development and / or proliferation of additional cancers, and death from cancer.

108. The method according to claim 107, wherein the treatment reduces cancer recurrence, and the recurrence is one or more of invasive ipsilateral breast tumor (IBTR) recurrence, locally invasive recurrence, and distant recurrence.

109. The method according to claim 107 or 108, wherein the treatment reduces the spread of the cancer, and the spread of the cancer is invasive contralateral breast cancer or additional primary invasive cancer.

110. The method according to any one of claims 1 to 109, wherein death from cancer is prevented by the treatment.

111. A method for maintaining remission in an adult patient previously diagnosed with HR+ / HER2- stage II or stage III early breast cancer, comprising administering to the patient a treatment comprising administering to the patient a treatment comprising ribociclib, in the range of 150 mg / day to 450 mg / day on days 1 to 21 of a 28-day cycle, in combination with an aromatase inhibitor, preferably letrozole or anastrozole, administered daily during the 28-day cycle.

112. A method for preventing recurrence of breast cancer in adult patients, comprising providing adjuvant therapy to a patient who has previously received treatment for HR+ / HER2- stage II or 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 according to any one of claims 26 to 31, administered daily during the 28-day cycle.

113. The method according to claim 112, wherein the prior treatment is surgical resection of the cancer.

114. A method for treating HR+ / HER2- stage II or III early breast cancer in adult patients, the method according to any one of claims 1 to 112, for use in the said method, comprising ribociclib or a pharmaceutically acceptable salt thereof and an aromatase inhibitor.

115. Use of ribociclib or a pharmaceutically acceptable salt thereof and an aromatase inhibitor in the manufacture of a pharmaceutical product for the treatment of HR+ / HER2- stage II or III early breast cancer in adult patients, wherein the pharmaceutical product is administered by the method described in any one of claims 1 to 112.

116. A kit for carrying out a method for treating HR+ / HER2- stage II or stage III early breast cancer in adult patients according to any one of claims 1 to 112.

117. A method for treating HR+ / HER2- stage II or stage III early breast cancer in an adult patient in remission, comprising administering ribociclib in combination with an aromatase inhibitor to the adult patient, wherein the administration maintains the adult patient's remission for at least three months.

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

119. The method according to claim 117 or 118, wherein the administration maintains complete remission in the adult patient for at least six months.

120. The method according to claim 117 or 118, wherein the administration maintains complete remission in the adult patient for at least nine months.

121. The method according to claim 117 or 118, wherein the administration maintains complete remission in the adult patient for at least 12 months.

122. The method according to claim 117 or 118, wherein the administration maintains complete remission in the adult patient for at least 15 months.

123. The method according to claim 117 or 118, wherein the administration maintains complete remission in the adult patient for at least 18 months.

124. The method according to claim 117 or 118, wherein the administration maintains complete remission in the adult patient for at least 21 months.

125. The method according to claim 117 or 118, wherein the administration maintains complete remission in the adult patient for at least 24 months.

126. The method according to claim 117 or 118, wherein the administration maintains complete remission in the adult patient for at least 27 months.

127. The method according to claim 117 or 118, wherein the administration maintains complete remission in the adult patient for at least 30 months.

128. The method according to claim 117 or 118, wherein the administration maintains complete remission in the adult patient for at least 33 months.

129. The method according to claim 117 or 118, wherein the administration maintains complete remission in the adult patient for at least 36 months.

130. The method according to any one of claims 117 to 129, wherein ribociclib and an aromatase inhibitor are administered over the course of treatment, and the administration maintains complete remission in the adult patient for at least the course of treatment.

131. The method according to any one of claims 117 to 129, wherein a dose of 400 mg of ribociclib is administered orally once daily on days 1 to 21 of a 28-day cycle, and an aromatase inhibitor is administered once daily every day during the 28-day cycle.

132. The method according to any one of claims 117 to 129, wherein a dose of 400 mg of ribociclib is administered orally once daily on days 1 to 21 of a 28-day cycle for a maximum treatment period of 3 years, and an aromatase inhibitor is administered once daily every day during the 28-day cycle for a maximum period of 3 years.

133. The method according to any one of claims 117 to 129, wherein a dose of 400 mg of ribociclib is administered orally once daily on days 1 to 21 of a 28-day cycle for a maximum treatment period of 5 years, and an aromatase inhibitor is administered once daily every day during the 28-day cycle for a maximum period of 5 years.

134. The method according to 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 according to claim 134, wherein the pharmaceutically acceptable salt is ribociclib succinate.

