Novel method for treating residual breast cancer by using trastuzumab metane

Abstract

The present invention relates to a method for treating a patient suffering from HER2-positive early breast cancer with the antibody-drug conjugate trastuzumab-mesan new conjugate (T-DM1), wherein the patient has a residual disease following preoperative systemic treatment.

Description

[0001] This application is a divisional application of the invention application with the application date of April 24, 2019, the Chinese application number of 201980067942.2, and the invention name of "Method of treating residual breast cancer with trastuzumab emtansine".

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 745,914, filed on October 15, 2018, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0004] The present disclosure relates to methods of treating residual breast cancer using trastuzumab emtansine (T-DM1). Background Art

[0005] Breast cancer is a highly important cause of morbidity and mortality worldwide. More than 1.3 million cases of breast cancer are diagnosed worldwide each year, and the number of deaths related to the disease exceeds 450,000 (Jemal A, Bray F, Center M, et al., Global cancer statistics. CA Cancer J Clin, 2011; 61(2): 69-90).

[0006] HER2 (ErbB2) receptor tyrosine kinase is a member of the epidermal growth factor receptor (EGFR) family of transmembrane receptors. In about 20% of human breast cancer (hereinafter referred to as HER2-positive breast cancer), HER2 overexpression is observed, and the invasive growth associated with these tumors is associated with poor clinical prognosis (Slamon et al., (1987) Science 235:177-182). HER2 protein overexpression can be determined using the assessment of fixed tumor blocks based on immunohistochemistry (Press MF, et al., (1993) Cancer Res 53:4960-70).

[0007] Trastuzumab (CAS180288-69-1, huMAb4D5-8, rhuMAb HER2, Genentech) is a recombinant DNA-derived IgG1κ monoclonal antibody, which is a humanized form of a murine anti-HER2 antibody (4D5) that selectively binds to the extracellular domain of HER2 with high affinity (Kd=5 nM) in cell-based assays (US5677171; US5821337; US6054297; US6165464; US6339142; US6407213; US6639055; US6719971; US6800738; US7074404; Coussens et al., (1985) Science 230:1132-9; Slamon et al., (1989) Science 244:707-12; Slamon et al., (2001) New Engl. J. Med. 344:783-792). Trastuzumab has been shown to inhibit the proliferation of human tumor cells overexpressing HER2 in both in vitro assays and in animals (Hudziak et al., (1989) Mol Cell Biol 9:1165-72; Lewis et al., (1993) Cancer Immunol Immunother; 37:255-63; Baselga et al., (1998) Cancer Res. 58:2825-2831). Trastuzumab is a mediator of antibody-dependent cellular cytotoxicity (ADCC) (Lewis et al., (1993) Cancer Immunol Immunother 37(4):255-263; Hotaling et al., (1996) Proc. Annual Meeting Am Assoc Cancer Res;37:471; Pegram MD, et al., (1997) [Proc Am Assoc Cancer Res;38:602; Sliwkowski et al., (1999) Seminars in Oncology 26(4), Suppl 12:60-70; Yarden Y. and Sliwkowski, M. (2001) Nature Reviews: Molecular Cell Biology, Macmillan Magazines, Ltd., Vol. 2:127-137).

[0008] It was approved in 1998 for the treatment of patients with metastatic breast cancer that overexpresses HER2 who have been treated with a wide range of existing anticancer therapies (Baselga et al., (1996) J. Clin. Oncol. 14:737-744) and has since been used in more than 300,000 patients (Slamon DJ, et al., N Engl J Med 2001;344:783-92; Vogel CL, et al., J Clin Oncol 2002;20:719-26; Marty M, et al., J Clin Oncol 2005;23:4265-74; Romond EH, et al., TN Engl J Med 2005;353:1673-84; Piccart-Gebhart MJ, et al., N Engl J Med 2005;353:1659-72; Slamon D, et al., Breast Cancer Res Treat 2006, 100 (Suppl 1): 52). In 2006, FDA approved (Trastuzumab, Genentech Inc.) is indicated for the adjuvant treatment of patients with HER2-positive, node-positive breast cancer as part of a treatment regimen that includes doxorubicin, cyclophosphamide, and paclitaxel.

[0009] Another approach to antibody-targeted therapy is to use antibodies to deliver cytotoxic drugs specifically to cancer cells that express antigens. Antibody-drug conjugates or ADCs are monoclonal antibodies that have been coupled to highly potent cytotoxic agents. ADCs represent a novel approach to confer tumor selectivity to systemically administered anti-tumor therapeutics. ADCs are designed to deliver highly potent cytotoxic agents to tumor cells using tumor-specific and / or overexpressed surface antigens. The potential of this approach is to create a more favorable therapeutic window for such agents than that obtained by administering them as free drugs.

[0010] Maytansinoids, derivatives of the antimitotic drug maytansine, bind to microtubules in a manner similar to vinca alkaloids (Issell BF et al., (1978) Cancer Treat. Rev. 5: 199-207; Cabanillas F et al., (1979) Cancer Treat Rep, 63: 507-9). DM1 is a thiol-containing maytansine alkaloid derived from the naturally occurring ester anatomycin P3 (Remillard S, Rebhun LI, Howie GA, et al., (1975) Science 189(4207): 1002-1005.3; Cassady JM, Chan KK, Floss HG. (2004) Chem Pharm Bull 52(1): 1-26.4). The related phytoester maytansine has been used as a chemotherapeutic agent in approximately 800 patients at a dose of 2.0 mg / m every 3 weeks. 2 The administration of maytansine was studied with a single administration or for 3 consecutive days (Issell BF, Crooke ST. (1978) Maytansine. Cancer Treat Rev 5: 199-207). Despite preclinical activity, the activity of maytansine in the clinic is modest at doses that can be safely delivered. Dose-limiting toxicity (DLT) is gastrointestinal disease, including nausea, vomiting and diarrhea (usually followed by constipation). These toxicities are dose-related but not schedule-related. Peripheral neuropathy (mainly paresthesia) is reported to be most pronounced in patients with neuropathy. Subclinical transient increases in liver transaminases, alkaline phosphatase and total bilirubin are reported. Constitutional toxicity is common, including weakness, drowsiness, irritability and insomnia. Less common toxicities include infusion-site phlebitis and mild bone marrow suppression. Due to the narrow therapeutic window, further development of the drug was abandoned in the 1980s.

[0011] Trastuzumab emtansine conjugates (T-DM1, trastuzumab-MCC-DM1, ado-trastuzumab emtansine conjugates, ) is a novel antibody-drug conjugate (ADC) for the treatment of HER2-positive breast cancer, which consists of the cytotoxic agent DM1 (a thiol-containing maytansine alkaloid anti-microtubule agent) conjugated to trastuzumab on the lysine side chain via an MCC linker, with an average drug loading (drug to antibody ratio) of approximately 3.5. After binding to HER2 expressed on tumor cells, T-DM1 undergoes receptor-mediated internalization, leading to the intracellular release of cytotoxic catabolites containing DM1 and subsequent cell death.

[0012] Currently, patients with HER2-positive early breast cancer who do not achieve a pathological complete response to neoadjuvant therapy consisting of standard chemotherapy and HER2-targeted therapy have a significantly higher risk of disease recurrence and significantly reduced survival compared with those who do achieve a pathological complete response. In HER2-positive patients, achieving a pathological complete response is associated with a 62% to 73% reduction in the risk of invasive disease or death and a 65% reduction in the risk of death from any cause after 3 years (Schneeweiss 2018; de Azambuja Lancet Oncol 2014; Gianni Lancet Oncol 2014). However, only approximately 30% to 40% of these patients achieve a pathological complete response (Schneeweiss 2018; de Azambuja Lancet Oncol 2014; Gianni Lancet Oncol 2014; Untch JCO 2011). Therefore, there remains an unmet medical need for treating those cancer patients who do not achieve a pathological complete response to neoadjuvant therapy. Summary of the invention

[0013] The present disclosure generally relates to methods of treating breast cancer patients using the antibody-drug conjugate trastuzumab emtansine (T-DM1).

[0014] In one aspect, the present disclosure relates to a method of adjuvant therapy, the method comprising administering an effective amount of trastuzumab emtansine conjugate (T-DM1) as a monotherapy to a patient with HER2-positive early breast cancer, wherein the patient has residual disease after preoperative systemic treatment. In certain embodiments, the residual disease is present in the breast, lymph nodes, or in the breast and lymph nodes. In certain embodiments, preoperative systemic treatment includes HER2 targeted therapy, such as trastuzumab. In certain embodiments, HER2 targeted therapy also includes pertuzumab, lapatinib, neratinib, dacomitinib and / or afatinib. In certain embodiments, HER2 targeted therapy includes trastuzumab and pertuzumab. In certain embodiments, HER2 targeted therapy includes trastuzumab and also includes an agent selected from lapatinib, neratinib, dacomitinib and afatinib. In certain embodiments, preoperative systemic treatment also includes taxanes. In certain embodiments, the patient is an adult patient. In certain embodiments, definitive surgery is performed on the patient before administering T-DM1. In certain embodiments, T-DM1 is administered to the patient no more than 12 weeks after definitive surgery. In certain embodiments, the patient has completed at least 16 weeks of preoperative systemic treatment with a taxane-containing chemotherapy regimen and HER2-targeted therapy. In certain embodiments, the patient has completed at least 6 cycles of taxane-containing chemotherapy. In certain embodiments, T-DM1 is administered to the patient at a dose of 3.6 mg / kg every 3 weeks. In certain embodiments, T-DM1 is administered to the patient at a dose of 3.6 mg / kg every 3 weeks for fourteen cycles. In certain embodiments, adjuvant therapy significantly increases invasive disease-free survival (IDFS) compared to adjuvant therapy using trastuzumab. In certain embodiments, adjuvant therapy reduces the risk of recurrence of invasive disease by 50% compared to adjuvant therapy using trastuzumab. In certain embodiments, adjuvant therapy results in a reduction in distant recurrence compared to adjuvant therapy using trastuzumab. In certain embodiments, adjuvant therapy reduces the risk of distant recurrence by 40% compared to adjuvant trastuzumab.

[0015] On the one hand, the present disclosure relates to trastuzumab emtansine conjugate (T-DM1), which is used in the adjuvant treatment of HER2-positive early breast cancer in patients, wherein the adjuvant therapy is a monotherapy, and wherein the patient has residual disease after preoperative systemic treatment. In certain embodiments, the residual disease is present in the breast, in the lymph nodes, or in the breast and lymph nodes. In certain embodiments, preoperative systemic treatment includes HER2 targeted therapy. In certain embodiments, HER2 targeted therapy includes trastuzumab. In certain embodiments, HER2 targeted therapy also includes pertuzumab, lapatinib, neratinib, dacomitinib and / or afatinib. In certain embodiments, HER2 targeted therapy includes trastuzumab and pertuzumab. In certain embodiments, HER2 targeted therapy includes trastuzumab, and also includes an agent selected from lapatinib, neratinib, dacomitinib and afatinib. In certain embodiments, preoperative systemic therapy also includes taxanes. In certain embodiments, the patient is an adult patient. In certain embodiments, definitive surgery is performed on the patient before administering T-DM1. In certain embodiments, adjuvant therapy significantly increases invasive disease-free survival (IDFS) compared to adjuvant therapy with trastuzumab. In certain embodiments, adjuvant therapy reduces the risk of invasive disease recurrence by 50% compared to adjuvant therapy with trastuzumab. In certain embodiments, adjuvant therapy leads to a reduction in distant recurrence compared to adjuvant therapy with trastuzumab. In certain embodiments, adjuvant therapy reduces the risk of distant recurrence by 40% compared to adjuvant trastuzumab.

[0016] On the one hand, the present disclosure relates to the use of trastuzumab emtansine conjugate (T-DM1) in the preparation of a drug for adjuvant therapy of HER2-positive early breast cancer for a patient, wherein the adjuvant therapy is a monotherapy, and wherein the patient has residual disease after preoperative systemic treatment. In certain embodiments, the residual disease is present in the breast, in the lymph nodes, or in the breast and lymph nodes. In certain embodiments, preoperative systemic treatment includes HER2 targeted therapy. In certain embodiments, HER2 targeted therapy includes trastuzumab. In certain embodiments, HER2 targeted therapy also includes pertuzumab, lapatinib, neratinib, dacomitinib and / or afatinib. In certain embodiments, HER2 targeted therapy includes trastuzumab and pertuzumab. In certain embodiments, HER2 targeted therapy includes trastuzumab, and also includes an agent selected from lapatinib, neratinib, dacomitinib and afatinib. In certain embodiments, preoperative systemic therapy also includes taxanes. In certain embodiments, the patient is an adult patient. In certain embodiments, definitive surgery is performed on the patient before administering T-DM1. In certain embodiments, adjuvant therapy significantly increases invasive disease-free survival (IDFS) compared to adjuvant therapy with trastuzumab. In certain embodiments, adjuvant therapy reduces the risk of invasive disease recurrence by 50% compared to adjuvant therapy with trastuzumab. In certain embodiments, adjuvant therapy leads to a reduction in distant recurrence compared to adjuvant therapy with trastuzumab. In certain embodiments, adjuvant therapy reduces the risk of distant recurrence by 40% compared to adjuvant trastuzumab.

[0017] In one aspect, the present disclosure relates to a method for treating breast cancer in a patient with HER2-positive early breast cancer who has residual disease in the breast or axillary lymph nodes after neoadjuvant therapy with chemotherapy and HER2-targeted therapy, the method comprising (i) removing all clinically significant tumor cells in the breast and axillary lymph nodes by definitive surgery; (ii) subjecting the patient to adjuvant therapy with T-DM1 in the absence of prior or concurrent adjuvant therapy with chemotherapy. In certain embodiments, the patient has residual disease in the breast or axillary lymph nodes after neoadjuvant therapy with taxanes and HER2-targeted therapy. In certain embodiments, the patient has completed at least 16 weeks of neoadjuvant therapy with a taxane-containing chemotherapy regimen and a HER2-targeted therapy. In certain embodiments, the patient has completed at least 6 cycles of a taxane-containing chemotherapy regimen. In certain embodiments, the patient is subjected to adjuvant therapy with T-DM1 no more than 12 weeks after definitive surgery. In certain embodiments, definitive surgery is performed at least 14 days after completion of neoadjuvant therapy. In certain embodiments, definitive surgery is performed no later than 9 weeks after completion of neoadjuvant therapy. In certain embodiments, the patient is treated with adjuvant therapy with T-DM1 infusion at a dosage of 3.6 mg / kg every 3 weeks. In certain embodiments, the patient is treated with fourteen cycles of adjuvant therapy with T-DM1 infusion at a dosage of 3.6 mg / kg every 3 weeks. In certain embodiments, compared with the adjuvant therapy using trastuzumab, the treatment significantly increases invasive disease-free survival (IDFS). In certain embodiments, compared with the adjuvant therapy using trastuzumab, treatment reduces distant recurrence. In certain embodiments, compared with the adjuvant therapy using trastuzumab, adjuvant therapy reduces the risk of invasive disease recurrence by 50%. In certain embodiments, compared with adjuvant trastuzumab, adjuvant therapy reduces the risk of distant recurrence by 40%.

