Method of treating residual breast cancer with ado-trastuzumab emtansine

Abstract

To provide a medicament for patients with HER2 positive early stage breast cancers who do not achieve complete pathologic remission using neo-adjuvant therapy consisting of standard chemotherapies and HER2 targeted therapies.SOLUTION: Provided is a medicament for adjuvant therapy in patients with DM1 positive early breast cancer comprising an effective amount of trastuzumab emtansine (T - HER2), wherein T - DM1 is administered as a single therapy, wherein the first administration occurs over about 80 minutes to about 100 minutes and the subsequent administrations occur over about 20 minutes to about 40 minutes, and wherein the patients have residual disease in the breast and / or lymph nodes following preoperative systemic treatment, wherein the preoperative systemic treatment comprises HER2 targeted therapy and taxanes.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 745,914, filed October 15, 2018, the disclosure of which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates to methods of using trastuzumab emtansine (T-DM1) for the treatment of residual breast cancer. [Background technology]

[0003] Breast cancer is a significant cause of morbidity and mortality worldwide. More than 1.3 million cases of breast cancer are diagnosed worldwide each year, with more than 450,000 deaths related to the disease (Jemal A, Bray F, Center M, et al. "Global cancer statistics." CA Cancer J Clin 2011;61(2):69-90).

[0004] HER2 (ErbB2) receptor tyrosine kinase is a member of the epidermal growth factor receptor (EGFR) family of transmembrane receptors. HER2 overexpression is observed in approximately 20% of human breast cancers (hereinafter referred to as HER2-positive breast cancer) and is associated with the aggressive growth and poor clinical outcomes associated with these tumors (Slamon et al. (1987) Science 235:177-182). HER2 protein overexpression can be determined using immunohistochemistry-based evaluation of fixed tumor blocks (Press MF, et al. (1993) Cancer Res 53:4960-70).

[0005] Trastuzumab (CAS 180288-69-1, HERCEPTIN®, huMAb4D5-8, rhuMAb HER2, Genentech) is a recombinant DNA-derived IgG1κ monoclonal antibody that selectively binds to the extracellular domain of HER2 with high affinity in cell-based assays (Kd=5 nM). It is a humanized form of the murine anti-HER2 antibody (4D5) (U.S. Pat. Nos. 5,677,171, 5,821,337, 6,054,297, 6,165,464, 6,339,142, 6,407,213, 6,639,055, 6,719,971, 6,800,738, 7,074,404; Coussens et al. (1985) Science 230:1132-9; Slamon et al. (1985) Science 230:1132-9). al (1989) Science 244:707-12; Slamon et al (2001) New Engl. J. Med. 344:783-792). Trastuzumab has been shown to inhibit the growth of HER2-overexpressing human tumor cells 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).

[0006] HERCEPTIN® was approved in 1998 for the treatment of patients with HER2-overexpressing metastatic breast cancer who had received extensive prior anticancer therapy (Baselga et al, (1996) J. Clin. Oncol. 14:737-744) and has since been used in over 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, the FDA approved HERCEPTIN® (trastuzumab, Genentech Inc.) as part of a treatment regimen containing doxorubicin, cyclophosphamide, and paclitaxel for the adjuvant treatment of patients with HER2-positive, node-positive breast cancer.

[0007] An alternative approach to antibody-targeted therapy is to utilize antibodies to deliver cytotoxic drugs specifically to antigen-expressing tumor cells. Antibody-drug conjugates, or ADCs, are monoclonal antibodies to which highly potent cytotoxic drugs have already been conjugated. ADCs represent a novel approach to impart tumor selectivity to systemically administered antitumor therapies. Using tumor-specific and / or overexpressed surface antigens, ADCs are designed to target the delivery of highly potent cytotoxic drugs to tumor cells. The potential of this approach is to generate a more beneficial therapeutic window for such agents than would be achievable by administering them as free drugs.