136. The method according to any one of claims 117 to 135, wherein the adult patient had never been treated with a 600 mg dose of ribociclib.

137. The method according to any one of claims 117 to 136, wherein the adult patient had never been diagnosed with HR+ / HER2- advanced or metastatic breast cancer.

138. The method according to any one of claims 117 to 137, wherein ribociclib and an aromatase inhibitor are administered as adjuvant therapy.

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

140. The method according to any one of claims 117 to 139, wherein the aforementioned dose of ribociclib is administered in tablet form.

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

142. The method according to claim 141, wherein the ribociclib salt is ribociclib succinate.

143. The method according to any one of claims 117 to 142, wherein the aromatase inhibitor is letrozole.

144. The method according to any one of claims 117 to 142, wherein the aromatase inhibitor is anastrozole.

145. The method according to any one of claims 117 to 144, wherein the aromatase inhibitor is letrozole, and the letrozole is administered once daily in a dose ranging from 1 mg to 4 mg.

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

147. The method according to any one of claims 117 to 144, wherein the aromatase inhibitor is anastrozole, and the anastrozole is administered in a dose ranging from 0.5 mg once daily to 1.5 mg once daily.

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

149. The method according to any one of claims 117 to 148, further comprising administering a gonadotropin-releasing hormone agonist to the adult patient.

150. The method according to claim 149, wherein the gonadotropin-releasing hormone agonist is goserelin.

151. The method according to claim 150, wherein goserelin is administered in a dose in the range of 2 mg to 5 mg.

152. The method according to claim 151, wherein the dose of goserelin is 3.6 mg.

153. The method according to any one of claims 150 to 152, wherein goserelin is administered subcutaneously.

154. The method according to any one of claims 150 to 153, wherein goserelin is administered once every four weeks.

155. The method according to any one of claims 117 to 148, wherein the patient is a postmenopausal woman.

156. The method according to any one of claims 117 to 154, wherein the patient is a premenopausal woman or a man.

157. The method according to any one of claims 117 to 156, wherein the breast cancer has a histological subtype that is ductal carcinoma or lobular carcinoma.

158. The method according to any one of claims 117 to 156, wherein the breast cancer is stage IIA cancer or stage IIB cancer.

159. The method according to any one of claims 117 to 156, wherein the breast cancer is stage IIA cancer.

160. The method according to any one of claims 117 to 156, wherein the breast cancer is stage IIB cancer.

161. The method according to any one of claims 117 to 156, wherein the breast cancer is stage IIIA cancer, stage IIIB cancer, or stage IIIC cancer.

162. The method according to any one of claims 117 to 156, wherein the breast cancer is stage IIIA cancer.

163. The method according to any one of claims 117 to 156, wherein the breast cancer is stage IIIB cancer.

164. The method according to any one of claims 117 to 156, wherein the breast cancer is stage IIIC cancer.

165. The method according to any one of claims 117 to 156, wherein the treatment is administered regardless of the lymph node status of the breast cancer.

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

167. The method according to any one of claims 117 to 156, wherein the breast cancer has a lymph node state selected from N0, N1, N2, and N3.

168. The method according to any one of claims 117 to 156, wherein the breast cancer has a lymph node state of N0.

169. The method according to any one of claims 117 to 156, wherein the breast cancer has lymph node status N1 to N3.

170. The method according to any one of claims 117 to 156, wherein the breast cancer has a lymph node state of N1.

171. The method according to any one of claims 117 to 156, wherein the breast cancer has an N2 lymph node state.

172. The method according to any one of claims 117 to 156, wherein the breast cancer has an N3 lymph node state.

173. The method according to any one of claims 117 to 156, wherein the breast cancer comprises one or more cells having a histological grade selected from G1, G2, or G3.

174. The method according to any one of claims 117 to 156, wherein the breast cancer comprises one or more cells having the histological grade G1.

175. The method according to any one of claims 117 to 156, wherein the breast cancer comprises one or more cells having the histological grade G2.

176. The method according to any one of claims 117 to 156, wherein the breast cancer comprises one or more cells having the histological grade G3.

177. The method according to any one of claims 117 to 156, wherein the breast cancer includes tumors of classification T0, T1, T2, T3, or T4.

178. The method according to any one of claims 117 to 156, wherein the breast cancer includes a tumor of classification T1, T2, or T3.

179. The method according to any one of claims 117 to 156, wherein the breast cancer includes a tumor of classification T0.

180. The method according to any one of claims 117 to 156, wherein the breast cancer includes a tumor of classification T1.

181. The method according to any one of claims 117 to 156, wherein the breast cancer includes a tumor of classification T2.