[0018] In one aspect, the present disclosure relates to a method for treating breast cancer in a patient with HER2-positive early breast cancer who has residual disease after neoadjuvant therapy, the method comprising administering an effective amount of T-DM1 to the patient after the patient has undergone definitive surgery. In one aspect, the residual disease is pathological residual invasive disease. In certain embodiments, the residual disease is pathological residual invasive disease in the breast and / or axillary lymph nodes. In certain embodiments, the method does not include prior or concurrent adjuvant therapy with chemotherapy. In certain embodiments, the neoadjuvant therapy comprises a taxane and a HER2-targeted therapy. In certain embodiments, the neoadjuvant therapy comprises a taxane and trastuzumab. In certain embodiments, the patient has completed at least 16 weeks of neoadjuvant therapy. In certain embodiments, the patient has completed at least 6 cycles of neoadjuvant chemotherapy containing a taxane. In certain embodiments, the patient is treated with T-DM1 no more than 12 weeks after definitive surgery. In certain embodiments, definitive surgery is performed at least 14 days after completion of neoadjuvant therapy. In certain embodiments, definitive surgery is performed no later than 9 weeks after completion of neoadjuvant therapy. In certain embodiments, the patient is treated with a T-DM1 infusion at a dosage of 3.6 mg / kg every 3 weeks. In certain embodiments, the patient is treated with a T-DM1 infusion at a dosage of 3.6 mg / kg every 3 weeks for fourteen cycles. In certain embodiments, treatment significantly increases invasive disease-free survival (IDFS) compared to adjuvant therapy with trastuzumab. In certain embodiments, treatment reduces distant recurrence compared to adjuvant therapy with trastuzumab. In certain embodiments, adjuvant therapy reduces the risk of invasive disease recurrence by 50% compared to adjuvant therapy with trastuzumab. In certain embodiments, adjuvant therapy reduces the risk of distant recurrence by 40% compared to adjuvant trastuzumab.

[0019] In another aspect, the present disclosure relates to a method for reducing the risk of cancer recurrence in a patient with HER2-positive early breast cancer, comprising administering an effective amount of T-DM1 to the patient, wherein the patient has not achieved a pathological complete response to neoadjuvant therapy, and the patient has undergone definitive surgery prior to the administration of T-DM1. In certain embodiments, the method does not include prior or concurrent adjuvant therapy with chemotherapy. In certain embodiments, the neoadjuvant therapy comprises a taxane and a HER2-targeted therapy. In certain embodiments, the neoadjuvant therapy comprises a taxane and trastuzumab. In certain embodiments, the patient has completed at least 16 weeks of neoadjuvant therapy. In certain embodiments, the patient has completed at least 6 cycles of neoadjuvant therapy containing taxanes. In certain embodiments, the patient is treated with T-DM1 no more than 12 weeks after definitive surgery. In certain embodiments, definitive surgery is performed at least 14 days after completion of neoadjuvant therapy. In certain embodiments, definitive surgery is performed no later than 9 weeks after completion of neoadjuvant therapy. In certain embodiments, the patient is treated with T-DM1 infusions at a dose of 3.6 mg / kg every 3 weeks. In certain embodiments, the patient is treated with T-DM1 infusion at a dose of 3.6 mg / kg every 3 weeks for 14 cycles. In certain embodiments, the treatment significantly increases invasive disease-free survival (IDFS) compared to adjuvant therapy with trastuzumab. In certain embodiments, treatment reduces distant recurrence compared to adjuvant therapy with trastuzumab. In certain embodiments, adjuvant therapy reduces the risk of invasive disease recurrence by 50% compared to adjuvant therapy with trastuzumab. In certain embodiments, adjuvant therapy reduces the risk of distant recurrence by 40% compared to adjuvant trastuzumab. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 is a schematic diagram of the KATHERINE study design.

[0021] Figure 2A-2C A summary of the baseline characteristics of the treatment groups in the KATHERINE trial is described.

[0022] Figure 3 Kaplan–Meier plots of invasive-disease-free survival are depicted. Invasive-disease-free survival was defined as the time from randomization to the first occurrence of ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive disease recurrence, distant disease recurrence, contralateral invasive breast cancer, or death from any cause. CI denotes confidence interval; HR, hazard ratio.

[0023] Figure 4AKaplan-Meier plots are depicted for distant recurrence, defined as evidence of breast cancer at any anatomical site (excluding ipsilateral invasive breast tumor or recurrence of localized invasive breast cancer) with histological confirmation or clinical diagnosis of recurrent invasive breast cancer. No statistical adjustment was performed for multiple comparisons.

[0024] Figure 4B The site of the first invasive disease event among patients was summarized.

[0025] Figure 5 Secondary efficacy end points of the KATHERINE trial are summarized.

[0026] Fig. 6A and Figure 6B A forest plot of invasive disease-free survival is depicted. CI denotes confidence interval. Hormone receptor-negative indicates estrogen receptor (ER)-negative and progesterone receptor (PgR)-negative. Hormone receptor-positive indicates ER-positive, PgR-positive, or both. HER2 denotes human epidermal growth factor receptor. ICH denotes immunohistochemistry. IDFS denotes invasive disease-free survival. ISH denotes in situ hybridization.

[0027] Figure 7 The risk of a first invasive disease event due to neoadjuvant HER2-targeted therapy in the intention-to-treat population was summarized.

[0028] Figure 8 Kaplan–Meier plots of overall survival for the overall patient population are depicted. DETAILED DESCRIPTION

[0029] Reference will now be made in detail to certain embodiments of the present disclosure, examples of which are shown in the accompanying structures and formulas. Although the present disclosure is described in conjunction with the enumerated embodiments, it should be understood that they are not intended to limit the present disclosure to those embodiments. On the contrary, the present disclosure is intended to encompass all substitutions, modifications, and equivalents that may be included within the scope of the present disclosure as defined by the claims. Those skilled in the art will recognize that many methods and materials similar to or equivalent to the methods and materials described herein may be used in the practice of the present disclosure. The present disclosure is by no means limited to the methods and materials described.

[0030] All references cited throughout this disclosure are expressly incorporated herein by reference in their entirety. If one or more of the incorporated documents, patents, and similar materials differ or conflict with this application, including but not limited to defined terms, term usage, described techniques, or the like, this application shall prevail.

[0031] To make the disclosure clearer but not limiting, the specific implementation is divided into the following subsections:

[0032] I. Definitions;

[0033] Ⅱ. Trastuzumab emtansine conjugate;

[0034] III. Formulation of trastuzumab emtansine conjugate;

[0035] IV. Administration of trastuzumab emtansine conjugate;

[0036] V. Products; and

[0037] VI. Exemplary Embodiments.

[0038] I. definition

[0039] When used in the present specification and claims, the words "comprise", "comprising", "include", "including" and "comprises", "comprising", "includes", "including", "includes" are intended to specify the presence of stated features, integers, components or steps, but they do not exclude the presence or addition of one or more other features, integers, components, steps or groups thereof.

[0040] The terms "treat" and "treatment" refer to prophylactic or preventive treatment, wherein the purpose is to prevent or slow (mitigate) undesirable physiological changes or disorders, such as the growth, development or spread of hyperproliferative diseases (e.g., cancer). For the purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, symptom relief, alleviation of disease severity, stabilization of the disease state (i.e., no worsening), delayed or slowed disease progression, improvement or alleviation of the disease state, and relief (whether partial or complete relief), whether detectable or undetectable. "Treatment" may also mean an extension of survival compared to the expected survival without treatment. Individuals in need of treatment include individuals who already have a disease or illness, as well as those who are susceptible to the disease or illness or those who are to prevent the disease or illness.

[0041] The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by uncontrolled cell growth. A "tumor" comprises one or more cancer cells. Examples of cancer include, but are not limited to, carcinomas, lymphomas, blastomas, sarcomas, and leukemias or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinomas (e.g., epithelial squamous cell carcinomas); lung cancer, including small cell lung cancer, non-small cell lung cancer ("NSCLC"), lung adenocarcinomas, and lung squamous cell carcinomas; peritoneal cancer; hepatocellular carcinoma; gastric cancer, including gastrointestinal cancer; pancreatic cancer; glioblastoma; cervical cancer; ovarian cancer; liver cancer; bladder cancer; hepatoma; breast cancer; colon cancer; rectal cancer; colorectal cancer; endometrial or uterine cancer; salivary gland cancer; kidney cancer; prostate cancer; vulvar cancer; thyroid cancer; hepatic carcinoma; anal cancer; penile cancer; and head and neck cancer.

[0042] The term "early breast cancer (EBC)" or "early breast cancer" is used herein to refer to breast cancer that has not spread beyond the breast or axillary lymph nodes. This includes in situ and stage I, IIA, IIB, and IIIA breast cancer, as well as breast cancer that has progressed beyond stage IIIA but has not yet progressed to stage IV.

[0043] Reference to a tumor or cancer as "Stage 0," "Stage I," "Stage II," "Stage III," or "Stage IV," and various substages within this classification, refers to the classification of the tumor or cancer using either an overall staging or Roman numeral staging system known in the art. Although the actual stage of a cancer depends on the type of cancer, in general, Stage 0 cancers are in situ lesions, Stage I cancers are small localized tumors, Stage II and Stage III cancers are locally advanced tumors that demonstrate local lymph node involvement, and Stage IV cancers represent metastatic cancers. The specific stage of each type of tumor is known to the skilled clinician.

[0044] The term "metastatic breast cancer" refers to a condition in which cancer cells have traveled from the original site through blood or lymphatic vessels to one or more other locations in the body, forming one or more secondary tumors in one or more organs other than the breast.

[0045] "Advanced" cancer refers to cancer that has spread beyond the original site or organ, either due to local invasion or metastasis. Thus, the term "advanced" cancer includes both locally advanced and metastatic disease.

[0046] Even if anticancer agents (such as chemotherapy) are administered to a cancer patient, a "refractory" cancer may still progress. An example of a refractory cancer is a platinum-refractory cancer.

[0047] "Recurrent" cancer is cancer that has returned at the original site or at a distant site after responding to initial therapy (such as surgery).

[0048] "Locally recurrent" cancer is cancer that comes back after treatment in the same location as a previously treated cancer.

[0049] An "operable" or "resectable" cancer is one that is confined to a major organ and is amenable to surgery (removal).

[0050] As used herein, a "non-resectable" or "unresectable" cancer is a cancer that cannot be removed (resected) by surgery.

[0051] "HER2-positive" cancers include cancer cells with higher than normal levels of HER2. Examples of HER2-positive cancers include HER2-positive breast cancer and HER2-positive gastric cancer. Optionally, HER2-positive cancers have an immunohistochemistry (IHC) score of 2+ or 3+ and / or an in situ hybridization (ISH) amplification rate of ≥2.0.

[0052] In this context, a "patient" or "subject" is a human patient. The patient may be a "cancer patient", ie a patient suffering from or at risk of suffering from one or more symptoms of cancer, in particular symptoms of gastric cancer or breast cancer.

[0053] As used herein, a "patient population" refers to a group of cancer patients. Such a population can be used to demonstrate statistically significant efficacy and / or safety of a drug, such as Kadcyla.

[0054] As used herein, a "relapsed" patient is one that has signs or symptoms of cancer after remission. Optionally, the patient has relapsed after adjuvant or neoadjuvant therapy.

[0055] Patients with "residual disease" are those who have not achieved a pathological complete response (PCR) to therapy. In certain embodiments, the residual disease is pathological residual invasive disease in the breast and / or axillary lymph nodes.

[0056] A cancer or biological sample that "exhibits HER expression, amplification or activation" is a sample that expresses (including overexpressing) a HER receptor, amplifies a HER gene, and / or otherwise demonstrates HER receptor activation or phosphorylation in a diagnostic test.

[0057] As used herein, "neoadjuvant therapy" or "preoperative therapy" or "preoperative systemic therapy" refers to therapy given before surgery. The goal of neoadjuvant therapy is to provide immediate systemic therapy to potentially eliminate micrometastases that could otherwise spread if standard surgery followed by systemic therapy was followed. Neoadjuvant therapy can also help reduce the size of a tumor, allowing for complete resection of an initially unresectable tumor or preservation of some organs and their function. In addition, neoadjuvant therapy allows for in vivo evaluation of drug efficacy, which can guide the selection of subsequent treatments.

[0058] As used herein, "adjuvant therapy" refers to therapy given after definitive surgery to reduce the risk of disease recurrence. The goal of adjuvant therapy is to prevent cancer from coming back, thereby reducing the chance of cancer-related death. Adjuvant therapy herein specifically excludes neoadjuvant therapy.

[0059] The term "definitive surgery" is used within the medical community. Definitive surgery includes, for example, procedures, surgeries, or other methods that result in the removal or excision of a tumor, including those that result in the removal or excision of all macroscopic tumors. Definitive surgery includes, for example, complete or radical excision or complete gross excision of a tumor. Definitive surgery includes procedures that occur in one or more stages, and includes, for example, multi-stage surgical procedures in which one or more surgeries or other procedures are performed prior to excision of the tumor. Definitive surgery includes procedures that remove or excise a tumor, including affected organs, parts of organs and tissues, and surrounding organs, such as lymph nodes, parts of organs or tissues. Removal may not be complete, so that tumor cells may remain even if not detected.

[0060] "Survival" refers to the time the patient is still alive, including disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS). Survival can be estimated by the Kaplan-Meier method, and any differences in survival can be calculated by stratified log-rank tests.

[0061] “Progression-free survival” (PFS) is defined as the time from the first day of treatment to documented disease progression (including isolated CNS progression) or death from any cause on study, whichever occurs first.

[0062] "Disease-free survival (DFS)" refers to a defined period of time during which a patient does not have a recurrence of cancer, such as about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 10 years, etc., starting from the start of treatment or initial diagnosis. In one aspect of the present disclosure, DFS is analyzed according to the intention-to-treat principle, i.e., the patient is evaluated based on the therapy to which he or she is assigned. Events used in the DFS analysis may include local, regional, and distant recurrence of cancer, the occurrence of secondary cancers, and death from any cause in patients without prior events (e.g., recurrence of breast cancer or a second primary cancer).

[0063] "Invasive disease-free survival" (IDFS) is the time from randomization to the date of the first invasive disease event (e.g., ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive disease recurrence, distant disease recurrence, contralateral invasive breast cancer, or death from any cause).

[0064] As used herein, "overall survival" refers to a defined period of time that a patient survives from the start of treatment or initial diagnosis, such as about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 10 years, etc. In studies based on the present disclosure, the event used for survival analysis was death due to any cause.

[0065] As used herein, "extending survival" refers to increasing DFS and / or OS in treated patients relative to untreated patients or relative to a control treatment regimen. After initiation of treatment or initial diagnosis, monitoring survival is for at least about six months, or at least about 1 year, or at least about 2 years, or at least about 3 years, or at least about 4 years, or at least about 5 years, or at least about 10 years, etc.

[0066] The "hazard ratio" in a survival analysis summarizes the difference between two survival curves and represents the reduction in the risk of death in the treatment group compared to the control group during the follow-up period. The hazard ratio is a statistical definition of the rate of occurrence of an event. For the purposes of this disclosure, the hazard ratio is defined as representing the probability of an event in the experimental group divided by the probability of an event in the control group at any specific time point.

[0067] As used herein, "monotherapy" refers to a treatment regimen that includes only a single therapeutic agent for treating a cancer or tumor during the course of a treatment period.

[0068] As used herein, "maintenance therapy" refers to a treatment regimen given to reduce the likelihood of disease recurrence or progression. Maintenance therapy can be provided for any length of time, including extended periods of time until the end of the subject's life. Maintenance therapy can be provided after initial therapy or in conjunction with initial or other therapies. Dosages for maintenance therapy can vary and can include reduced doses compared to doses used for other types of therapy.