[0008] Maytansinoids, derivatives of the antimitotic drug maytansine, bind to microtubules in a manner similar to vinca alkaloid drugs (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 maytansinoid derived from the natural product ester ansamitocin 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). A related plant ester, maytansine, has been studied as a chemotherapy agent in approximately 800 patients, with a dose of 2.0 mg / m2 given either as a single dose or on three consecutive days every three weeks. 2 (Issell BF, Crooke ST. (1978) Maytansine. Cancer Treat Rev 5:199-207). Despite preclinical activity, the clinical activity of maytansine has been modest at doses that could be safely delivered. The dose-limiting toxicity (DLT) was gastrointestinal toxicity, consisting of nausea, vomiting, and diarrhea (often followed by constipation). These toxicities were dose-dependent but not schedule-dependent. Peripheral neuropathy (primarily sensory) has been reported, most commonly in patients with pre-existing neuropathy. Asymptomatic, transient elevations in hepatic transaminases, alkaline phosphatase, and total bilirubin have been reported. Constitutional toxicity, including weakness, lethargy, dysphoria, and insomnia, was common. More rare toxicities included infusion-site phlebitis and mild myelosuppression. Further development of the drug was halted in the 1980s due to a narrow therapeutic window.

[0009] Trastuzumab emtansine (T-DM1, trastuzumab-MCC-DM1, adotrastuzumab emtansine, KADCYLA®), a novel antibody-drug conjugate (ADC) for the treatment of HER2-positive breast cancer, consists of the cytotoxic agent DM1 (a thiol-containing maytansinoid antimicrotubule agent) conjugated to trastuzumab at its 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.

[0010] Currently, patients with HER2-positive early-stage breast cancer who do not achieve pathologic complete remission using neoadjuvant therapy consisting of standard chemotherapy and HER2-targeted therapy are at significantly higher risk of disease recurrence and have reduced survival compared with patients who achieve pathologic complete remission. In HER2-positive patients, achieving pathologic complete remission is associated with a 62%–73% reduction in the risk of invasive disease or death and a 65% reduction in the risk of death from any cause at 3 years (Schneeweiss 2018, de Azambuja Lancet Oncol 2014, Gianni Lancet Oncol 2014). However, pathologic complete remission is achieved in only approximately 30%–40% of these patients (Schneeweiss 2018, de Azambuja Lancet Oncol 2014, Gianni Lancet Oncol 2014, Untch JCO 2011). Thus, there remains an unmet medical need to treat those cancer patients who do not achieve a pathological complete response to neoadjuvant therapy. Summary of the Invention

[0011] The present disclosure relates generally to methods of treating breast cancer patients with the antibody-drug conjugate, trastuzumab emtansine (T-DM1).

[0012] In one aspect, the present disclosure relates to 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. In certain embodiments, the residual disease is present in the breast, in the lymph nodes, or in the breast and the lymph nodes. In certain embodiments, the preoperative systemic treatment comprises a HER2-targeted therapy, such as trastuzumab. In certain embodiments, the HER2-targeted therapy further comprises pertuzumab, lapatinib, neratinib, dacomitinib, and / or afatinib. In certain embodiments, the HER2-targeted therapy comprises trastuzumab and pertuzumab. In certain embodiments, the HER2-targeted therapy comprises trastuzumab and further comprises an agent selected from the group consisting of lapatinib, neratinib, dacomitinib, and afatinib. In certain embodiments, the preoperative systemic treatment further comprises a taxane. In certain embodiments, the patient is an adult patient. In certain embodiments, the patient undergoes definitive surgery before administration of T-DM1. In certain embodiments, the patient is administered T-DM1 within 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 a HER2-targeted therapy. In certain embodiments, the patient has completed at least 6 cycles of taxane-containing chemotherapy. In certain embodiments, the patient is administered T-DM1 at a dose of 3.6 mg / kg every 3 weeks. In certain embodiments, the patient is administered T-DM1 at a dose of 3.6 mg / kg every 3 weeks for 14 cycles. In certain embodiments, the adjuvant therapy substantially increases invasive disease-free survival (IDFS) compared to adjuvant therapy with trastuzumab. In certain embodiments, the adjuvant therapy results in a 50% reduction in the risk of invasive disease recurrence compared to adjuvant therapy with trastuzumab, hi certain embodiments, the adjuvant therapy results in a reduction in distant recurrence compared to adjuvant therapy with trastuzumab.In certain embodiments, the adjuvant therapy results in a 40% reduction in the risk of distant recurrence compared to adjuvant trastuzumab.