182. The method according to any one of claims 117 to 156, wherein the breast cancer includes a tumor of classification T3.

183. The method according to any one of claims 117 to 156, wherein the breast cancer includes a tumor of classification T4.

184. The method according to any one of claims 117 to 156, wherein the breast cancer has a Ki67 status of 20 or less.

185. The method according to any one of claims 117 to 156, wherein the breast cancer has a Ki67 status higher than 20.

186. The method according to any one of claims 117 to 185, wherein the adult patient has undergone surgery for the early-stage breast cancer before being administered ribociclib and an aromatase inhibitor.

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

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

189. The method according to claim 188, wherein the endocrine therapy was a past aromatase inhibitor therapy.

190. The method according to claim 188, wherein the aforementioned past aromatase inhibitor was letrozole or anastrozole.

191. The method according to any one of claims 117 to 185, wherein the adult patient underwent surgery for the early-stage breast cancer immediately before being administered ribociclib and an aromatase inhibitor.

192. The method according to any one of claims 186 to 191, wherein the surgical procedure includes the complete surgical resection of the cancer.

193. The method according to any one of claims 186 to 191, wherein the surgical procedure was a mastectomy.

194. The method according to any one of claims 186 to 191, wherein the patient has received neoadjuvant therapy.

195. The method according to claim 194, wherein the neoadjuvant therapy was chemotherapy.

196. The method according to any one of claims 117 to 195, wherein the adult patient resides in a geographical area selected from North America, Western Europe, or Oceania.

197. The method according to any one of claims 117 to 195, wherein the patient is of Asian descent.

198. The method according to any one of claims 117 to 195, wherein the patient is between 18 and 45 years of age.

199. The method according to any one of claims 117 to 195, wherein the patient is 45 to 54 years old.

200. The method according to any one of claims 117 to 195, wherein the patient is between 54 and 64 years old.

201. The method according to any one of claims 117 to 195, wherein the patient is over 64 years of age.

202. The method according to any one of claims 117 to 195, wherein the patient has a BMI of 25 or more.

203. The method according to any one of claims 117 to 195, wherein the patient has a BMI of less than 25.

204. The method according to any one of claims 117 to 203, wherein the treatment improves the patient's condition compared to a patient who has not received the treatment and / or compared to the patient's condition before the treatment.

205. The method according to any one of claims 117 to 203, wherein the treatment reduces the risk of invasive disease.

206. The method according to any one of claims 117 to 203, wherein the treatment reduces the risk of invasive disease in the adult patient, and when the risk is calculated compared to other patients who received the same treatment as the adult patient except that they did not receive ribociclib, the hazard ratio corresponds to less than 1.

207. The method according to any one of claims 117 to 203, wherein the treatment reduces the risk of invasive disease in the adult patient, and when the risk is calculated compared to other patients who received the same treatment as the adult patient except that they did not receive ribociclib, the hazard ratio corresponds to 0.78 or less.

208. The method according to any one of claims 117 to 203, wherein the adult patient is a premenopausal woman or man, the treatment reduces the risk of invasive disease, and the hazard ratio is 0.72 or less when the risk is calculated compared to another premenopausal woman or man who received the same treatment as the aforementioned premenopausal woman or man, except that he did not receive ribociclib.

209. The method according to any one of claims 117 to 203, wherein the adult patient is diagnosed with HR+ / HER2- stage III early breast cancer, the treatment reduces the adult patient's risk of invasive disease, and the hazard ratio is 0.74 or less when the risk is calculated compared to other patients who received the same treatment as the adult patient except that they did not receive ribociclib.

210. The method according to any one of claims 117 to 203, wherein the adult patient is diagnosed with HR+ / HER2- stage II early breast cancer, the treatment reduces the risk of invasive disease, and the hazard ratio is 0.76 or less when the risk is calculated compared to other patients who received the same treatment as the adult patient except that they did not receive ribociclib.

211. The method according to any one of claims 117 to 203, wherein the adult patient is diagnosed with HR+ / HER2- stage III early breast cancer, the treatment results in at least a 25% reduction in the risk of invasive disease, and the risk corresponds to a hazard ratio of 0.75 when calculated compared to other patients who received the same treatment as the adult patient except that they did not receive ribociclib.

212. The method according to any one of claims 117 to 203, wherein the treatment reduces the risk of invasive disease to the same level as that of a subgroup of patients including patients with stage II early breast cancer, stage III early breast cancer, patients who are premenopausal women or men, and patients who are postmenopausal women.