[0069] As defined herein, the term "trastuzumab", and “huMAb4D5-8” are used interchangeably.

[0070] "Epitope 4D5" or "4D5 epitope" or "4D5" is the region in the extracellular domain of HER2 to which antibody 4D5 (ATCC CRL10463) and trastuzumab bind. The epitope is close to the transmembrane domain of HER2 and is within domain IV of HER2. In order to screen for antibodies that bind to the 4D5 epitope, a conventional cross-blocking assay such as described in Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory, Ed Harlow and David Lane (1988) is required. Alternatively, epitope mapping can be performed to assess whether an antibody binds to the 4D5 epitope of HER2 (e.g., any one or more residues in the region from about residue 529 to about residue 625, inclusive, of HER2).

[0071] As defined herein, the terms "T-DM1," "trastuzumab-MCC-DM1," "ado-trastuzumab emtansine conjugate," "trastuzumab emtansine conjugate" and Used interchangeably, and refers to trastuzumab linked to the DM1 portion of the maytansine alkaloid drug via a linker moiety MCC, including all mixtures of various loaded and attached antibody-drug conjugates, wherein 1, 2, 3, 4, 5, 6, 7 and 8 drug moieties are covalently attached to trastuzumab (see US 7097840; US 2005 / 0276812; US 2005 / 0166993, the entire contents of which are incorporated herein by reference). Trastuzumab-MCC-DM1 contains an average of 3.5 DM1 molecules / antibody.

[0072] "Chemotherapy" is the use of chemotherapeutic agents that can be used to treat cancer.

[0073] "HER2 targeted therapy" or "HER2 directed therapy" are used interchangeably herein and refer to the use of agents that target the HER2 pathway. Non-limiting examples of agents that target the HER2 pathway include trastuzumab, pertuzumab, lapatinib, neratinib, dacomitinib, and afatinib.

[0074] Pertuzumab (also known as recombinant humanized monoclonal antibody 2C4, rhuMAb 2C4, Genentech, Inc, South San Francisco) is another antibody therapy targeting Her2. Pertuzumab is a Her dimerization inhibitor (HDI) that has the ability to inhibit Her2 from forming active heterodimers or homodimers with other Her receptors (e.g., EGFR / Her 1, Her2, Her3, and Her4). See, e.g., Harari and Yarden Oncogene 19:6102-14 (2000); Yarden and Sliwkowski. Nat Rev Mol Cell Biol 2:127-37 (2001); Sliwkowski, Nat Struct Biol 10:158-9 (2003); Cho et al., Nature 421:756-60 (2003); and Malik et al., Pro Am Soc Cancer Res 44:176-7 (2003); US 7560111.

[0075] Lapatinib, neratinib, dacomitinib, and afatinib are small molecule HER2 kinase inhibitors. Lapatinib (CAS 231277-92-2), as lapatinib ditosylate (Tyverb / ) to inhibit the tyrosine kinase activity of HER2 / neu and EGFR (epidermal growth factor receptor). Other dual inhibitors of HER2 / neu and EGFR are neratinib (CAS 698387-09-6, ) and afatinib (CAS 850140-72-6, ), while dacomitinib (CAS1110813-31-4, ) is an inhibitor of EGFR, HER2 and HER4 tyrosine kinases, i.e. a pan-HER inhibitor.

[0076] The term "effective amount" refers to the amount of a drug that effectively treats cancer in a patient. An effective amount of a drug can reduce the number of cancer cells; reduce tumor size; inhibit (i.e., slow down and preferably stop) cancer cells from infiltrating surrounding organs; inhibit (i.e., slow down and preferably stop) tumor metastasis; inhibit tumor growth to a certain extent; and / or alleviate one or more symptoms associated with cancer to a certain extent. To some extent, the drug can prevent growth and / or kill existing cancer cells, it can inhibit cell growth and / or have cytotoxicity. An effective amount can prolong progression-free survival (e.g., measured according to response evaluation criteria for solid tumors, RECIST or CA-125 changes), lead to an objective response (including partial response PR or complete response Cr), increase overall survival, and / or improve one or more cancer symptoms (e.g., assessed by FOSI). The term "effective amount" specifically includes an amount suitable for achieving any primary or secondary endpoint of the clinical trial described in Example 1.

[0077] "Taxanes" are chemotherapy that inhibit mitosis and interfere with microtubules. Examples of taxanes include paclitaxel ( Bristol-Myers Squibb Oncology, Princeton, NJ; Abraxane, a colorless albumin-engineered nanoformulation of paclitaxel or nab-paclitaxel TM ; American Pharmaceutical Partners, Schaumberg, Illinois) and docetaxel ( Rorer, Antony, France). "Taxane-based" or "taxane-containing" therapy are used interchangeably herein and refer to a therapy that includes a taxane.

[0078] As used herein, "chemoresistant" cancer means that the cancer patient has progressed while receiving a chemotherapy regimen (ie, the patient is "chemorefractory"), or the patient has progressed within 12 months (eg, within 6 months) after completing a chemotherapy regimen.

[0079] As used herein, a fixed dose (flat dose) of a therapeutic agent refers to a dose that is administered to a human patient without regard to the patient's body weight (WT) or body surface area (BSA). Thus, a fixed dose is not a mg / kg dose or mg / m 2 dose, but rather an absolute dose of the therapeutic agent.

[0080] As used herein, a "loading" dose generally includes an initial dose of a therapeutic agent administered to a patient, followed by one or more maintenance doses thereof. Typically, a single loading dose is administered, but multiple loading doses are contemplated herein. Typically, the amount of the loading dose administered exceeds the amount of the maintenance dose administered, and / or the loading dose is administered more frequently than the maintenance dose, to achieve a desired steady-state concentration of the therapeutic agent earlier than can be achieved with the maintenance dose.

[0081] As used herein, a "maintenance" dose refers to one or more therapeutic agents administered to a patient during a treatment period. Typically, maintenance doses are administered at spaced treatment intervals, such as about every week, about every 2 weeks, about every 3 weeks, or about every 4 weeks, preferably every 3 weeks.

[0082] As used herein, "infusion" and "infusing" refer to the introduction of a solution containing a drug into the body through a vein for therapeutic purposes. Typically, this is achieved through an intravenous (IV) bag.

[0083] As used herein, an "intravenous bag" or "IV bag" is a bag that can hold a solution that can be administered through a patient's vein. In certain embodiments, the solution is a saline solution (e.g., about 0.9% or about 0.45% NaCl). Optionally, the IV bag is formed of a polyolefin or polyvinyl chloride.

[0084] As used herein, "co-administering" refers to the intravenous administration of two (or more) drugs during the same administration period, rather than sequential infusion of two or more drugs. Typically, this will involve combining the two (or more) drugs into the same IV bag prior to co-administration.

[0085] A drug administered "concurrently" with one or more other drugs refers to a drug administered on the same day as one or more other drugs, and (optionally) concurrently with one or more other drugs, within the same treatment cycle. For example, for a cancer therapy given every 3 weeks, each drug is administered concurrently on Day 1 of a 3-week cycle.

[0086] A "vial" is a container suitable for holding a liquid or lyophilized formulation. In certain embodiments, the vial is a disposable vial, such as a 20cc disposable vial with a stopper.

[0087] The term "package insert" is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and / or warnings concerning the use of such therapeutic products.

[0088] An “adverse event” is any unfavorable and undesirable sign, symptom, or disease that is temporally related (regardless of its attribution) to the use of an investigational (drug) product or other protocol-imposed intervention; including: AEs that occur during the protocol-specified AE reporting period and have not been previously observed in a patient, including signs or symptoms related to breast cancer that were not present prior to the AE reporting period; complications occurring as a result of a protocol-specified intervention (e.g., invasive procedures such as biopsies); if applicable, AEs related to drug washout, run-in without treatment, or other protocol-specified interventions that occur prior to assignment of study treatment; pre-existing medical conditions (other than the condition under study) that, in the opinion of the investigator, have worsened in severity or frequency or changed in character during the protocol-specified AE reporting period.

[0089] An adverse event was classified as a "serious adverse event" (SAE) if it met the following criteria: resulted in death (i.e., the AE actually caused or contributed to death); was life-threatening (i.e., the investigator considered the AE to put the patient at immediate risk of death, but did not include AEs that occurred in a more severe form and could cause death); required or prolonged hospitalization; resulted in persistent or significant disability / incapacity (i.e., the AE would significantly disrupt the patient's ability to carry out normal life functions); resulted in a congenital anomaly / birth defect in a newborn / infant of a mother exposed to the investigational product; or was considered by the investigator to be a medically significant event based on medical judgment (e.g., could endanger the patient or might require medical / surgical intervention to prevent one of the above outcomes). All AEs that did not meet any of the significance criteria were considered non-significant AEs. The terms "serious" and "significant" are not synonymous. Severity (or intensity) refers to the grade of a specific AE, such as mild (grade 1), moderate (grade 2), or severe (grade 3) myocardial infarction. "Significant" is a regulatory definition (see previous definitions) based on patient or event outcomes or action criteria, generally associated with events that pose a threat to the patient's life or function. Significance (not severity) is used as a guide to define regulatory reporting obligations from the sponsor to the applicable regulatory authorities. Severity and significance should be independently assessed when recording AEs and SAEs on the eCRF.

[0090] Ⅱ. Trastuzumab emtansine conjugate

[0091] The present disclosure includes the use of trastuzumab emtansine conjugate (T-DM1), an antibody-drug conjugate (CAS Reg. No. 139504-50-0, trastuzumab-MCC-DM1, N 2’ -(3-{1-[4-(trastuzumab)~1 / 3.5carbamoylcyclohexylmethyl]-2,5-dioxo-pyrrolidin-3-ylsulfanyl}-propionyl)-deacetyl maytansine), the structure of which is:

[0092]

[0093] Wherein Tr is trastuzumab (US5208020; US 6441163) connected to the maytansine alkaloid drug part DM1 by the linker part MCC. The microtubule inhibitory drug maytansine alkaloid DM1 is synthesized from the maytansine alkaloid maytansinol and is mainly connected to the antibody lysine residue using the heterobifunctional reagent SMCC. In the above structure of the trastuzumab maytansine conjugate (trastuzumab-MCC-DM1), the ratio of drug to antibody or drug loading is represented by p, ranging from 1 to about 8 integers. Trastuzumab-MCC-DM1 includes all mixtures of various loaded and attached antibody-drug conjugates, wherein 1, 2, 3, 4, 5, 6, 7 and 8 drug parts are covalently attached to the antibody trastuzumab (US 7097840; US2005 / 0276812; US2005 / 0166993). On average, trastuzumab emtansine conjugates contained 3.5 DM1 molecules per antibody.

[0094] Trastuzumab can be produced by mammalian cell (Chinese hamster ovary, CHO) suspension culture. The HER2 (or c-erbB2) proto-oncogene encodes a 185 kDa transmembrane receptor protein that is structurally related to the epidermal growth factor receptor. Trastuzumab is an anti-HER2 antibody having the murine 4D5 antibody (ATCC CRL 10463, deposited at the American Type Culture Collection, 12301 Parklawn Drive, Rockville, Md. 20852, pursuant to the Budapest Treaty Can 24, 1990) or antigen-binding residues derived therefrom. Exemplary humanized 4D5 antibodies include huMAb4D5-1, huMAb4D5-2, huMAb4D5-3, huMAb4D5-4, huMAb4D5-5, huMAb4D5-6, huMAb4D5-7, and huMAb4D5-8 As described in US 5821337.

[0095] Trastuzumab emtansine conjugate can be prepared according to, for example, Example 1 of US Application Publication No. 20110165155, which is incorporated herein by reference in its entirety.

[0096] III. Formulation of trastuzumab emtansine conjugate

[0097] Trastuzumab emtansine conjugate (ado-trastuzumab emtansine conjugate, T-DM1) can be formulated according to standard pharmaceutical specifications. Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc. The specific carrier, diluent or excipient used will depend on the mode and purpose of application of the disclosed compound. Solvents are usually selected based on solvents that are generally recognized by those skilled in the art as safe for administration to mammals (GRAS). Generally, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble in water or miscible with water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG 400, PEG300), etc. and mixtures thereof. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavoring agents, flavoring agents and other known additives to provide an aesthetically pleasing display of the drug (e.g., a compound of the present disclosure or a pharmaceutical composition thereof) or to facilitate the preparation of a pharmaceutical product (e.g., a drug).

[0098] The formulations can be prepared using conventional dissolution and mixing procedures. For example, the drug substance (i.e., a compound of the present disclosure or a stable form of a compound (e.g., a complex with a cyclodextrin derivative or other known complexing agent)) is dissolved in a suitable solvent in the presence of one or more of the above-mentioned excipients. The compounds of the present disclosure are generally formulated into pharmaceutical dosage forms to provide an easily controlled drug dosage and enable the patient to follow the prescription.

[0099] The pharmaceutical composition (or formulation) for administration can be packaged in a variety of ways, depending on the method used to administer the drug. Typically, articles for distribution include containers in which the pharmaceutical formulation is deposited in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), pouches, ampoules, plastic bags, metal cylinders, etc. The container may also include a tamper-proof assembly to prevent inadvertent contact with the contents of the package. In addition, the container is provided with a label describing the contents of the container. The label may also include appropriate warnings.

[0100] The pharmaceutical preparations can be prepared for various routes and types of administration in the form of lyophilized preparations, ground powders or aqueous solutions together with pharmaceutical diluents, carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences (1995), 18th edition, Mack Publ. Co., Easton, PA). They can be formulated by mixing with a physiological pharmaceutical carrier (i.e., a carrier that is non-toxic to the receptor at the dose and concentration employed) at an appropriate pH and desired purity at ambient temperature. The pH of the preparation depends primarily on the specific use and concentration of the compound, but can be in the range of about 3 to about 8.

[0101] Pharmaceutical preparations are preferably sterile. In particular, preparations to be used for in vivo administration should be sterile. Such sterilization is easily achieved by filtration through a sterile filtration membrane.

[0102] Pharmaceutical compositions can typically be stored as solid compositions, lyophilized formulations, or as aqueous solutions.

[0103] The pharmaceutical preparations described in the present disclosure will be administered and applied in a manner consistent with good medical practice, i.e., dosage, concentration, schedule, course of treatment, vehicle, and route of administration. Factors to be considered in this context include the specific disorder being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the timing of administration, and other factors known to practitioners.

[0104] Acceptable diluents, carriers, excipients and stabilizers are nontoxic to the receptor at the dosages and concentrations used, including buffers such as phosphates, citrates and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl, ethanol or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., zinc protein complexes); and / or nonionic surfactants such as TWEEN TM Including Tween 80, PLURONICS TM, or polyethylene glycol (PEG) including PEG400. The active pharmaceutical ingredient can be encapsulated in microcapsules (e.g., hydroxymethylcellulose or gelatin microcapsules and poly (methyl methacrylate) microcapsules, respectively) prepared, for example, by coacervation techniques or by interfacial polymerization, encapsulated in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in coarse emulsions. This technology is disclosed in Remington's Pharmaceutical Sciences, 18th edition, (1995) Mack Publ. Co., Easton, PA. Other examples of pharmaceutical preparations can be found in Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, Vol 3, 2nd edition, New York, NY.

[0105] The pharmaceutical preparation includes a pharmaceutical preparation suitable for the administration route detailed herein. The preparation can be conveniently present in the form of a unit dose and can be prepared by any method known in the pharmaceutical field. The technology and preparation are generally set forth in Remington's Pharmaceutical Sciences, 18th edition, (1995) Mack Publishing Co., Easton, PA. Such a method includes the step of associating the active ingredient with a carrier constituting one or more auxiliary ingredients. In general, the preparation method is to uniformly and closely combine the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, the product is molded.