[0013] In one aspect, the present disclosure relates to trastuzumab emtansine (T-DM1) for use in adjuvant therapy of HER2-positive early breast cancer in a patient, wherein the adjuvant therapy is 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 the lymph nodes. In certain embodiments, the preoperative systemic treatment comprises a HER2-targeted therapy. In certain embodiments, the HER2-targeted therapy comprises trastuzumab. In certain embodiments, the HER2-targeted therapy further comprises pertuzumab, lapatinib, neratinib, dacomitinib, and / or afatinib. In certain embodiments, the HER2-targeted therapy comprises trastuzumab and pertuzumab. In certain embodiments, the HER2-targeted therapy comprises trastuzumab and further comprises an agent selected from the group consisting of lapatinib, neratinib, dacomitinib, and afatinib. In certain embodiments, the preoperative systemic treatment further comprises a taxane. In certain embodiments, the patient is an adult patient. In certain embodiments, the patient undergoes definitive surgery before administration of T-DM1. In certain embodiments, the adjuvant therapy substantially increases invasive disease-free survival (IDFS) compared to adjuvant therapy with trastuzumab. In certain embodiments, the adjuvant therapy results in a 50% reduction in the risk of invasive disease recurrence compared to adjuvant therapy with trastuzumab. In certain embodiments, the adjuvant therapy results in a reduction in distant recurrence compared to adjuvant therapy with trastuzumab. In certain embodiments, the adjuvant therapy results in a 40% reduction in the risk of distant recurrence compared to adjuvant therapy with trastuzumab.

[0014] In one aspect, the present disclosure relates to the use of trastuzumab emtansine (T-DM1) in the manufacture of a medicament for use in adjuvant therapy of HER2-positive early breast cancer in a patient, wherein the adjuvant therapy is 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 the lymph nodes. In certain embodiments, the preoperative systemic treatment comprises a HER2-targeted therapy. In certain embodiments, the HER2-targeted therapy comprises trastuzumab. In certain embodiments, the HER2-targeted therapy further comprises pertuzumab, lapatinib, neratinib, dacomitinib, and / or afatinib. In certain embodiments, the HER2-targeted therapy comprises trastuzumab and pertuzumab. In certain embodiments, the HER2-targeted therapy comprises trastuzumab and further comprises an agent selected from the group consisting of lapatinib, neratinib, dacomitinib, and afatinib. In certain embodiments, the preoperative systemic treatment further comprises a taxane. In certain embodiments, the patient is an adult patient. In certain embodiments, the patient undergoes definitive surgery before administration of T-DM1. In certain embodiments, the adjuvant therapy substantially increases invasive disease-free survival (IDFS) compared to adjuvant therapy with trastuzumab. In certain embodiments, the adjuvant therapy results in a 50% reduction in the risk of invasive disease recurrence compared to adjuvant therapy with trastuzumab. In certain embodiments, the adjuvant therapy results in a reduction in distant recurrence compared to adjuvant therapy with trastuzumab. In certain embodiments, the adjuvant therapy results in a 40% reduction in the risk of distant recurrence compared to adjuvant therapy with trastuzumab.