213. The method according to any one of claims 117 to 203, wherein the treatment does not result in a deterioration of overall survival, and the hazard ratio corresponds to 0.76 when the risk is calculated compared to other patients who received the same treatment as the adult patient except that they did not receive the ribociclib.

214. The method according to any one of claims 117 to 203, wherein the treatment reduces and / or prevents one or more risks of cancer recurrence, cancer spread, development and / or proliferation of additional cancers, and death from cancer.

215. The method according to any one of claims 117 to 203, wherein the treatment reduces cancer recurrence, and the recurrence is one or more of invasive ipsilateral breast tumor (IBTR) recurrence, locally invasive recurrence, and distant recurrence.

216. The method according to any one of claims 117 to 203, wherein the treatment reduces the spread of cancer, and the spread of cancer is invasive contralateral breast cancer or additional primary invasive cancer.

217. A method for treating HR+ / HER2- stage II or III early breast cancer in adult patients, comprising ribociclib or a pharmaceutically acceptable salt thereof and an aromatase inhibitor for use in a method according to any one of claims 117 to 216.

218. Use of ribociclib or a pharmaceutically acceptable salt thereof and an aromatase inhibitor in the manufacture of a pharmaceutical product for the treatment of HR+ / HER2- stage II or III early breast cancer in adult patients, wherein the pharmaceutical product is administered by the method according to any one of claims 117 to 216.

219. A kit for carrying out a method for treating HR+ / HER2- stage II or stage III early breast cancer in adult patients according to any one of claims 117 to 216.

220. A method for treating an adult patient diagnosed with HER+ / HER2- stage II or stage III early breast cancer, comprising administering to the patient an adjuvant therapy comprising (i) a dose of ribociclib ranging from 150 mg / day to 450 mg / day administered on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle, wherein the method improves one or more of the patient's overall survival (OS), distant disease-free survival (DDFS), or recurrence-free survival (RFS).

221. A method for improving one or more of the overall survival (OS), distant disease-free survival (DDFS), or recurrence-free survival (RFS) of a patient diagnosed with HR+ / HER2- stage II or stage III early breast cancer, comprising administering to the patient an adjuvant treatment comprising (i) ribociclib in a dose ranging from 150 mg / day to 450 mg / day administered on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle.

222. A method for reducing the risk of local or regional invasive recurrence of early breast cancer in adult patients diagnosed with HR+ / HER2- stage II or stage III early breast cancer, comprising administering to the patient an adjuvant therapy comprising (i) ribociclib in a dose ranging from 150 mg / day to 450 mg / day administered on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle.

223. A method for reducing the risk of invasive recurrence of early breast cancer in one or more of the bone, liver, lungs, or pleura of an adult patient diagnosed with HR+ / HER2- stage II or stage III early breast cancer, comprising administering to the patient an adjuvant treatment comprising (i) ribociclib in a dose ranging from 150 mg / day to 450 mg / day on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle.

224. The method according to any one of claims 220 to 223, wherein the treatment is administered regardless of the lymph node status of the breast cancer.

225. A method for reducing the risk of early breast cancer recurrence in an adult patient diagnosed with HR+ / HER2- stage II or stage III early breast cancer, comprising administering to the patient an adjuvant treatment comprising (i) ribociclib in a dose ranging from 150 mg / day to 450 mg / day on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle, wherein the treatment is administered regardless of the lymph node status of the breast cancer.

226. The method according to any one of claims 220 to 225, wherein the breast cancer has a lymph node state of N0, N1, N2, or N3.

227. The method according to claim 226, wherein the breast cancer has a lymph node state of N0.

228. The method according to any one of claims 220 to 227, wherein the early-stage breast cancer is stage II, for example, stage IIA.

229. The method according to any one of claims 220 to 227, wherein the early-stage breast cancer is stage III, for example, stage IIIB or IIIC.

230. The method according to any one of claims 220 to 229, wherein the breast cancer is a subtype of ductal carcinoma.

231. The method according to any one of claims 220 to 230, wherein the patient is of Asian descent.

232. The method according to any one of claims 220 to 231, wherein the method is an adjuvant treatment 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 according to claim 232, wherein the patient has never undergone a mastectomy.

234. The method according to any one of claims 220 to 233, wherein the dose of ribociclib is 400 mg / day.

235. The method according to any one of claims 220 to 234, wherein the ribociclib is administered in the form of a salt, preferably as ribociclib succinate.

236. The method according to any one of claims 220 to 235, wherein the aromatase inhibitor is letrozole or anastrozole.

237. The method according to claim 236, wherein the aromatase inhibitor is letrozole, preferably administered at a dose of 2.5 mg / day.