[0106] The pharmaceutical composition can be in the form of a sterile injection preparation, such as a sterile injection aqueous or oily suspension. The suspension can be prepared according to known techniques using those suitable dispersants or wetting agents and suspending agents already mentioned above. The sterile injection preparation can be a solution or suspension in a nontoxic parenteral acceptable diluent or solvent, such as a solution in 1,3-butanediol, or made into a lyophilized powder. Acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils can be used conventionally as solvents or suspension media. For this reason, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can also be used in the preparation of injections.

[0107] The amount of active ingredient that can be combined with carrier materials to produce a single dosage form will vary according to the treated host and the specific mode of administration. For example, a time-delayed release formulation for oral administration to a human may contain about 1 mg to 1000 mg of active ingredient compounded with a suitable and convenient amount of carrier material, which may account for about 5% to about 95% (weight to weight) of the total composition. Pharmaceutical compositions may be prepared to provide an amount of administration that is easy to measure. For example, an aqueous solution for intravenous infusion may contain about 3 μg to 500 μg of active ingredient per milliliter of solution, so that a suitable volume may be infused at a rate of about 30 mL / hr.

[0108] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes to render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0109] The preparation can be packaged in a unit dose or multidose container, such as a sealed ampoule and vial, and can be stored under freeze drying (lyophilization) conditions, requiring only the addition of a sterile liquid carrier for injection, such as water, before use. Extemporaneous injection solutions and suspensions are prepared by sterile powders, granules and tablets of the aforementioned types. Preferred unit dose formulations are those containing daily doses or unit daily subdoses as described herein above, or active ingredients of their appropriate fractions.

[0110] Typically, the initial pharmaceutically effective amount of T-DM1 administered per dose is about 0.3 to 15 mg / kg / day of the patient's body weight.

[0111] Commercial T-DM1 preparations ( Trastuzumab emtansine conjugate) is a sterile, white to off-white, preservative-free lyophilized powder in disposable vials. Each vial includes 100 mg or 160 mg of trastuzumab emtansine conjugate. After reconstitution, each disposable vial includes trastuzumab emtansine conjugate (20 mg / mL), polysorbate 20 [0.02% (w / v)], sodium succinate (10 mM), and sucrose [6% (w / v)], with a pH of 5.0 and a density of 1.026 g / mL. After dilution, the resulting solution containing 20 mg / mL trastuzumab emtansine conjugate is administered by intravenous infusion.

[0112] IV. Administration of trastuzumab emtansine conjugate

[0113] The present disclosure relates to the use of trastuzumab emtansine conjugate (T-DM1) as adjuvant therapy. In certain embodiments, T-DM1 is used as an adjuvant therapy for treating HER2-positive early breast cancer in patients, such as adult patients. In certain embodiments, T-DM1 is used as an adjuvant therapy for treating patients with HER2-positive non-metastatic invasive breast cancer. In certain embodiments, T-DM1 can be administered as a monotherapy, for example, in individuals with residual disease after preoperative systemic treatment.

[0114] In certain embodiments, the adjuvant therapy methods and uses disclosed herein substantially increase invasive disease-free survival (IDFS) compared to adjuvant therapy with trastuzumab. In certain embodiments, adjuvant therapy reduces the risk of invasive disease recurrence by about 40%, about 50%, or about 60% compared to adjuvant therapy with trastuzumab. For example, but not limited to, the adjuvant therapy disclosed herein reduces the risk of invasive disease recurrence by 50% compared to adjuvant therapy with trastuzumab. In certain embodiments, adjuvant therapy results in a reduction in distant recurrence compared to adjuvant therapy with trastuzumab. For example, but not limited to, adjuvant therapy reduces the risk of distant recurrence by 40% compared to adjuvant trastuzumab.

[0115] The present disclosure provides methods for adjuvant therapy, which include administering T-DM1. For example, but not limited to, the method of adjuvant therapy includes administering an effective amount of T-DM1 as a monotherapy to a patient with HER2-positive early breast cancer, wherein the patient has residual disease after preoperative systemic treatment.

[0116] In certain embodiments, the residual disease is in the breast and / or lymph nodes. For example, but not limited to, the residual disease is in the breast. Alternatively and / or additionally, the residual disease is in the lymph nodes, such as the axillary lymph nodes. In certain embodiments, the residual disease is in the breast and lymph nodes.

[0117] In certain embodiments, preoperative systemic therapy includes HER2 targeted therapy, such as one or more HER2 targeted therapies. Non-limiting examples of HER2 targeted therapy include trastuzumab, pertuzumab, lapatinib, neratinib, dacomitinib and / or afatinib. In certain embodiments, HER2 targeted therapy is trastuzumab. In certain embodiments, HER2 targeted therapy is pertuzumab. In certain embodiments, HER2 targeted therapy is lapatinib. In certain embodiments, HER2 targeted therapy is neratinib. In certain embodiments, HER2 targeted therapy is dacomitinib. In certain embodiments, HER2 targeted therapy is afatinib.

[0118] In certain embodiments, preoperative systemic therapy may include administration of a taxane. Non-limiting examples of taxanes include paclitaxel and docetaxel. In certain embodiments, the taxane is paclitaxel. In certain embodiments, the taxane is docetaxel.

[0119] In certain embodiments, the method may include administering a taxane-containing chemotherapy regimen and a HER2-targeted therapy. For example, but not limited to, the patient has completed at least 16 weeks of preoperative systemic treatment with a taxane-containing chemotherapy regimen and a HER2-targeted therapy prior to treatment with T-DM1. In certain embodiments, the patient has completed at least 6 cycles of taxane-containing chemotherapy.

[0120] In certain embodiments, the methods of the present disclosure may further include definitive surgery. For example, but not limited to, definitive surgery is performed on the patient before administering T-DM1. In certain embodiments, T-DM1 is administered to the patient no more than 1 week, no more than 2 weeks, no more than 3 weeks, no more than 4 weeks, no more than 5 weeks, no more than 6 weeks, no more than 7 weeks, no more than 8 weeks, no more than 9 weeks, no more than 10 weeks, no more than 11 weeks, or no more than 12 weeks after definitive surgery. In certain embodiments, T-DM1 is administered to the patient no more than 12 weeks after definitive surgery.

[0121] The disclosed subject matter further provides methods for treating breast cancer in patients with HER2-positive early breast cancer who have residual disease in the breast or axillary lymph nodes after neoadjuvant therapy with chemotherapy and HER2-targeted therapy. In certain embodiments, the method may include definitive surgery to remove all clinically evident tumor cells in the breast and axillary lymph nodes and subjecting the patient to monotherapy adjuvant therapy with T-DM1.

[0122] In certain embodiments, the patient has residual disease in the breast or axillary lymph nodes after neoadjuvant therapy with a taxane and HER2-targeted therapy. In certain embodiments, the patient has completed at least 16 weeks of neoadjuvant therapy with a taxane-containing chemotherapy. In certain embodiments, the patient has completed at least 6 cycles of taxane-containing chemotherapy. In certain embodiments, the patient is treated with adjuvant T-DM1 no more than 12 weeks after definitive surgery.

[0123] The disclosed subject matter further provides methods for treating HER2-positive early breast cancer in a patient who has residual disease after neoadjuvant therapy. In certain embodiments, the method comprises administering an effective amount of T-DM1 to the patient after definitive surgery. In certain embodiments, the residual disease is pathological residual invasive disease. In certain embodiments, the residual disease is pathological residual invasive disease in the lymph nodes. In certain embodiments, the residual disease is pathological residual invasive disease in the breast. In certain embodiments, the residual disease is pathological residual invasive disease in the lymph nodes and the breast.

[0124] The disclosed subject matter provides methods for reducing the risk of cancer recurrence in patients with HER2-positive early breast cancer. In certain embodiments, the method comprises administering an effective amount of T-DM1 to the patient, wherein the patient has not achieved a pathological complete response to neoadjuvant therapy, and the patient has undergone definitive surgery prior to administering T-DM1.

[0125] In certain embodiments, neoadjuvant therapy comprises taxanes and / or HER2 targeted therapy. In certain embodiments, neoadjuvant therapy comprises taxanes and HER2 targeted therapy. For example, but not limited to, neoadjuvant therapy comprises taxanes and trastuzumab. In certain embodiments, patients treated according to the methods of the present disclosure have completed at least 16 weeks of neoadjuvant therapy. In certain embodiments, patients have completed at least 6 cycles of neoadjuvant therapy containing taxanes. In certain embodiments, patients are treated with T-DM1 no more than 12 weeks after definitive surgery.

[0126] In certain embodiments, the methods of the present disclosure do not include prior or concurrent adjuvant treatment with chemotherapy.

[0127] In certain embodiments, the methods of the present disclosure may include administering T-DM1 at a dose of 3.6 mg / kg every 3 weeks. For example, but not limited to, T-DM1 may be administered to a patient at a dose of 3.6 mg / kg every 3 weeks for 14 cycles.

[0128] The present disclosure further provides trastuzumab emtansine conjugate (T-DM1) and pharmaceutical compositions thereof, which are used as adjuvant therapy for HER2-positive early breast cancer in patients. In certain embodiments, T-DM1 is administered as a monotherapy, and the patient has residual disease after preoperative systemic treatment. In certain embodiments, the residual disease is present in the breast, in the lymph nodes, or in the breast and lymph nodes. In certain embodiments, preoperative systemic treatment includes targeted HER2 therapy, such as trastuzumab or trastuzumab and pertuzumab, lapatinib, neratinib, dacomitinib and / or afatinib. In certain embodiments, preoperative systemic treatment also includes taxanes. In certain embodiments, definitive surgery is performed on the patient before administering T-DM1.

[0129] On the other hand, the disclosed subject matter provides the use of T-DM1 in the preparation of a medicament for adjuvant therapy of HER2-positive early breast cancer in a patient, wherein the adjuvant therapy is a monotherapy, and wherein the patient has residual disease after preoperative systemic treatment. In certain embodiments, the residual disease is present in the breast, in the lymph nodes, or in the breast and lymph nodes. In certain embodiments, preoperative systemic therapy includes targeted HER2 therapy, such as trastuzumab or trastuzumab and pertuzumab, lapatinib, neratinib, dacomitinib and / or afatinib. In certain embodiments, preoperative systemic therapy also includes taxanes. In certain embodiments, definitive surgery is performed on the patient before administering T-DM1.

[0130] Trastuzumab emtansine conjugate (T-DM1) and its pharmaceutical composition can be any route in the method of the present disclosure, and appropriately applied according to the condition being treated. For example, but not limiting, suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, inhalation, intradermal, intrathecal, epidural and infusion techniques), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal. Topical application can also involve the use of transdermal administration, such as transdermal patches or iontophoresis devices. For local immunosuppressive therapy, the compound can be administered by intralesional administration, including perfusion before transplantation or otherwise contacting the transplant with an inhibitor. It should be understood that the preferred route may vary with, for example, the condition of the recipient. In the case of oral administration of the compound, the compound can be formulated into pills, capsules, tablets, etc. with a pharmaceutical carrier, a glidant or an excipient. In the case of parenteral administration of the compound, the compound may be formulated with a pharmaceutically acceptable parenteral vehicle or diluent in a unit dosage injection form, as described in detail below.

[0131] V. Products

[0132] Articles or "kits" containing T-DM1 that can be used in the treatment methods herein are provided. In certain embodiments, the kit includes a container containing T-DM1. The kit may further include a label or package insert on or associated with the container. The term "package insert" is used to refer to instructions typically included in commercial packaging of therapeutic products, which contain information related to the use of such therapeutic products, indications, usage, dosage, administration, contraindications and / or warnings. Suitable containers include, for example, bottles, vials, syringes, blister packs, etc. The container can be formed of a variety of materials such as glass or plastic. The container can hold T-DM1 or a formulation thereof that is effective for use in the treatment methods herein, and can have a sterile access port (for example, the container can be an intravenous solution bag or a vial with a stopper that can be pierced by a hypodermic injection needle). The label or package insert indicates that the composition is used in the treatment methods described and claimed herein. The article may contain another container that includes a pharmaceutical buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextrose solution. The article of manufacture may further include other materials desirable from a commercial and user perspective, including other buffers, diluents, filters, needles, and syringes.

[0133] The kit may further include instructions for administration of T-DM1. For example, if the kit includes T-DM1 and a second pharmaceutical formulation, the kit may further include instructions for administering the first pharmaceutical composition and the second pharmaceutical composition simultaneously, sequentially, or separately to a patient in need thereof.

[0134] In certain embodiments, the kit is suitable for delivering solid oral forms of T-DM1, such as tablets or capsules. Such kits preferably include a plurality of unit doses. Such kits may include a card with doses oriented in the order of their intended use. An example of such a kit is a blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms. If desired, a memory aid may be provided, for example, in the form of numbers, letters or other markings or with calendar insert events specifying the dates on which the doses may be administered in the treatment schedule.

[0135] In certain embodiments, the articles herein include an intravenous (IV) bag comprising a stable mixture of T-DM1 suitable for administration to a cancer patient. Optionally, the mixture is in a saline solution; for example, comprising about 0.9% NaCl or about 0.45% NaCl. An exemplary IV bag is a polyolefin or polyvinyl chloride infusion bag, such as a 250 mL IV bag. According to certain embodiments of the present disclosure, the bag comprises about 100 mg to about 160 mg of T-DM1.

[0136] Optionally, the mixture in the IV bag is stable for up to 24 hours at a temperature of 5° C. or 30° C. The stability of the mixture can be assessed by one or more assays selected from the group consisting of color, appearance and clarity (CAC), concentration and turbidity analysis, particle analysis, size exclusion chromatography (SEC), ion exchange chromatography (IEC), capillary zone electrophoresis (CZE), image capillary isoelectric focusing (iCIEF), and potency assays.

[0137] VI. Exemplary Embodiments

[0138] A. In certain non-limiting embodiments, the presently disclosed subject matter provides a method of adjuvant therapy comprising administering an effective amount of trastuzumab emtansine conjugate (T-DM1) as a monotherapy to a patient with HER2-positive early breast cancer, wherein the patient has residual disease after preoperative systemic therapy.

[0139] A1. The preceding method according to A, wherein the residual disease is present in the breast.

[0140] A2. The preceding method according to A, wherein the residual disease is present in the lymph nodes.

[0141] A3. The preceding method according to A, wherein the residual disease is present in the breast and lymph nodes.

[0142] A4. The aforementioned method according to any one of A-A3, wherein the preoperative systemic treatment comprises HER2-targeted therapy.

[0143] A5. The aforementioned method according to A4, wherein the HER2 targeted therapy comprises trastuzumab.

[0144] A6. The aforementioned method according to A5, wherein the HER2 targeted therapy further comprises Pertuzumab.

[0145] A7. The aforementioned method according to A4 or A5, wherein the HER2 targeted therapy further comprises an agent selected from the group consisting of lapatinib, neratinib, dacomitinib, afatinib and a combination thereof.

[0146] A8. The preceding method according to any one of A-A7, wherein the preoperative systemic treatment further comprises a taxane.

[0147] A9. The foregoing method according to any one of A-A8, wherein the patient is an adult patient.

[0148] A10. The preceding method according to any one of A-A9, wherein the patient undergoes definitive surgery prior to administration of T-DM1.