[0015] In one aspect, the present disclosure relates to a method for treating breast cancer in a patient with HER2-positive early-stage breast cancer, wherein the patient has residual disease in the breast or axillary lymph nodes after neoadjuvant therapy with chemotherapy and a HER2-targeted therapy, the method comprising: (i) removing all clinically evident tumor cells in the breast and axillary lymph nodes by definitive surgery; and (ii) administering adjuvant treatment with T-DM1 to the patient without prior or concurrent adjuvant treatment with chemotherapy. In certain embodiments, the patient has residual disease in the breast or axillary lymph nodes after neoadjuvant therapy with a taxane and a HER2-targeted therapy. In certain embodiments, the patient has completed at least 16 weeks of a taxane-containing chemotherapy regimen and neoadjuvant therapy with a HER2-targeted therapy. In certain embodiments, the patient has completed at least six cycles of a taxane-containing chemotherapy regimen. In certain embodiments, the patient receives adjuvant treatment with T-DM1 within 12 weeks of definitive surgery. In certain embodiments, the definitive surgery is performed at least 14 days after completion of neoadjuvant therapy. In certain embodiments, the definitive surgery is performed within 9 weeks after completion of neoadjuvant therapy. In certain embodiments, the patient receives adjuvant treatment with T-DM1 infused at a dose of 3.6 mg / kg every 3 weeks. In certain embodiments, the patient receives adjuvant treatment with T-DM1 infused at a dose of 3.6 mg / kg every 3 weeks for 14 cycles. In certain embodiments, the treatment substantially increases invasive disease-free survival (IDFS) compared to adjuvant treatment with trastuzumab. In certain embodiments, the treatment results in a reduction in distant recurrence compared to adjuvant treatment with trastuzumab. In certain embodiments, the adjuvant therapy results in a 50% reduction in the risk of invasive disease recurrence compared to adjuvant treatment with trastuzumab. In certain embodiments, the adjuvant therapy results in a 40% reduction in the risk of distant recurrence compared to adjuvant trastuzumab.

[0016] In one aspect, the present disclosure relates to a method for treating HER2-positive early breast cancer in a patient with 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 treatment 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 six cycles of taxane-containing neoadjuvant chemotherapy. In certain embodiments, the patient is treated with T-DM1 within 12 weeks of definitive surgery. In certain embodiments, the definitive surgery is performed at least 14 days after completion of neoadjuvant therapy. In certain embodiments, the definitive surgery is performed within 9 weeks after completion of neoadjuvant therapy. In certain embodiments, the patient is treated with T-DM1 infused at a dose of 3.6 mg / kg every 3 weeks. In certain embodiments, the patient is treated with T-DM1 infused at a dose of 3.6 mg / kg every 3 weeks for 14 cycles. In certain embodiments, the treatment substantially increases invasive disease-free survival (IDFS) compared to adjuvant treatment with trastuzumab. In certain embodiments, the treatment results in a reduction in distant recurrence compared to adjuvant treatment with trastuzumab. In certain embodiments, the adjuvant therapy results in a 50% reduction in the risk of invasive disease recurrence compared to adjuvant treatment with trastuzumab. In certain embodiments, the adjuvant therapy results in a 40% reduction in the risk of distant recurrence compared to adjuvant trastuzumab.

[0017] In another aspect, the present disclosure relates to a method for reducing the risk of cancer recurrence in a patient with HER2-positive early-stage breast cancer, the method comprising administering to the patient an effective amount of T-DM1, wherein the patient has not achieved pathological complete remission with neoadjuvant therapy and the patient has undergone definitive surgery prior to administration of T-DM1. In certain embodiments, the method does not include prior or concurrent adjuvant treatment 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 six cycles of taxane-containing neoadjuvant therapy. In certain embodiments, the patient is treated with T-DM1 within 12 weeks of definitive surgery. In certain embodiments, the definitive surgery is performed at least 14 days after completion of neoadjuvant therapy. In certain embodiments, definitive surgery is performed within 9 weeks after completion of neoadjuvant therapy. In certain embodiments, patients are treated with T-DM1 infusions at a dose of 3.6 mg / kg every 3 weeks. In certain embodiments, patients are treated with T-DM1 infusions at a dose of 3.6 mg / kg every 3 weeks for 14 cycles. In certain embodiments, the treatment substantially increases invasive disease-free survival (IDFS) compared to adjuvant treatment with trastuzumab. In certain embodiments, the treatment results in a reduction in distant recurrence compared to adjuvant treatment with trastuzumab. In certain embodiments, the adjuvant therapy results in a 50% reduction in the risk of invasive disease recurrence compared to adjuvant therapy with trastuzumab. In certain embodiments, the adjuvant therapy results in a 40% reduction in the risk of distant recurrence compared to adjuvant trastuzumab. [Brief explanation of the drawings]