238. The method according to claim 236, wherein the aromatase inhibitor is anastrozole, preferably administered at a dose of 1 mg / day.

239. The method according to any one of claims 220 to 238, wherein the dose of ribociclib is 400 mg / day, the ribociclib is administered in the form of ribociclib succinate, and the aromatase inhibitor is letrozole or anastrozole, preferably 2.5 mg / day of letrozole or 1 mg / day of anastrozole.

240. The method according to any one of claims 220 to 239, wherein improvement in OS, DDFS and / or RFS, or reduction in the risk of breast cancer recurrence, is achieved in the patient for at least 36 months.

241. Ribociclib for use in a method to improve one or more of the overall survival (OS), distant disease-free survival (DDFS), or recurrence-free survival (RFS) of an adult patient diagnosed with HR+ / HER2- stage II or stage III early breast cancer, wherein the method comprises administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg / day to 450 mg / day administered on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle.

242. A method for reducing the risk of local or regional invasive recurrence of early breast cancer in adult patients diagnosed with HR+ / HER2- stage II or stage III early breast cancer, comprising administering to the patient an adjuvant therapy comprising (i) ribociclib in doses ranging from 150 mg / day to 450 mg / day administered on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle, ribociclib for use in the method.

243. A method for reducing the risk of invasive recurrence of early breast cancer in one or more of the bone, liver, lungs, or pleura of an adult patient diagnosed with HR+ / HER2- stage II or stage III early breast cancer, comprising administering to the patient an adjuvant treatment comprising (i) ribociclib in doses ranging from 150 mg / day to 450 mg / day administered on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle, ribociclib for use in the method.

244. Ribociclib for use according to any one of claims 241 to 243, wherein the treatment is administered regardless of the lymph node status of the breast cancer.

245. A method for reducing the risk of early breast cancer recurrence in adult patients diagnosed with HR+ / HER2- stage II or stage III early breast cancer, comprising administering to the patient an adjuvant treatment comprising (i) a dose of ribociclib ranging from 150 mg / day to 450 mg / day administered on days 1 to 21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle, wherein the treatment is administered regardless of the lymph node status of the breast cancer, and ribociclib for use in the method.

246. Ribociclib for use according to any one of claims 241 to 245, wherein the breast cancer has a lymph node status of N0, N1, N2, or N3.

247. The ribociclib for use according to claim 246, wherein the breast cancer has a lymph node state of N0.

248. Ribociclib for use according to any one of claims 241 to 247, wherein the early-stage breast cancer is stage II, such as stage IIA.

249. Ribociclib for use according to any one of claims 241 to 247, wherein the early-stage breast cancer is stage III, such as stage IIIIB or IIIC.

250. Ribociclib for use according to any one of claims 241 to 249, wherein the breast cancer is a ductal carcinoma 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 an adjuvant treatment 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 never undergone a mastectomy.

254. Ribociclib for use according to any one of claims 241 to 253, wherein the dose of ribociclib is 400 mg / 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 as ribociclib succinate.

256. Ribociclib for use according to any one of claims 241 to 255, wherein the aromatase inhibitor is letrozole or anastrozole.

257. The ribociclib for use according to claim 256, wherein the aromatase inhibitor is letrozole, preferably administered at a dose of 2.5 mg / day.

258. The ribociclib for use according to claim 256, wherein the aromatase inhibitor is anastrozole, preferably administered at a dose of 1 mg / day.

259. Ribociclib for use according to any one of claims 241 to 258, wherein the dose of ribociclib is 400 mg / day, the ribociclib is administered in the form of ribociclib succinate, and the aromatase inhibitor is letrozole or anastrozole, preferably 2.5 mg / day of letrozole or 1 mg / day of anastrozole.

260. Ribociclib for use according to any one of claims 241 to 259, wherein improvement of OS, DDFS and / or RFS, or reduction of the risk of breast cancer recurrence, is achieved in the patient for at least 36 months.

261. A method for 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 has no signs or symptoms of cancer, comprising administering to the patient an adjuvant treatment comprising: (i) a dose of ribociclib succinate to a total dose of 400 mg / day of ribociclib administered on days 1 to 21 of a 28-day cycle; and (ii) a dose of either 2.5 mg / day of letrozole or 1 mg / day of anastrozole administered daily during the 28-day cycle.

262. The adjuvant therapy comprises a dose of 2.5 mg / day of letrozole, ribociclib succinate for use according to claim 261.