[0149] A11. The preceding method according to A10, wherein T-DM1 is administered to the patient no more than 12 weeks after definitive surgery.

[0150] A12. The preceding method according to any one of A-A11, wherein the patient has completed at least 16 weeks of preoperative systemic treatment with a taxane-containing chemotherapy regimen and a HER2-targeted therapy.

[0151] A13. The preceding method according to any one of A-A12, wherein the patient has completed at least 6 cycles of taxane-containing chemotherapy.

[0152] A14. The preceding method according to any one of A-A13, wherein T-DM1 is administered to the patient at a dose of 3.6 mg / kg every 3 weeks.

[0153] A15. The preceding method according to any one of A-A14, wherein T-DM1 is administered to the patient at a dose of 3.6 mg / kg every 3 weeks for fourteen cycles.

[0154] A16. The preceding method according to any one of A-A15, wherein the adjuvant therapy significantly increases invasive disease-free survival (IDFS) compared to adjuvant therapy with trastuzumab.

[0155] A17. The preceding method according to any one of A-A16, wherein the adjuvant therapy reduces the risk of recurrence of invasive disease by 50% compared to adjuvant therapy with trastuzumab.

[0156] A18. The preceding method according to any one of A-A17, wherein the adjuvant therapy results in a reduction in distant recurrence compared to adjuvant therapy with trastuzumab.

[0157] A19. The preceding method according to any one of A-A18, wherein the adjuvant therapy reduces the risk of distant recurrence by 40% compared to adjuvant trastuzumab.

[0158] B. In certain embodiments, the presently disclosed subject matter provides trastuzumab emtansine conjugate (T-DM1) for use in adjuvant therapy of HER2-positive early breast cancer in a patient, wherein the adjuvant is a monotherapy, and wherein the patient has residual disease after preoperative systemic therapy.

[0159] B1. The aforementioned use of T-DM1 according to B, wherein the residual disease is present in the breast, in the lymph nodes, or in the breast and lymph nodes.

[0160] B2. The aforementioned use of T-DM1 according to B or B1, wherein the preoperative systemic treatment comprises HER2 targeted therapy.

[0161] B3. The aforementioned use of T-DM1 according to B2, wherein the HER2 targeted therapy comprises trastuzumab or trastuzumab and pertuzumab, lapatinib, neratinib, dacomitinib and / or afatinib.

[0162] B4. The aforementioned use of T-DM1 according to any one of B-B3, wherein the preoperative systemic treatment further comprises a taxane.

[0163] B5. The aforementioned use of T-DM1 according to any one of B-B4, wherein the patient is an adult patient.

[0164] B6. The aforementioned use of T-DM1 according to any one of B-B5, wherein the patient undergoes definitive surgery before administering T-DM1.

[0165] B7. The aforementioned use of T-DM1 according to any one of B-B6, wherein the adjuvant therapy significantly increases invasive disease-free survival (IDFS) compared to adjuvant therapy with trastuzumab.

[0166] B8. The aforementioned use of T-DM1 according to any one of B-B7, wherein the adjuvant therapy reduces the risk of recurrence of invasive disease by 50% compared to adjuvant therapy with trastuzumab.

[0167] B9. The aforementioned use of T-DM1 according to any one of B-B8, wherein the adjuvant therapy results in a reduction in distant recurrence compared to adjuvant therapy with trastuzumab.

[0168] B10. The aforementioned use of T-DM1 according to any one of B-B9, wherein the adjuvant therapy reduces the risk of distant recurrence by 40% compared to adjuvant trastuzumab.

[0169] C. In certain embodiments, the presently disclosed subject matter provides use of a trastuzumab emtansine conjugate (T-DM1) in the preparation of a medicament for adjuvant therapy of HER2-positive early breast cancer in a patient, wherein the adjuvant is a monotherapy, and wherein the patient has residual disease after preoperative systemic therapy.

[0170] C1. The aforementioned use according to C, wherein the residual disease is present in the breast, in the lymph nodes, or in the breast and lymph nodes.

[0171] C2. The aforementioned use according to C or C1, wherein the preoperative systemic treatment comprises HER2 targeted therapy.

[0172] C3. The aforementioned use according to C2, wherein the HER2 targeted therapy comprises trastuzumab or trastuzumab and pertuzumab, lapatinib, neratinib, dacomitinib and / or afatinib.

[0173] C4. The aforementioned use according to any one of C-C3, wherein the preoperative systemic treatment further comprises a taxane.

[0174] C5. The aforementioned use according to any one of C-C4, wherein the patient is an adult patient.

[0175] C6. The aforementioned use according to any one of C-C5, wherein the patient undergoes definitive surgery before administering T-DM1.

[0176] C7. The aforementioned use according to any one of C-C6, wherein the adjuvant therapy significantly increases invasive disease-free survival (IDFS) compared to adjuvant therapy with trastuzumab.

[0177] C8. The aforementioned use according to any one of C-C7, wherein the adjuvant therapy reduces the risk of recurrence of invasive disease by 50% compared to adjuvant therapy with trastuzumab.

[0178] C9. The aforementioned use according to any one of C-C8, wherein the adjuvant therapy results in a reduction in distant recurrence compared to adjuvant therapy with trastuzumab.

[0179] C10. The aforementioned use according to any one of C-C9, wherein the adjuvant therapy reduces the risk of distant recurrence by 40% compared to adjuvant trastuzumab.

[0180] D. In certain non-limiting embodiments, the presently disclosed subject matter provides methods for treating breast cancer in a patient with HER2-positive early-stage breast cancer who has residual disease in the breast or axillary lymph nodes after neoadjuvant therapy with chemotherapy and HER2-targeted therapy, the method comprising:

[0181] (i) definitive surgical removal of all clinically evident tumor cells from the breast and axillary lymph nodes; and

[0182] (ii) the patient receives adjuvant therapy with trastuzumab emtansine conjugate (T-DM1) as monotherapy.

[0183] D1. The preceding method according to D, wherein the patient has residual disease in the breast or axillary lymph nodes after neoadjuvant therapy with a taxane and a HER2-targeted therapy.

[0184] D2. The preceding method according to D or D1, wherein the patient has completed at least 16 weeks of neoadjuvant therapy with taxane-containing chemotherapy.

[0185] D3. The preceding method according to any one of D-D2, wherein the patient has completed at least 6 cycles of taxane-containing chemotherapy.

[0186] D4. The preceding method according to any one of D-D3, wherein the patient is treated adjuvantly with T-DM1 no more than 12 weeks after definitive surgery.

[0187] D5. The preceding method according to any one of D-D4, wherein the patient is treated with adjuvant T-DM1 infused at a dose of 3.6 mg / kg every 3 weeks.

[0188] D6. The preceding method according to any one of D-D5, wherein the patient is treated with adjuvant T-DM1 infusion at a dose of 3.6 mg / kg every 3 weeks for fourteen cycles.

[0189] D7. The preceding method according to any one of D-D6, wherein the treatment significantly increases invasive disease-free survival (IDFS) compared to adjuvant treatment with trastuzumab.

[0190] D8. The preceding method according to any one of D-D7, wherein the treatment results in a reduction in distant recurrence compared to adjuvant treatment with trastuzumab.

[0191] E. In certain non-limiting embodiments, the presently disclosed subject matter provides a method for treating HER2-positive early breast cancer in a patient with residual disease after neoadjuvant therapy, the method comprising administering to the patient an effective amount of trastuzumab emtansine conjugate (T-DM1) after the patient has undergone definitive surgery.

[0192] E1. The preceding method according to E, wherein the residual disease is pathological residual invasive disease.

[0193] E2. The preceding method according to E or El, wherein the residual disease is pathological residual invasive disease in the lymph nodes.

[0194] E3. The preceding method according to any one of E-E2, wherein the residual disease is pathological residual invasive disease in the breast.

[0195] E4. The preceding method according to any one of E-E3, wherein the method does not comprise prior or concurrent adjuvant treatment with chemotherapy.

[0196] E5. The preceding method according to any one of E-E4, wherein the neoadjuvant therapy comprises a taxane and a HER2-targeted therapy.

[0197] E6. The preceding method according to any one of E-E5, wherein the neoadjuvant therapy comprises a taxane and trastuzumab.

[0198] E7. The preceding method according to any one of E-E6, wherein the patient has completed at least 16 weeks of neoadjuvant therapy.

[0199] E8. The preceding method according to any one of E-E7, wherein the patient has completed at least 6 cycles of neoadjuvant therapy containing a taxane.

[0200] E9. The preceding method according to any one of E-E8, wherein the patient is treated with T-DM1 no more than 12 weeks after definitive surgery.

[0201] E10. The preceding method according to any one of E-E9, wherein the patient is treated with T-DM1 infused at a dose of 3.6 mg / kg every 3 weeks.

[0202] E11. The preceding method according to any one of E-E10, wherein the patient is treated with T-DM1 infusion at a dose of 3.6 mg / kg every 3 weeks for fourteen cycles.

[0203] E12. The preceding method according to any one of E-E11, wherein the treatment significantly increases invasive disease-free survival (IDFS) compared to adjuvant treatment with trastuzumab.

[0204] E13. The preceding method according to any one of E-E12, wherein the treatment results in a reduction in distant recurrence compared to adjuvant treatment with trastuzumab.

[0205] F. In certain non-limiting embodiments, the presently disclosed subject matter provides a method for reducing the risk of cancer recurrence in a patient with HER2-positive early breast cancer, comprising administering to the patient an effective amount of trastuzumab emtansine conjugate (T-DM1), wherein the patient has not achieved a pathological complete response to neoadjuvant therapy and the patient has undergone definitive surgery prior to the administration of T-DM1.

[0206] F1. The aforementioned method according to F, wherein the method does not include prior or concurrent adjuvant treatment with chemotherapy.

[0207] F2. The preceding method according to F or F1, wherein the neoadjuvant therapy comprises a taxane and a HER2-targeted therapy.

[0208] F3. The preceding method according to any one of F-F2, wherein the neoadjuvant therapy comprises a taxane-containing chemotherapy regimen and trastuzumab.

[0209] F4. The preceding method according to any one of F-F3, wherein the patient has completed at least 16 weeks of neoadjuvant therapy.

[0210] F5. The preceding method according to any one of F-F4, wherein the patient has completed at least 6 cycles of taxane-containing neoadjuvant therapy.

[0211] F6. The preceding method according to any one of F-F5, wherein the patient is treated with T-DM1 no more than 12 weeks after definitive surgery.

[0212] F7. The preceding method according to any one of F-F6, wherein the patient is treated with T-DM1 infused at a dose of 3.6 mg / kg every 3 weeks.

[0213] F8. The aforementioned method according to any one of F-F7, wherein the patient is treated with T-DM1 infusion at a dose of 3.6 mg / kg every 3 weeks for fourteen cycles.

[0214] F9. The preceding method according to any one of F-F8, wherein the treatment significantly increases invasive disease-free survival (IDFS) compared to adjuvant treatment with trastuzumab.

[0215] F10. The preceding method according to any one of F-F9, wherein the treatment results in a reduction in distant recurrence compared to adjuvant treatment with trastuzumab.

[0216] F11. The preceding method according to any one of D-F10, wherein the adjuvant therapy reduces the risk of recurrence of invasive disease by 50% compared to adjuvant therapy with trastuzumab.

[0217] F12. The preceding method according to any one of D-F11, wherein the adjuvant therapy reduces the risk of distant recurrence by 40% compared to adjuvant trastuzumab.

[0218] Example

[0219] To illustrate the present disclosure, the following examples are included. However, it should be understood that these examples do not limit the present disclosure, but are merely intended to suggest exemplary methods of implementing the present disclosure.

[0220] Example 1 - Clinical trial design

[0221] Phase III clinical study

[0222] This phase 3, open-label study (NCT01772472 / BO27938 / NSABPB-50-I / GBG 77; KATHERINE) enrolled patients with HER2-positive early breast cancer who had received neoadjuvant taxane-containing chemotherapy plus HER2-targeted therapy containing trastuzumab and had pathological residual invasive disease in the breast and / or axillary lymph nodes. Patients were randomized to receive adjuvant T-DM1 or trastuzumab for 14 cycles. The primary endpoint was invasive disease-free survival (IDFS). The efficacy stopping margin for this single prespecified interim analysis of IDFS was P < 0.0124 or a hazard ratio of 0.732 or less.

[0223] patient

[0224] The patient population of this study was patients with primary non-metastatic HER2-positive breast cancer.

[0225] Inclusion criteria

[0226] Patients must meet the following criteria to enter the study:

[0227] 1. HER2-positive breast cancer. HER2-positive status will be based on pre-treatment biopsy material and defined as an immunohistochemistry (IHC) score of 3+ and / or positive confirmed prospectively by in situ hybridization (ISH) by a central laboratory at study enrollment. ISH positivity is defined as a ratio of HER2 gene copy number to chromosome 17 copy signal number ≥ 2.0. Formalin-fixed paraffin-embedded tumor tissue blocks or partial blocks must be available for central assessment of HER2 expression. If tissue blocks cannot be sent due to local regulations, at least 8 unstained slides should be sent for HER2 testing, and up to 5 additional slides should be sent for exploratory biomarker studies. The central laboratory will perform both IHC and ISH assays; however, only one positive result is required for eligibility. If insufficient material from the pre-treatment biopsy is available for submission, central HER2 testing of residual tumor tissue may be performed to determine eligibility starting at the time of definitive surgery. Patients with synchronous bilateral invasive disease are eligible as long as both lesions are HER2-positive.

[0228] 2. Histologically confirmed invasive breast cancer.

[0229] 3. Presenting clinical stage: T1–4, N0–3, M0 (Note: patients with T1a / bN0 tumors will not be eligible).

[0230] 4. Completion of preoperative systemic chemotherapy and HER2-targeted therapy. Systemic therapy must include at least 6 cycles of chemotherapy with a total duration of at least 16 weeks, including at least 9 weeks of trastuzumab and at least 9 weeks of taxane chemotherapy. In addition to taxane chemotherapy, patients may also receive anthracyclines as part of preoperative therapy. Patients receiving dose-dense chemotherapy regimens are eligible, provided that at least 8 weeks of taxane therapy and at least 8 weeks of trastuzumab have been given. Paclitaxel can be dose-escalated within 6 weeks (225 mg / m 2 q2w) dose-dense regimen. Patients can receive more than one HER2-targeted therapy. Note: HER2-targeted therapy alone will not meet the requirement for a preoperative systemic chemotherapy cycle. All systemic chemotherapy should be completed before surgery.

[0231] 5. Appropriate excision: Surgical removal of all clinically evident disease in the breast and lymph nodes as follows:

[0232] Breast Surgery: Mastectomy with no significant residual disease at the resection margins or breast-conserving surgery with negative histological resection margins. For patients who undergo breast-conserving surgery, specimens from the resection margins must be histologically free of invasive tumor and DCIS (as determined by a local pathologist). If pathological examination indicates tumor at the resection line, additional surgical procedures may be performed to obtain clear resection margins. If tumor is still present at the resection margins after reexcision, the patient must have undergone a mastectomy to be eligible. Patients with positive margins for lobular carcinoma in situ (LCIS) are eligible without further resection.

[0233] Lymph node surgery: If a fine needle aspiration, core biopsy, or sentinel lymph node biopsy is positive before preoperative therapy, additional surgical evaluation of the axilla is indicated after preoperative therapy. If micrometastases are present only in the sentinel lymph nodes preoperatively (i.e., if the largest lymph node metastasis in the sentinel lymph node is 0.2 mm or smaller in diameter), no additional surgical evaluation of the axilla is required. If a sentinel lymph node biopsy performed before preoperative therapy is negative, no additional surgical evaluation of the axilla is required after preoperative therapy. If the only sentinel lymph node identified by isotope scanning is in the internal mammary chain, surgical evaluation of the axilla is recommended.