[0018] [Figure 1] FIG. 1 is a schematic diagram of the KATHERINE study design. [Figure 2A] FIG. 1 shows a summary of baseline characteristics of the KATHERINE clinical trial treatment arms. [Figure 2B] FIG. 1 shows a summary of baseline characteristics of the KATHERINE clinical trial treatment arms. [Figure 2C] FIG. 1 shows a summary of baseline characteristics of the KATHERINE clinical trial treatment arms. [Figure 3] Kaplan-Meier plot of invasive disease-free survival. Invasive disease-free survival was defined as the time from randomization to the first of the following: ipsilateral invasive breast tumor recurrence, ipsilateral local invasive disease recurrence, distant disease recurrence, contralateral invasive breast cancer, or death from any cause. CI means confidence interval, and HR means hazard ratio. [Figure 4A] Kaplan-Meier plot of distant recurrence, defined as evidence of breast cancer in any anatomical site other than recurrence of ipsilateral invasive breast tumor or locally invasive breast cancer, that was either histologically confirmed or clinically diagnosed as recurrent invasive breast cancer. No statistical adjustment was made for multiple comparisons. [Figure 4B] FIG. 1 shows an overview of the site of the first invasive lesion event in patients. [Figure 5] FIG. 1 shows a summary of secondary efficacy endpoints from the KATHERINE clinical trial. [Figure 6A] Forest plot of invasive disease-free survival. [Figure 6B] Forest plot of invasive disease-free survival. CI means confidence interval. Hormone receptor negative means estrogen receptor (ER) negative and progesterone receptor (PgR) negative, and hormone receptor positive means ER positive, PgR positive, or both. HER2 means human epidermal growth factor receptor. ICH means immunohistochemistry. IDFS means invasive disease-free survival. ISH means in situ hybridization. [Figure 7]FIG. 1 shows an overview of the risk of first invasive disease event with neoadjuvant HER2-targeted therapy in the intent-to-treat population. [Figure 8] 1 is a Kaplan-Meier plot of overall survival for the patient population. DETAILED DESCRIPTION OF THE INVENTION

[0019] Reference will now be made in detail to certain embodiments of the present disclosure, examples of which are illustrated in the accompanying structures and formulas. While the present disclosure will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the disclosure to those embodiments. On the contrary, the present disclosure is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the present disclosure as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present disclosure. The present disclosure is in no way limited to the methods and materials described.

[0020] All references cited throughout this disclosure are expressly incorporated herein by reference in their entirety. In the event that one or more of the incorporated literature, patents, and similar materials differs from or conflicts with this application (including, but not limited to, defined terms, term usage, techniques described, etc.), this application controls.

[0021] For clarity of disclosure, and not by way of limitation, the detailed description is divided into the subsections that follow. I. Definition; II. Trastuzumab emtansine, III. Trastuzumab emtansine formulations, IV. Administration of trastuzumab emtansine; V. Products; VI. EXEMPLARY EMBODIMENTS

[0022] I. Definition

[0023] The words "comprise," "comprising," "include," "including," and "includes," when used in this specification and claims, 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.

[0024] The terms "treat" and "treatment" refer to both therapeutic treatment and prophylactic or preventative measures, the purpose of which is to prevent or slow (alleviate) an undesired physiological change or disease (such as the growth, onset, or spread of a hyperproliferative condition such as cancer). For purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, whether detectable or undetectable, diminishment of the extent of the disease, stabilization of (i.e., not worsening of) the disease state, delaying or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or complete). "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disease as well as those prone to have the condition or disease or those in whom the condition or disease is to be prevented.