263. The adjuvant therapy comprises a dose of 1 mg / day of anastrozole, wherein the adjuvant therapy comprises ribociclib succinate for use according to claim 261.

264. Ribociclib 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. The ribociclib succinate for use according to claim 264, wherein the breast cancer has a lymph node state of N0.

266. The ribociclib succinate for use according to any one of claims 261 to 265, wherein the early-stage breast cancer is stage II, such as stage IIA.

267. The ribociclib succinate for use according to any one of claims 261 to 265, wherein the early-stage breast cancer is stage III, such as stage IIIB.

268. Ribociclib succinate for use according to any one of claims 261 to 265, wherein the early-stage breast cancer is stage III, such as IIC.

269. Ribociclib succinate for use according to any one of claims 261 to 268, wherein the breast cancer is a ductal carcinoma subtype.

270. Ribociclib succinate for use according to any one of claims 261 to 269, wherein the patient is of Asian descent.

271. Ribociclib succinate for use according to any one of claims 261 to 270, wherein the method is an adjuvant treatment because 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. Ribociclib succinate for use according to claim 271, wherein the patient has never undergone a mastectomy.

273. Ribociclib succinate for use according to any one of claims 261 to 272, wherein the method improves the patient's overall survival (OS), distant disease-free survival (DDFS), and / or recurrence-free survival (RFS) of the breast cancer for at least 36 months; or the method reduces the patient's risk of recurrence of the breast cancer for at least 36 months.

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

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

276. A method for treating cancer in an adult patient requiring treatment for HR+ / HER2- stage II or stage III early breast cancer, comprising: (i) administering to the patient 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 to 21 of a 28-day cycle; and (ii) administering to the patient daily during the 28-day cycle an aromatase inhibitor, preferably letrozole or anastrozole.

277. The method according to any one of claims 274 to 276, wherein the ribociclib is a pharmaceutically acceptable ribociclib salt.

278. The method according to claim 277, wherein the ribociclib salt is ribociclib succinate.

279. The method according to any one of claims 274, 275, 277, and 278, wherein the dose of ribociclib is not 600 mg / day.

280. The method according to any one of claims 274 to 278, wherein the dose of ribociclib is 200 mg / day or 400 mg / day.

281. The method according to claim 280, wherein ribociclib is administered as ribociclib succinate, and the total dose of ribociclib is 200 mg / day.

282. The method according to claim 280, wherein ribociclib is administered as ribociclib succinate, and the total dose of ribociclib is 400 mg / day.

283. The method according to claim 280, wherein the ribociclib is administered at a dose of 400 mg / day over a certain period, and thereafter at a dose of 200 mg / day of ribociclib.

284. The method according to any one of claims 274 to 283, wherein the aforementioned dose of ribociclib is administered orally.

285. The method according to any one of claims 274 to 284, wherein the dose of ribociclib is administered in tablet form.

286. The method according to any one of claims 274 to 285, wherein the aromatase inhibitor is letrozole or anastrozole.

287. The method according to any one of claims 274 to 286, wherein the aromatase inhibitor is administered orally.

288. The method according to claim 286 or 287, wherein the letrozole is administered in a dose ranging from 1 mg / day to 4 mg / day.

289. The method according to claim 288, wherein the letrozole is administered at a dose of 2.5 mg / day.

290. The method according to claim 286 or 287, wherein the anastrozole is administered in a dose ranging from 0.5 mg / day to 1.5 mg / day.

291. The method according to claim 290, wherein the anastrozole is administered at a dose of 1 mg / day.

292. A method for treating recurrent breast cancer in an adult patient who has received at least one prior treatment for HR+ / HER2- stage II or III early breast cancer and who does not have any detectable signs or symptoms of breast cancer, the method comprising administering to the patient an adjuvant treatment comprising: (i) a dose of ribociclib succinate to a total dose of 400 mg / day of ribociclib administered on days 1 to 21 of a 28-day cycle; and (ii) a dose of either 2.5 mg / day of letrozole or 1 mg / day of anastrozole administered daily during the 28-day cycle.

293. A method for treating an adult patient in remission from HR+ / HER2- stage II or stage III early breast cancer who requires adjuvant therapy, the method comprising administering to the patient an adjuvant therapy comprising: (i) a dose of ribociclib succinate to a total dose of 400 mg / day of ribociclib administered on days 1 to 21 of a 28-day cycle; and (ii) a dose of either 2.5 mg / day of letrozole or 1 mg / day of anastrozole administered daily during the 28-day cycle.