[0234] If a sentinel lymph node biopsy is positive after preoperative therapy, additional surgical evaluation of the axilla is recommended. If a sentinel lymph node evaluation is negative after preoperative therapy, no additional surgical evaluation of the axilla is necessary. Axillary lymph node dissection without sentinel lymph node evaluation may be performed after preoperative therapy.

[0235] 6. Pathological evidence of residual invasive cancer in the breast or axillary lymph nodes after completion of preoperative therapy. If invasive disease is present in both breasts, residual invasive cancer must be present in at least 1 breast or axillary lymph node after surgery.

[0236] 7. The interval from the date of initial surgery to the date of randomization is no more than 12 weeks.

[0237] 8. Known hormone receptor status. Hormone receptor positive status can be determined by known positive ER or known PgR positive status. Hormone receptor negative status must be determined by known negative ER and known negative PgR.

[0238] 9. Sign a written informed consent approved by the Institutional Review Board (IRB) / Ethics Committee (EC) of the research institution.

[0239] 10. Age ≥ 18 years old

[0240] 11. Eastern Cooperative Oncology Group (ECOG) activity status of 0 or 1

[0241] 12. Life expectancy ≥ 6 months

[0242] 13. Adequate organ function during the screening period, defined as:

[0243] a. Absolute neutrophil count ≥ 1200 cells / mm 3

[0244] b. Platelet count ≥ 100,000 cells / mm 3

[0245] c. Hemoglobin ≥ 9.0 g / dL; patients can receive red blood cell transfusions to achieve this level

[0246] d. Serum creatinine <1.5× upper limit of normal (ULN)

[0247] e. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN

[0248] f. Serum AST and ALT ≤ 1.5 × ULN

[0249] g. Serum total bilirubin (TBILI) ≤ 1.0 × ULN (within the normal range), but direct bilirubin in patients with Gilbert's syndrome should be within the normal range

[0250] h. Serum alkaline phosphatase (ALK) ≤ 1.5 × ULN

[0251] i. After receiving neoadjuvant chemotherapy, the LVEF screened on ECHO or MUGA is ≥50%, and the absolute value of LVEF does not decrease by more than 15% compared with the LVEF before chemotherapy. Alternatively, if the LVEF before chemotherapy was not assessed, the LVEF screening must be ≥55% after completing neoadjuvant chemotherapy.

[0252] i. LVEF may be repeated up to 3 weeks after the initial screening assessment to assess eligibility.

[0253] 14. For non-postmenopausal (≥12 months of non-therapy-induced amenorrhea) or surgically infertile (no ovaries and / or uterus) women: agree to abstain from sex or use a single or combined contraceptive method that results in an annual failure rate of <1% during treatment and for at least 7 months after the last dose of study drug.

[0254] a. Abstinence is acceptable only if it is consistent with the patient's preference and customary lifestyle. Periodic abstinence (e.g., calendar, ovulation, symptothermal contraception, or post-ovulation methods) and withdrawal are not acceptable methods of contraception. Examples of contraception with annual failure rates of less than <1% include tubal ligation, male sterilization, hormonal implants, appropriate use of established combined oral or injectable hormonal contraceptives, and certain intrauterine devices. Alternatively, two methods (e.g., two barrier methods such as condoms and cervical caps) can be combined to achieve an annual failure rate of <1%. Spermicide must always be used to supplement barrier methods.

[0255] b. Male patients whose partners are pregnant must use condoms or actually abstain from sexual intercourse during pregnancy.

[0256] 15. Negative serum pregnancy test in premenopausal women (including women who have had tubal ligation) and women who are less than 12 months postmenopausal.

[0257] 16. Hepatitis B virus (HBV) and hepatitis C virus (HCV) serology needs to be documented: HB surface antigen (HBsAg) and / or total HB core antibody (anti-HBc) in addition to HCV antibody testing. The most recent serology testing must have been performed within 3 months prior to starting neoadjuvant therapy. If such testing has not yet been performed, it must be performed during the screening period.

[0258] Exclusion criteria

[0259] Patients who meet any of the following criteria will be excluded from the study:

[0260] Disease-related exclusion criteria:

[0261] 1. Stage IV (metastatic) breast cancer.

[0262] 2. Any history of previous breast cancer (ipsilateral or contralateral) other than lobular CIS.

[0263] 3. Evidence of clinically significant residual or recurrent disease after preoperative therapy and surgery.

[0264] 4. Conclusion of the overall response of PD to preoperative systemic therapy based on the investigator's conclusion.

[0265] 5. Treatment with any anticancer study drug within 28 days prior to the start of study treatment.

[0266] 6. History of other malignancies within the past 5 years, excluding appropriately treated CIS of the cervix, non-melanoma skin cancer, stage I uterine cancer, or other non-breast cancer malignancies with outcomes similar to those mentioned above.

[0267] 7. Patients in whom radiotherapy is recommended for breast cancer treatment but is contraindicated for medical reasons (e.g., patients with connective tissue disease or prior ipsilateral breast irradiation).

[0268] 8. Current NCI CTCAE (version 4.0) grade ≥ 2 peripheral neuropathy.

[0269] 9. History of exposure to the following cumulative doses of anthracyclines:

[0270] Doxorubicin > 240 mg / m 2 .

[0271] Epirubicin or liposomal doxorubicin-hydrochloride >480 mg / m 2 .

[0272] For other anthracyclines, exposure equivalent to doxorubicin > 240 mg / m 2 .

[0273] 10. Cardiopulmonary dysfunction as defined by any of the following:

[0274] a. History of symptomatic CHF according to NCI CTCAE (version 4.0) ≥ 3 or NYHA criteria ≥ II

[0275] b. Angina requiring use of antianginal medications, severe arrhythmias that cannot be controlled by appropriate medications, severe conduction abnormalities, or clinically important valvular disease.

[0276] c. High risk of uncontrolled arrhythmia: tachycardia, resting heart rate >100 / min, significant ventricular arrhythmia (ventricular tachycardia), or higher-grade atrioventricular block (second-degree atrioventricular block type 2 [Mobitz 2] or third-degree atrioventricular block).

[0277] d. Significant symptoms (grade ≥ 2) related to left ventricular dysfunction, arrhythmia, or cardiac ischemia during or after preoperative therapy.

[0278] e. History of LVEF reduction to <40% during prior trastuzumab treatment (e.g., preoperative therapy).

[0279] f. Uncontrolled hypertension (systolic blood pressure > 180 mmHg and / or diastolic blood pressure > 100

[0280] mmHg).

[0281] g. Evidence of ECG requirement for continuous oxygen therapy for transmural infarction.

[0282] 11. Prior treatment with trastuzumab emtansine conjugate.

[0283] General exclusion criteria

[0284] 12. Current severe uncontrolled systemic illness (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease; wound healing disorders; ulcers).

[0285] 13. For female patients, currently pregnant and / or breastfeeding.

[0286] 14. Major surgical procedures unrelated to breast cancer or major trauma within approximately 28 days prior to randomization or anticipated need for major surgery during study treatment.

[0287] 15. Any known active liver disease, e.g., disease due to HBV, HCV, autoimmune liver disease, or sclerosing cholangitis. Patients with positive HBV or HCV serology but without known active disease must meet the eligibility criteria for ALT, AST, TBILI, INR, aPTT, and alkaline phosphatase (ALK) on at least two consecutive occasions (at least 1 week apart) during the screening period of 30 days.

[0288] 16. Concurrent, major, uncontrolled infection or known HI infection.

[0289] 17. History of intolerance, including grade 3 to 4 infusion reactions or hypersensitivity reactions to trastuzumab or murine proteins or any components of the product.

[0290] 18. Active, unresolved infection requiring treatment at screening.

[0291] 19. The investigator's assessment is unable or unwilling to comply with the requirements of the protocol.

[0292] Study Design

[0293] Consenting and eligible patients will be randomized in a 1:1 ratio to one of the following treatment groups:

[0294] Group A: intravenous injection of trastuzumab emtansine conjugate 3.6 mg / kg q3w for 14 cycles.

[0295] Group B: Trastuzumab 6 mg / kg intravenously q3w for 14 cycles (a loading dose of 8 mg / kg should be given after an interval of more than 6 weeks from the last dose of trastuzumab).

[0296] The study will enroll approximately 1,484 patients with documented residual invasive disease in the breast or axillary lymph nodes on pathology after completion of preoperative therapy. Patients must have completed preoperative systemic therapy, including at least 6 cycles of a total duration of at least 16 weeks, including at least 9 weeks of trastuzumab and at least 9 weeks of taxane chemotherapy (or, if receiving a dose-dense chemotherapy regimen, at least 6-8 weeks of taxane therapy and at least 8 weeks of trastuzumab).

[0297] HER2-targeted therapy and chemotherapy can be given at the same time; patients can receive more than one HER2-targeted therapy. Patients can receive anthracyclines as part of preoperative therapy.

[0298] Patients will receive up to 14 cycles of study treatment; treatment will be discontinued prior to 14 cycles if disease relapses, toxicity is unacceptable, or the sponsor terminates the study. Patients who discontinue trastuzumab emtansine where appropriate due to toxicity concerns may complete the duration of study trastuzumab therapy. Following discontinuation or completion of study treatment, patients will continue to be followed for efficacy and safety goals until the end of the study.

[0299] Radiation therapy and / or hormonal therapy (for patients with hormone receptor-positive tumors) should be given concurrently with study treatment if indicated according to the following guidelines:

[0300] Patients who develop hormone receptor-positive disease should start hormonal therapy (aromatase inhibitors, tamoxifen, etc).

[0301] For patients undergoing breast-conserving surgery, radiation to the whole breast is indicated. Primary tumor bed boost radiation may be performed based on local policy. Regional nodal radiation is indicated if the patient has clinical T3 (except T3N0) or T4 disease and / or clinical N2 or N3 disease at initial presentation; recommended for T3N0 or if there is residual disease in the lymph nodes.

[0302] For patients after mastectomy, chest wall and regional lymph node radiation is indicated if the patient has clinical T3 (except T3N0) or T4 disease and / or clinical N2 or N3 disease at initial diagnosis; it is recommended for T3N0 or if there is residual disease in the lymph nodes. For patients after mastectomy who do not meet these criteria, radiation therapy is at the discretion of the investigator according to institutional standards.

[0303] A permuted block randomization scheme will be used to ensure an approximately 1:1 assignment of patients to receive either trastuzumab emtansine or trastuzumab for the following stratification factors:

[0304] Clinical stage at presentation: inoperable (stage T4NxM0 or TxN2-3M0), versus operable (stage T1-3N0-1M0)

[0305] Hormone receptor status: estrogen receptor (ER) or progesterone receptor (PgR) positive, versus ER and PgR negative / unknown

[0306] Preoperative HER2-targeted therapy: trastuzumab, and trastuzumab plus other HER2-targeted agents

[0307] · Evaluation of pathological lymph node status after preoperative therapy: positive lymph nodes vs. negative lymph nodes / no

[0308] Efficacy outcome measures

[0309] Primary efficacy outcome measures

[0310] The primary efficacy outcome measures for this study were as follows:

[0311] The primary efficacy outcome measure was IDFS, defined as the time from randomization to the date of the first occurrence of any of the following events:

[0312] ipsilateral invasive breast tumor recurrence (i.e., invasive breast cancer with breast parenchyma identical to the original primary lesion).

[0313] ipsilateral locoregional invasive breast cancer recurrence (i.e., invasive breast cancer in the axilla, regional lymph nodes, chest wall, and / or skin of the ipsilateral breast).

[0314] Distant recurrence (i.e., evidence of breast cancer at any anatomic site other than the two sites listed above) that has been histologically confirmed or clinically diagnosed as recurrent invasive breast cancer.

[0315] Contralateral invasive breast cancer.

[0316] Death attributed to any cause, including breast cancer, non-breast cancer, or

[0317] Unknown cause (but cause of death should be specified whenever possible).

[0318] Secondary efficacy outcome measures

[0319] Secondary efficacy outcome measures included the following:

[0320] IDFS including second primary non-breast cancer: The primary endpoint was defined the same as IDFS but included events of second primary non-breast cancer invasive cancer (excluding non-melanoma skin cancer and carcinoma in situ [CIS] of any site)

[0321] DFS: defined as the time from randomization to the first IDFS event (including a second primary non-breast cancer event or contralateral or ipsilateral ductal carcinoma in situ (DCIS))

[0322] OS: defined as the time from randomization to death due to any reason

[0323] DRFI: defined as the time between randomization and the date of distant breast cancer recurrence

[0324] Safety Outcome Measures

[0325] Clinical and laboratory AEs will be reported according to NCI CTCAE version 4.0. LVEF will be assessed by echocardiography (ECHO) or multi-gated acquisition (MUGA).

[0326] Safety will be measured by determining the incidence, nature, and severity of AEs. Safety outcome measures are the following protocol-specific AEs:

[0327] The incidence, type and severity of all AEs based on the NCI CTCAE version 4.0.

[0328] The incidence, type, and severity of SAEs.

[0329] The incidence and types of AEs leading to discontinuation, dose modification, or dose delay.

[0330] Causes of death in the study.

[0331] Abnormal laboratory values.

[0332] Reduced LVEF.

[0333] Cardiac events, defined as death from cardiac causes or severe CHF (NYHA class III or IV), a decrease in LVEF ≥10 percentage points from baseline to LVEF <50%. Patient-Reported Outcome (PRO) Measures

[0334] The PRO measures for this study were as follows:

[0335] The incidence of treatment-related symptoms and assessment of health-related quality of life (HRQOL) measured using the EORTC QLQ-C30 questionnaire and the QLQBR23 module.

[0336] Use EuroQol EQ-5D TM The questionnaire measures health status and assesses health status.

[0337] Dosage, Administration and Compliance

[0338] Trastuzumab emtansine conjugate

[0339] Trastuzumab emtansine conjugate (T-DM1) will be administered IV on Day 1 of a 3-week cycle q3w at a dose of 3.6 mg / kg. If timing coincides with a holiday that does not allow for administration, administration should be given within 5 working days of the scheduled date. The total dose will be calculated based on the patient's body weight on Day 1 (or up to 3 days prior) of each cycle, with no upper limit. A change in body weight of <10% from baseline does not require recalculation of the dose.

[0340] The trastuzumab emtansine conjugate dose may be reduced to 2.4 mg / kg according to the dose modification guidelines. A delay of up to 42 days from the last dose is permitted.

[0341] The first infusion of trastuzumab emtansine conjugate will be administered over 90 minutes (±10 minutes). The infusion may be slowed or interrupted for patients who experience infusion-related symptoms. Vital signs must be assessed before and after administration. After the initial dose, patients will be observed for at least 90 minutes for fever, chills, or other infusion-related symptoms. If the previous infusion was well tolerated (without any signs or symptoms of an infusion reaction), subsequent doses of trastuzumab emtansine conjugate may be administered over 30 minutes (±10 minutes) and observed for at least 30 minutes after the infusion. If applicable, local health authority guidance must be followed for further observation and monitoring. Prophylactic medications for nausea and infusion reactions (e.g., acetaminophen or other analgesics, antihistamines such as diphenhydramine, or corticosteroids) may be administered at the investigator's discretion.

[0342] Trastuzumab

[0343] Trastuzumab will be administered IV at a maintenance dose of 6 mg / kg on day 1 of a 3-week cycle. A loading dose of 8 mg / kg is required if >6 weeks have passed since the previous trastuzumab dose. If the timing coincides with a holiday that does not allow administration, administration should be given within 5 working days of the scheduled date.

[0344] Trastuzumab infusion should be given according to local guidelines and / or prescribing information.

[0345] Example 2 - Clinical Trial Results

[0346] Results from the Phase III KATHERINE (NCT01772472 / BO27938 / NSABPB-50-I / GBG 77) trial comparing adjuvant trastuzumab emtansine conjugate (T-DM1) with trastuzumab in patients with HER2-positive early breast cancer and residual invasive disease after neoadjuvant chemotherapy provide HER2-targeted therapy in this example.

[0347] Study Design

[0348] KATHERINE is a randomized, multicenter, open-label, phase 3 clinical trial in which eligible patients were randomized to receive either T-DM1 or trastuzumab as adjuvant therapy ( Figure 1 ).

[0349] Study Supervision

[0350] The study was designed by a steering committee consisting of members of the German Breast Group (GBG), the National Surgical Adjuvant Breast and Bowel Project (NSABP) Foundation, independent investigators, and the sponsor (F. Hoffmann–La Roche / Genentech) and conducted under the guidance of an independent data monitoring committee (IDMC). The sponsor collected data using a platform owned and managed by the NSABP Foundation. The IDMC reviewed the prespecified interim analysis and recommended reporting of the results. The sponsor and the agreed study steering committee jointly reviewed the proposal and interim analysis results. The steering committee vouches for the completeness and correctness of the data and analyses and for the accuracy of the protocol studies. The study was conducted in accordance with the amended Declaration of Helsinki and this protocol and was approved by the institutional review board at each participating center. All patients provided written informed consent.

[0351] patient

[0352] Eligible patients had histologically confirmed HER2-positive nonmetastatic invasive primary breast cancer (T1–4, N0–3, M0) with pathologically documented residual invasive disease in the breast and / or axillary lymph nodes after neoadjuvant therapy and surgical resection. HER2 status was based on pretreatment biopsy specimens and centrally confirmed prior to study enrollment. Patients had to have completed at least 6 cycles (16 weeks) of preoperative chemotherapy and at least 9 weeks of taxane therapy and at least 9 weeks of trastuzumab therapy (dose-dense regimens allowed for shorter treatment durations). Anthracyclines and other HER2-targeted agents were permitted. Exclusion criteria included initial clinical stage T1a / bN0; gross residual disease at resection margins; recurrent or progressive disease after preoperative systemic therapy; cardiopulmonary impairment, including a history of New York Heart Association class II or greater heart failure or a decrease in left ventricular ejection fraction to less than 40% with prior trastuzumab use; and prior cumulative exposure to more than 240 mg / m2 of doxorubicin. 2 equivalent.

[0353] According to the American Society of Clinical Oncology / American College of Pathologists guidelines, HER2-positive status is defined as an immunohistochemical score of 3+ and / or HER2 amplification by in situ hybridization, defined as a ratio of HER2 gene copy number to chromosome 17 copy signal number equal to or greater than 2.0 based on local pathology of the primary tumor.

[0354] treat

[0355] Patients were randomized in a 1:1 ratio within 12 weeks after surgery using an interactive voice or web-response system, with a stratified randomization scheme according to clinical stage at presentation (inoperable [tumor stage T4 or lymph node stage N2 or N3, and metastatic stage M0] vs. operable [tumor stage T1 to T3, lymph node stage N0 or N1, and metastatic stage M0]); hormone receptor status per local laboratory (positive, vs. negative or unknown); preoperative HER2-targeted therapy (trastuzumab, vs. trastuzumab plus other HER2-targeted agents); and lymph node status assessed after neoadjuvant therapy (node-positive, vs. node-negative / not performed).

[0356] Patients received either T-DM1 3.6 mg per kg body weight or trastuzumab 6 mg per kg body weight administered intravenously every 3 weeks for 14 cycles. A trastuzumab loading dose of 8 mg per kg was administered if more than 6 weeks had passed since the last trastuzumab dose. Patients who discontinued T-DM1 due to toxicity could complete 14 study treatment cycles of trastuzumab at the discretion of the investigator. Endocrine and radiation therapy were performed according to institutional standards and protocols.

[0357] Evaluate

[0358] Reassessment of metastatic disease after neoadjuvant therapy and surgery but before randomization was not mandatory. Disease recurrence was assessed every 3 months for 2 years, every 6 months from years 3 to 5, and annually from years 6 to 10. Patients were evaluated for toxicity before each dose of study drug. Left ventricular ejection fraction was assessed in the last week of cycle 2, every 4 cycles thereafter, at months 3, 6, 12, 18, and 24 after completion of study drug, and then annually until year 5.

[0359] Statistical analysis

[0360] The primary end point was invasive disease-free survival, defined as the date from randomization to the first invasive disease event: recurrence of ipsilateral invasive breast cancer, recurrence of ipsilateral locoregional invasive disease, recurrence of distant disease, contralateral invasive breast cancer, or death from any cause. The standardized definition of efficacy end points (STEEP) included a second primary non-breast cancer as an event for invasive disease-free survival (Hudis JCO 2007); this definition was included as a secondary end point. Other secondary end points included disease-free survival, overall survival, distant recurrence-free survival, and safety.

[0361] Based on the requirement for 384 invasive disease events, a sample size of 1484 patients was planned to provide 80% power to detect a hazard ratio of 0.75 with a 2-sided significance level of 5% in the primary analysis. This calculation assumed 3-year invasive disease-free survival rates of 75.6% (T-DM1) and 70.0% (trastuzumab), respectively. An interim analysis of invasive disease-free survival was planned when approximately 267 (67%) target invasive disease events had occurred, with a power stopping boundary of P < 0.0124 or an observed hazard ratio of 0.732 or less. The results of the interim analysis were beyond the scope of the earlier report.

[0362] Primary analyses were performed in the intention-to-treat population. Survival without invasive disease was compared between groups with the use of a stratified log-rank test. Hazard ratios and their 95% confidence intervals (CIs) were estimated with the use of Cox proportional hazards models. The 3-year event-free rate in each treatment group was estimated with the use of the Kaplan-Meier method. Data from patients without a documented event were censored to the date on which the patient was last known to be alive and event-free.

[0363] If the interim invasive-disease-free survival analysis exceeded the prespecified limit, a first interim overall survival analysis was planned. The overall type I error for overall survival was controlled at 0.05 with the use of the Lan–DeMets alpha-spending function with the O'Brien–Fleming bound.

[0364] result

[0365] 1486 patients were enrolled and randomized (T-DM1, n = 743; trastuzumab, n = 743). In the intention-to-treat population, the median follow-up was approximately 41 months. Baseline characteristics were balanced between treatment groups ( Figure 2A-2C ). Hormone receptor-positive disease was present in 72.3% of patients. 76.9% of patients received anthracyclines, and an additional 19.5% received other HER2-targeted therapy (usually pertuzumab) as part of neoadjuvant therapy.

[0366] effect

[0367] The primary endpoint was met in this preplanned interim analysis. Patients who received T-DM1 had a statistically significant improvement in invasive disease-free survival compared with trastuzumab (hazard ratio, 0.50; 95% CI, 0.39 to 0.64; P < 0.0001) ( Figure 3 A hazard ratio of 0.50 indicated that monovalent adjuvant therapy with T-DM1 reduced the risk of recurrence of invasive disease by 50% compared with adjuvant therapy with trastuzumab.

[0368] Invasive disease-free survival events occurred in 91 patients (12.2%) who received T-DM1 and in 165 patients (22.2%) who received trastuzumab. The 3-year invasive disease-free survival rates were estimated to be 88.3% (T-DM1) and 77.0% (trastuzumab). Distant recurrence as first invasive disease occurred in 78 patients (10.5%) who received T-DM1 and in 118 patients (15.9%) who received trastuzumab. Figure 4A , Figure 4B ).

[0369] The risk of distant recurrence was lower in the T-DM1 group than in the trastuzumab group (hazard ratio, 0.60; 95% CI, 0.45 to 0.79 ( Figure 5 The hazard ratio of 0.60 indicated that monovalent adjuvant therapy with T-DM1 reduced the risk of distant recurrence by 40% compared with adjuvant trastuzumab.

[0370] Including second primary nonbreast cancer as an invasive disease event, the number of patients with events increased to 95 (12.8%) in the T-DM1 group and 167 (22.5%) in the trastuzumab group; the difference in invasive disease-free survival still favored T-DM1 (hazard ratio, 0.51; 95% CI, 0.40 to 0.66; P<0.0001)( Figure 5 ).

[0371] Subgroup analysis of invasive disease-free survival showed that T-DM1 was significantly more effective in the subgroups of patients ( Fig. 6A and 6B The benefit was consistent across all groups, including those with hormone receptor-positive disease (hazard ratio, 0.48; 95% CI, 0.35 to 0.67), those with hormone receptor-negative disease (hazard ratio, 0.50; 95% CI, 0.33 to 0.74), those with pathological node-positive status after preoperative therapy (hazard ratio, 0.52; 95% CI, 0.38 to 0.71), those with node-negative disease (hazard ratio, 0.44; 95% CI, 0.28 to 0.68), those with small residual disease (ypT0 / ypT1a / ypT1b / ypTmic / ypTis (hazard ratio, 0.66; 95% CI, 0.44 to 1.00), those receiving neoadjuvant trastuzumab alone (hazard ratio, 0.49; 95% CI, 0.37 to 0.65), and those receiving neoadjuvant trastuzumab plus any other HER2-targeted therapy (hazard ratio, 0.54; 95% CI, 0.54 to 1.00). 0.27 to 1.06). Similar results were observed when T-DM1 was compared with trastuzumab in patients who received neoadjuvant trastuzumab alone, or in patients who received neoadjuvant trastuzumab plus pertuzumab. Benefit of adjuvant T-DM1 relative to adjuvant trastuzumab was observed independent of neoadjuvant HER2-targeted therapy. Among patients who received neoadjuvant trastuzumab with chemotherapy, invasive disease events occurred in 78 patients in the T-DM1 group and 141 patients in the adjuvant trastuzumab group (hazard ratio, 0.49; 95% CI, 0.37 to 0.65). Among patients who received neoadjuvant trastuzumab plus a second HER2-targeted therapy with chemotherapy, invasive disease events occurred in 13 patients in the T-DM1 group and 24 patients in the adjuvant trastuzumab group (hazard ratio, 0.54; 95% CI, 0.53 to 0.71). Pertuzumab was the second therapy in 93.8% of patients who received a second neoadjuvant HER2-targeted agent, and in this group, invasive disease events occurred in 12 patients in the T-DM1 group and in 24 patients in the adjuvant trastuzumab group (hazard ratio, 0.50; 95% CI, 0.25 to 1.00). Figure 7 ). Other HER2-targeted therapies used as second therapy include lapatinib, neratinib, dacomitinib, and afatinib.

[0372] There were 98 deaths (42 (5.7%) with T-DM1 and 56 (7.5%) with trastuzumab), and the overall survival analysis was not mature and did not cross the boundary (hazard ratio, 0.70; 95% CI, 0.47 to 1.05; P = .08) ( Figure 5 and Figure 8 The number of patients who died without prior invasive disease was 2 (T-DM1) and 3 (trastuzumab).

[0373] Security

[0374] A total of 1460 patients were included in the safety analysis (n = 740, T-DM1; n = 720, trastuzumab). The planned 14 cycles of randomized study treatment were completed by 70.9% (T-DM1) and 78.7% (trastuzumab) of patients. Sixty-five patients discontinued T-DM1 and continued to receive trastuzumab, completing a total of 14 treatment cycles. The most common grade 3 or higher adverse events were decreased platelet count and hypertension in the T-DM1 group and hypertension and radiation-induced skin injury in the trastuzumab group. Serious adverse events occurred in 94 patients (12.7%) receiving T-DM1 and 59 patients (8.2%) receiving trastuzumab. Adverse events leading to discontinuation of randomized treatment occurred in 18.0% of T-DM1-treated patients and 2.1% of trastuzumab-treated patients. Two fatal adverse events occurred, one in each group, including intracranial hemorrhage and encephalitis.

[0375] Radiation pneumonitis of any grade occurred in 11 patients treated with T-DM1 (1.5%) and in 5 patients treated with trastuzumab (0.7%). Increases in aminotransferases of any grade occurred more frequently with TDM-1 (alanine aminotransferase, 23.1%; aspartate aminotransferase, 28.4%) than with trastuzumab (alanine aminotransferase, 5.7%; aspartate aminotransferase, 5.6%). These increases led to discontinuation of T-DM1 in 1.5% of patients (alanine aminotransferase) and 1.6% of patients (aspartate aminotransferase). No patient in the trastuzumab group discontinued treatment because of increases in aminotransferases. Two adjudicated cases of nodular regenerative hyperplasia occurred in the T-DM1 group.

[0376] discuss

[0377] In the KATHERINE trial, adjuvant treatment with T-DM1 reduced the risk of invasive disease recurrence or death by 50% compared with adjuvant trastuzumab in patients with HER2-positive early breast cancer and residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy. Subgroup analyses showed consistent benefits regardless of hormone receptor status, the extent of residual disease at surgery, single or two HER2-targeted therapies in the neoadjuvant setting, and the patients’ baseline characteristics. Importantly, fewer patients who received T-DM1 (10.5%) experienced distant recurrence as a first invasive disease event compared with trastuzumab (15.9%). These results represent a major treatment advance in this high-risk population.

[0378] Currently, the choice of adjuvant therapy for patients with residual invasive disease after neoadjuvant therapy is based on data from trials in other settings. APHINITY showed a disease-free survival advantage with adjuvant chemotherapy plus pertuzumab plus trastuzumab dual HER2 blockade compared with chemotherapy alone in patients with node-positive or high-risk node-negative disease (hazard ratio 0.81; 95% CI 0.66 to 1.00; P = 0.045) (von Minckwitz NEJM 2017). Despite these data, the benefit of additional adjuvant dual blockade therapy after neoadjuvant dual blockade plus chemotherapy remains unknown. Subgroup analyses from KATHERINE suggest that T-DM1 may be an appropriate option for patients with residual disease and provide evidence that patients who receive neoadjuvant dual HER2 blockade plus trastuzumab and chemotherapy derive benefit from switching to T-DM1 (hazard ratio 0.54; 95% CI 0.27 to 1.06). This benefit was consistent with that observed in patients who received preoperative chemotherapy plus trastuzumab (hazard ratio, 0.49; 95% CI, 0.37 to 0.65).

[0379] The overall safety profile of T-DM1 was generally consistent with that observed in the metastatic setting, with an expected increase in adverse events associated with T-DM1 compared with trastuzumab alone.

[0380] References

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[0382] de Azambuja E, Holmes AP, Piccart-Gebhart M, et al., Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol 2014;15:1137-46.

[0383] Diéras V, Miles D, Verma S, et al., Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol 2017;18:732-742.

[0384] Diéras V, Harbeck N, Budd GT, et al., Trastuzumab emtansine in human epidermal growth factor receptor 2-positive metastatic breast cancer: an integrated safety analysis. J Clin Oncol. 2014;32(25):2750-2757.

[0385] Egloff H, Kidwell KM, Schott A. Ado-trastuzumab emtansine-induced pulmonary toxicity: a single-institution retrospective review. Case Rep Oncol. 2018;11:527-533.