294. The method according to any one of claims 274 to 293, wherein the treatment further comprises administering a gonadotropin-releasing hormone agonist.

295. The method according to claim 294, wherein the gonadotropin-releasing hormone agonist is goserelin.

296. The method according to claim 295, wherein goserelin is administered in a dose in the range of 2 mg to 5 mg.

297. The method according to claim 296, wherein the dose of goserelin is 3.6 mg.

298. The method according to any one of claims 294 to 297, wherein goserelin is administered subcutaneously.

299. The method according to any one of claims 294 to 298, wherein goserelin is administered once every four weeks.

300. The method according to any one of claims 274 to 299, wherein the patient is a postmenopausal woman.

301. The method according to any one of claims 274 to 293, wherein the patient is a premenopausal woman or a man.

302. The method according to any one of claims 274 to 301, wherein the treatment is administered to the patient for at least 12 months.

303. The method according to claim 302, wherein the treatment is administered to the patient for at least 24 months.

304. The method according to claim 302 or 303, wherein the treatment is administered to the patient for at least 36 months.

305. The method according to any one of claims 302 to 304, wherein the treatment is administered to the patient for at least 48 months.

306. The method according to any one of claims 302 to 305, wherein the treatment is administered to the patient for at least 60 months.

307. The method according to any one of claims 274 to 306, wherein the breast cancer is ER+ and PR+.

308. The method according to any one of claims 274 to 306, wherein the breast cancer is ER- and PR-+.

309. The method according to any one of claims 274 to 306, wherein the breast cancer is ER+ and PR-.

310. The method according to any one of claims 274 to 309, wherein the breast cancer has a histological subtype of ductal carcinoma.

311. The method according to any one of claims 274 to 310, wherein the breast cancer has a histological subtype of lobular carcinoma.

312. The method according to any one of claims 274 to 311, wherein the breast cancer is stage IIA cancer or stage IIB cancer.

313. The method according to claim 312, wherein the breast cancer is stage IIA cancer.

314. The method according to claim 312, wherein the breast cancer is stage IIB cancer.

315. The method according to any one of claims 274 to 311, wherein the breast cancer is stage IIIA cancer, stage IIIB cancer, or stage IIIC cancer.

316. The method according to claim 315, wherein the breast cancer is stage IIIA cancer.

317. The method according to claim 315, wherein the breast cancer is stage IIIB cancer.

318. The method according to claim 315, wherein the breast cancer is stage IIIC cancer.

319. The method according to any one of claims 274 to 318, wherein the treatment is administered regardless of the lymph node status of the breast cancer.

320. The method according to any one of claims 274 to 319, wherein the breast cancer has a lymph node state selected from N0, N1, N2, and N3.

321. The method according to claim 319 or 320, wherein the breast cancer has a lymph node state of N0.

322. The method according to claim 319 or 320, wherein the breast cancer has lymph node status N1 to N3.

323. The method according to claim 319 or 320, wherein the breast cancer has a lymph node state of N1.

324. The method according to claim 319 or 320, wherein the breast cancer has a lymph node state of N2.

325. The method according to claim 319 or 320, wherein the breast cancer has a lymph node state of N3.

326. The method according to any one of claims 274 to 325, wherein the breast cancer comprises one or more cells having a histological grade selected from G1, G2, or G3.

327. The method according to claim 326, wherein the breast cancer comprises one or more cells having the histological grade G1.

328. The method according to claim 326, wherein the breast cancer comprises one or more cells having the histological grade G2.

329. The method according to claim 326, wherein the breast cancer comprises one or more cells having the histological grade G3.

330. The method according to any one of claims 274 to 329, wherein the breast cancer includes tumors of classification T0, T1, T2, T3, or T4.

331. The method according to claim 330, wherein the breast cancer includes tumors of classification T1, T2, or T3.

332. The method according to claim 330, wherein the breast cancer includes a tumor of classification T0.

333. The method according to claim 330 or 331, wherein the breast cancer includes a tumor of classification T1.

334. The method according to claim 330 or 331, wherein the breast cancer includes a tumor of classification T2.

335. The method according to claim 330 or 331, wherein the breast cancer includes a tumor of classification T3.

336. The method according to claim 330, wherein the breast cancer includes a tumor of classification T4.

337. The method according to any one of claims 274 to 336, wherein the breast cancer has a Ki67 status of 20 or less.

338. The method according to any one of claims 274 to 336, wherein the breast cancer has a Ki67 status higher than 20.

339. The method according to any one of claims 274 to 338, wherein prior to the administration, the patient had received a loading dose of (i) ribociclib and / or (ii) endocrine therapy.