[0386] Gianni L, Eiermann W, Semiglazov V, et al., Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol 2014;15:640-7.

[0387] Gianni L, Pienkowski T, Im YH, et al., 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol 2016;17:791-800.

[0388] Gullo G, Walsh N, Fennelly D, et al., Impact of timing of trastuzumab initiation on long-term outcome of patients with early-stage HER2-positive breast cancer: the "one thousand HER2 patients" project. Br J Cancer 2018;119:374-380.

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[0390] Hurvitz SA, Martin M, Symmans WF, et al., Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2 - positive breast cancer (KRISTINE): a randomised, open - label, multicentre, phase 3 trial. Lancet Oncol 2018;19:115 - 126.

[0391] Junttila TT, Li G, Parsons K, Phillips GL, et al., Trastuzumab - DM1 (T - DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat 2011;128:347 - 56.

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[0394] Krop IE, Kim SB, Martin AG, et al., Trastuzumab emtansine versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol 2017;18:743-754.

[0395] Krop IE, Suter TM, Dang CT, et al., Feasibility and cardiac safety of trastuzumab emtansine after anthracycline-based chemotherapy as (neo)adjuvant therapy for human epidermal growth factor receptor 2-positive early-stage breast cancer. J Clin Oncol 2015;33:1136-42.

[0396] Lewis Phillips GD, Li G, Dugger DL, et al., Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res 2008;68:9280-90.

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[0398] Martin M, Holmes FA, Ejlertsen B, et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2017; 18: 1688-1700.

[0399] Masuda N, Lee SJ, Ohtani S, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med 2017; 376: 2147-2159.

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[0405] Untch M, Fasching PA, Konecny GE, et al., Pathologic complete response after neoadjuvant chemotherapy plus trastuzumab predicts favorable survival in human epidermal growth factor receptor 2-overexpressing breast cancer: results from the TECHNO trial of the AGO and GBG study groups. J Clin Oncol 2011;29:3351-7.

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[0410] The foregoing description is considered to be merely an illustration of the principles of the present disclosure. In addition, since many modifications and changes will be apparent to those skilled in the art, it is not desirable to limit the present disclosure to the exact configuration and process as described above. Therefore, it is contemplated that all suitable modifications and equivalents fall within the scope of the present disclosure as defined by the appended claims.

[0411] The present disclosure relates to the following embodiments:

[0412] 1. A method of adjuvant therapy comprising administering an effective amount of trastuzumab emtansine (T-DM1) as monotherapy to a patient with HER2-positive early breast cancer, wherein the patient has residual disease after preoperative systemic treatment.

[0413] 2. The method of claim 1 , wherein the residual disease is present in the breast.

[0414] 3. A method according to claim 1, wherein the residual disease is present in the lymph nodes.

[0415] 4. The method of claim 1 , wherein the residual disease is present in the breast and lymph nodes.

[0416] 5. A method according to any one of items 1-4, wherein the preoperative systemic treatment comprises HER2 targeted therapy.

[0417] 6. The method of claim 5, wherein the HER2 targeted therapy comprises trastuzumab.

[0418] 7. The method according to claim 6, wherein the HER2 targeted therapy further comprises Pertuzumab.

[0419] 8. The method according to item 5 or 6, wherein the HER2 targeted therapy further comprises an agent selected from the group consisting of lapatinib, neratinib, dacomitinib, afatinib and a combination thereof.

[0420] 9. The method according to any one of items 5-8, wherein the preoperative systemic treatment further comprises a taxane.

[0421] 10. A method according to any one of items 1-9, wherein the patient is an adult patient.

[0422] 11. The method according to any one of items 1-10, wherein the patient undergoes definitive surgery prior to administration of T-DM1.

[0423] 12. The method of claim 11, wherein T-DM1 is administered to the patient no more than 12 weeks after the definitive surgery.

[0424] 13. The method according to any one of items 1-12, wherein the patient has completed at least 16 weeks of preoperative systemic treatment with a taxane-containing chemotherapy regimen and a HER2-targeted therapy.

[0425] 14. The method according to any one of items 1-13, wherein the patient has completed at least 6 cycles of taxane-containing chemotherapy.

[0426] 15. The method according to any one of items 1-14, wherein T-DM1 is administered to the patient at a dose of 3.6 mg / kg every 3 weeks.

[0427] 16. The method according to any one of items 1-15, wherein T-DM1 is administered to the patient at a dose of 3.6 mg / kg every 3 weeks for fourteen cycles.

[0428] 17. The method according to any one of items 1-16, wherein the adjuvant therapy significantly increases invasive disease-free survival (IDFS) compared to adjuvant therapy with trastuzumab.

[0429] 18. The method according to any one of items 1-17, wherein the adjuvant therapy reduces the risk of recurrence of invasive disease by 50% compared to adjuvant therapy with trastuzumab.

[0430] 19. The method according to any one of items 1-18, wherein the adjuvant therapy results in a reduction in distant recurrence compared to adjuvant therapy with trastuzumab.

[0431] 20. The method according to any one of items 1-19, wherein the adjuvant therapy reduces the risk of distant recurrence by 40% compared to adjuvant trastuzumab.

[0432] 21. Trastuzumab emtansine (T-DM1) for use in the adjuvant treatment of HER2-positive early breast cancer in a patient, wherein the adjuvant is a monotherapy and wherein the patient has residual disease after preoperative systemic therapy.

[0433] 22. T-DM1 for use according to item 21, wherein the residual disease is present in the breast, in the lymph nodes, or in the breast and lymph nodes.

[0434] 23. T-DM1 for use according to item 21 or 22, wherein the preoperative systemic treatment comprises HER2 targeted therapy.

[0435] 24. T-DM1 for use according to item 23, wherein the HER2 targeted therapy comprises trastuzumab or trastuzumab and pertuzumab, lapatinib, neratinib, dacomitinib and / or afatinib.

[0436] 25. T-DM1 for use according to any one of items 21-25, wherein the preoperative systemic treatment further comprises a taxane.

[0437] 26. T-DM1 for use according to any one of items 21 to 25, wherein the patient is an adult patient.

[0438] 27. T-DM1 for use according to any one of items 21-26, wherein the patient undergoes definitive surgery prior to administration of T-DM1.

[0439] 28. T-DM1 for use according to any one of items 21-27, wherein the adjuvant therapy significantly increases invasive disease free survival (IDFS) compared to adjuvant therapy with trastuzumab.

[0440] 29. T-DM1 for use according to any one of items 21 to 28, wherein the adjuvant therapy reduces the risk of recurrence of invasive disease by 50% compared to adjuvant therapy with trastuzumab.

[0441] 30. T-DM1 for use according to any one of items 21-29, wherein the adjuvant therapy results in a reduction in distant recurrence compared to adjuvant therapy with trastuzumab.

[0442] 31. T-DM1 for use according to any one of items 21-30, wherein the adjuvant therapy reduces the risk of distant recurrence by 40% compared to adjuvant trastuzumab.

[0443] 32. Use of trastuzumab emtansine (T-DM1) in the preparation of a medicament for adjuvant therapy of HER2-positive early breast cancer in a patient, wherein the adjuvant is a monotherapy, and wherein the patient has residual disease after preoperative systemic therapy.

[0444] 33. The use according to claim 32, wherein the residual disease is present in the breast, in the lymph nodes, or in the breast and lymph nodes

[0445] 34. The use according to item 32 or 33, wherein the preoperative systemic treatment comprises HER2 targeted therapy.

[0446] 35. The use according to claim 34, wherein the HER2 targeted therapy comprises trastuzumab or trastuzumab and pertuzumab, lapatinib, neratinib, dacomitinib and / or afatinib.

[0447] 36. The use according to any one of items 32-35, wherein the preoperative systemic treatment further comprises a taxane.

[0448] 37. The use according to any one of items 32-36, wherein the patient is an adult patient.

[0449] 38. The use according to any one of items 32-37, wherein the patient undergoes definitive surgery prior to administration of T-DM1.

[0450] 39. The use according to any one of items 32-38, wherein the adjuvant therapy significantly increases invasive disease-free survival (IDFS) compared to adjuvant therapy with trastuzumab.

[0451] 40. The use according to any one of items 32-39, wherein the adjuvant therapy reduces the risk of recurrence of invasive disease by 50% compared to adjuvant therapy with trastuzumab.

[0452] 41. The use according to any one of items 32-40, wherein the adjuvant therapy results in a reduction in distant recurrence compared to adjuvant therapy with trastuzumab.

[0453] 42. The use according to any one of items 32-41, wherein the adjuvant therapy reduces the risk of distant recurrence by 40% compared to adjuvant trastuzumab.

[0454] 44. A method for treating breast cancer in a HER2-positive early breast cancer patient with residual disease in the breast or axillary lymph nodes after neoadjuvant therapy with chemotherapy and HER2-targeted therapy, the method comprising:

[0455] (i) definitive surgical removal of all clinically evident tumor cells from the breast and axillary lymph nodes; and

[0456] (ii) allowing the patient to receive adjuvant monotherapy with trastuzumab emtansine (T-DM1).

[0457] 45. The method of item 44, wherein the patient has residual disease in the breast or axillary lymph nodes after neoadjuvant therapy with a taxane and a HER2-targeted therapy.

[0458] 46. ​​The method according to any one of items 44 or 45, wherein the patient has completed at least 16 weeks of neoadjuvant therapy with taxane-containing chemotherapy.

[0459] 47. The method according to any one of items 44-46, wherein the patient has completed at least 6 cycles of taxane-containing chemotherapy.

[0460] 48. A method according to any one of items 44-47, wherein the patient receives adjuvant treatment with T-DM1 no more than 12 weeks after definitive surgery.

[0461] 49. A method according to any one of items 44-48, wherein the patient is treated with adjuvant therapy by infusion of T-DM1 at a dose of 3.6 mg / kg every 3 weeks.

[0462] 50. The method according to any one of items 44-49, wherein the patient is treated with adjuvant T-DM1 infused at a dose of 3.6 mg / kg every 3 weeks for fourteen cycles.

[0463] 51. A method according to any one of items 44-50, wherein the treatment significantly increases invasive disease-free survival (IDFS) compared to adjuvant treatment with trastuzumab.

[0464] 52. A method according to any one of items 44-51, wherein the treatment results in a reduction in distant recurrence compared to adjuvant therapy with trastuzumab.

[0465] 53. A method for treating HER2-positive early breast cancer in a patient having residual disease following neoadjuvant therapy, the method comprising administering to the patient an effective amount of trastuzumab emtansine (T-DM1) after the patient has undergone definitive surgery.

[0466] 54. A method according to claim 53, wherein the residual disease is pathological residual invasive disease.

[0467] 55. A method according to claim 53 or 54, wherein the residual disease is pathological residual invasive disease in the lymph nodes.

[0468] 56. A method according to any one of items 53-55, wherein the residual disease is pathological residual invasive disease in the breast.

[0469] 57. A method according to any one of items 53-56, wherein the method does not include prior or concurrent adjuvant chemotherapy.

[0470] 58. A method according to any one of items 53-57, wherein the neoadjuvant therapy comprises a taxane and a HER2-targeted therapy.

[0471] 59. The method according to any one of items 53-58, wherein the neoadjuvant therapy comprises a taxane and trastuzumab.

[0472] 60. A method according to any one of items 53-59, wherein the patient has completed at least 16 weeks of neoadjuvant therapy.

[0473] 61. The method according to any one of items 53-60, wherein the patient has completed at least 6 cycles of taxane-containing neoadjuvant therapy.

[0474] 62. A method according to any one of items 53-61, wherein the patient receives T-DM1 treatment no more than 12 weeks after definitive surgery.

[0475] 63. A method according to any one of items 53-62, wherein the patient is treated with T-DM1 infused at a dose of 3.6 mg / kg every 3 weeks.

[0476] 64. A method according to any one of items 53-63, wherein the patient is treated with T-DM1 infusion at a dose of 3.6 mg / kg every 3 weeks for fourteen cycles.

[0477] 65. A method according to any one of items 53-64, wherein the treatment significantly increases invasive disease-free survival (IDFS) compared to adjuvant treatment with trastuzumab.

[0478] 66. A method according to any one of items 53-65, wherein the treatment results in a reduction in distant recurrence compared to adjuvant treatment with trastuzumab.

[0479] 67. A method for reducing the risk of cancer recurrence in a patient with HER2-positive early breast cancer, comprising administering to the patient an effective amount of trastuzumab emtansine (T-DM1), wherein the patient has not achieved a pathological complete response to neoadjuvant therapy and the patient has undergone definitive surgery prior to the administration of T-DM1.

[0480] 68. A method according to claim 67, wherein the method does not include prior or concurrent adjuvant chemotherapy.

[0481] 69. The method of item 67 or 68, wherein the neoadjuvant therapy comprises a taxane and a HER2-targeted therapy.

[0482] 70. The method according to any one of items 67-69, wherein the neoadjuvant therapy comprises a taxane-containing chemotherapy regimen and trastuzumab.

[0483] 71. A method according to any one of items 67-70, wherein the patient has completed at least 16 weeks of neoadjuvant therapy.

[0484] 72. The method according to any one of items 67-71, wherein the patient has completed at least 6 cycles of taxane-containing neoadjuvant therapy.

[0485] 73. A method according to any one of items 67-72, wherein the patient receives T-DM1 treatment no more than 12 weeks after definitive surgery.

[0486] 74. A method according to any one of items 67-73, wherein the patient is treated with T-DM1 infused at a dose of 3.6 mg / kg every 3 weeks.

[0487] 75. A method according to any one of items 67-74, wherein the patient is treated with T-DM1 infusion at a dose of 3.6 mg / kg every 3 weeks for fourteen cycles.

[0488] 76. A method according to any one of items 67-75, wherein the treatment significantly increases invasive disease-free survival (IDFS) compared to adjuvant treatment with trastuzumab.

[0489] 77. A method according to any one of items 67-76, wherein the treatment results in a reduction in distant recurrence compared to adjuvant treatment with trastuzumab.

[0490] 78. The method according to any one of items 44-77, wherein the adjuvant therapy reduces the risk of recurrence of invasive disease by 50% compared to adjuvant therapy with trastuzumab.

[0491] 79. The method according to any one of items 44-78, wherein the adjuvant therapy reduces the risk of distant recurrence by 40% compared to adjuvant trastuzumab.

Claims

1. A method of adjuvant therapy comprising administering an effective amount of trastuzumab emtansine (T-DM1) as monotherapy to a patient with HER2-positive early breast cancer, wherein the patient has residual disease after preoperative systemic treatment.

2. The method of claim 1, wherein the residual disease is present in the breast.

3. The method of claim 1, wherein the residual disease is present in lymph nodes.

4. The method of claim 1, wherein the residual disease is present in the breast and lymph nodes.

5. The method of any one of claims 1-4, wherein the preoperative systemic treatment comprises HER2-targeted therapy.

6. The method of claim 5, wherein the HER2 targeted therapy comprises trastuzumab.

7. The method of claim 6, wherein the HER2 targeted therapy further comprises Pertuzumab.

8. The method of claim 5 or 6, wherein the HER2 targeted therapy further comprises an agent selected from the group consisting of lapatinib, neratinib, dacomitinib, afatinib, and a combination thereof.

9. The method of any one of claims 5-8, wherein the preoperative systemic therapy further comprises a taxane.

10. The method according to any one of claims 1-9, wherein the patient is an adult patient.

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