340. The method according to 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 according to claim 292 or 340, wherein the prior treatment is an adjuvant treatment following another prior treatment.

342. The method according to claim 340 or 341, wherein the prior treatment is a surgical procedure.

343. The method according to claim 342, wherein the surgical procedure includes complete surgical resection of the cancer.

344. The method according to claim 342 or 343, wherein the surgical procedure is a mastectomy.

345. The method according to claim 340 or 341, wherein the prior treatment is chemotherapy.

346. The method according to claim 345, wherein the prior treatment is adjuvant chemotherapy.

347. The method according to claim 345, wherein the prior treatment is neoadjuvant chemotherapy.

348. The method according to claim 340 or 341, wherein the prior treatment is endocrine therapy.

349. The method according to claim 340 or 341, wherein the prior treatment is radiotherapy.

350. The method according to any one of claims 292 and 340-349, wherein the prior treatment was ineffective in the patient.

351. The method according to any one of claims 274 to 350, wherein the patient resides in a geographical area selected from North America, Western Europe, or Oceania.

352. The method according to any one of claims 274 to 351, wherein the patient is of Asian descent.

353. The method according to any one of claims 274 to 352, wherein the patient is between 18 and 45 years of age.

354. The method according to any one of claims 274 to 352, wherein the patient is 45 to 54 years old.

355. The method according to any one of claims 274 to 352, wherein the patient is between 54 and 64 years old.

356. The method according to any one of claims 274 to 352, wherein the patient is over 64 years of age.

357. The method according to any one of claims 274 to 357, wherein the patient has a BMI of 25 or more.

358. The method according to any one of claims 274 to 357, wherein the patient has a BMI of less than 25.

359. The method according to any one of claims 274 to 358, wherein the treatment improves the patient's condition compared to a patient who has not received the treatment and / or compared to the patient's condition before the treatment.

360. The method according to any one of claims 274 to 359, wherein the treatment reduces the risk of invasive disease.

361. The method according to claim 360, wherein the treatment reduces the risk of invasive disease, and when the risk is calculated compared to a patient who has not received the treatment, the hazard ratio corresponds to less than 1.

362. The method according to claim 361, wherein the treatment reduces the risk of invasive disease, and when the risk is calculated compared to a patient who has not received the treatment, the hazard ratio corresponds to 0.78 or less.

363. The method according to any one of claims 274 to 299 and 301 to 362, wherein the patient is a premenopausal woman or man, the treatment reduces the risk of invasive disease, and when the risk is calculated compared to a patient receiving the treatment, it corresponds to a hazard ratio of 0.72 or less.

364. The method according to any one of claims 360 to 362, wherein the cancer is HR+ / HER2- stage III early breast cancer, the treatment reduces the risk of invasive disease, and the hazard ratio when the risk is calculated compared to a patient who has not received the treatment corresponds to 0.74 or less.

365. The method according to any one of claims 360 to 362, wherein the cancer is HR+ / HER2- stage II early breast cancer, the treatment reduces the risk of invasive disease, and the hazard ratio when the risk is calculated compared to a patient who has not received the treatment corresponds to 0.76 or less.

366. The method according to any one of claims 360 to 362, wherein the cancer is HR+ / HER2- stage III early breast cancer, the treatment results in at least a 25% reduction in the risk of invasive disease, and when the risk is calculated compared to a patient who has not received the treatment, it corresponds to a hazard ratio of 0.

75.

367. The method according to any one of claims 360 to 366, wherein the treatment reduces the risk of invasive disease to the same level as that of a subgroup of patients including patients with stage II early breast cancer, stage III early breast cancer, patients who are premenopausal women or men, and patients who are postmenopausal women.

368. The method according to any one of claims 274 to 367, wherein the treatment does not result in a deterioration of overall survival, and the hazard ratio when the risk is calculated compared to a patient who does not receive the treatment corresponds to 0.

76.

369. The method according to any one of claims 274 to 368, wherein the treatment reduces and / or prevents one or more risks of cancer recurrence, cancer spread, development and / or proliferation of additional cancers, and death from cancer.

370. The method according to claim 369, wherein the treatment reduces cancer recurrence, and the recurrence is one or more of invasive ipsilateral breast tumor (IBTR) recurrence, locally invasive recurrence, and distant recurrence.

371. The method according to claim 369, wherein the treatment reduces the spread of cancer, and the spread of cancer is invasive contralateral breast cancer or additional primary invasive cancer.

372. The method according to any one of claims 274 to 371, wherein the treatment prevents death from cancer.

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