[0025] The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. A "tumor" contains one or more cancerous cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia, or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), lung cancer (including small cell lung cancer, non-small cell lung cancer ("NSCLC"), adenocarcinoma of the lung, and squamous cell carcinoma of the lung), cancer of the peritoneum, hepatocellular carcinoma, gastric cancer or stomach cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer or uterine cancer, salivary gland cancer, kidney cancer or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, and head and neck cancer.

[0026] The term "early stage 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 term includes in situ and stages I, IIA, IIB, and IIIA breast cancer, as well as breast cancer that has progressed beyond stage IIIA but has not progressed to stage IV.

[0027] Designating a tumor or cancer as "Stage 0," "Stage I," "Stage II," "Stage III," or "Stage IV," and the various substages within this classification, refers to the classification of the tumor or cancer using Overall Stage Grouping or Roman Numeral Staging, as known in the art. The actual stage of the cancer depends on the type of cancer, but generally, Stage 0 cancer is an intraepithelial lesion, Stage I cancer is a small, localized tumor, Stage II and Stage III cancers are locally advanced tumors showing regional lymph node involvement, and Stage IV cancer represents metastatic cancer. The specific stages for each type of tumor are known to skilled clinicians.

[0028] The term "metastatic breast cancer" refers to a form of breast cancer in which the cancer cells spread from the original site through the blood or lymphatic vessels to one or more sites in other parts of the body and form one or more secondary tumors in one or more organs other than the breast.

[0029] An "advanced" cancer is one that has spread outside the site or organ of origin, either by local invasion or metastasis. Thus, the term "advanced" cancer includes both locally advanced and metastatic disease.

[0030] A "resistant" cancer is one that progresses despite anti-tumor agents such as chemotherapy being administered to the cancer patient. An example of a resistant cancer is platinum-resistant cancer.

[0031] A "recurrent" cancer is one that has regrown, either at the original site or at a distant site, after responding to initial therapy such as surgery.

[0032] "Locally recurrent" cancer is cancer that returns after treatment in the same place as the previously treated cancer.

[0033] An "operable" or "resectable" cancer is one that is confined to a major organ and suitable for surgery (resection).

[0034] A "non-resectable" or "unresectable" cancer, as used herein, is a cancer that cannot be removed (excised) by surgery.

[0035] "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.

[0036] As used herein, a "patient" or "subject" refers to a human patient. The patient may be a "cancer patient," i.e., a patient suffering from or at risk of suffering from one or more symptoms of cancer, particularly gastric cancer or breast cancer.

[0037] "Patient population," as used herein, refers to a group of cancer patients. Such populations can be used to demonstrate statistically significant efficacy and / or safety of a drug, such as Kadcyla.

[0038] A "relapsed" patient, as used herein, is a patient who has signs or symptoms of cancer after remission. Optionally, the patient has relapsed after adjuvant or neoadjuvant therapy.

[0039] 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.

[0040] A cancer or biological sample that "exhibits HER expression, amplification, or activation" is one that expresses (including overexpression) a HER receptor, has an amplified HER gene, and / or otherwise demonstrates activation or phosphorylation of a HER receptor in a diagnostic test.

[0041] "Neoadjuvant therapy" or "preoperative therapy" or "preoperative systemic treatment," as used herein, refers to therapy received before surgery. The purpose of neoadjuvant therapy is to provide immediate systemic treatment, potentially eradicating micrometastases that would otherwise grow if systemic treatment were administered after a standard course of surgery. Neoadjuvant therapy may also help reduce tumor size, allowing for the complete resection of an initially unresectable tumor or preserving part of an organ and its function. Furthermore, neoadjuvant therapy allows for in vivo evaluation of drug efficacy, which can guide subsequent treatment choices.

[0042] "Adjuvant therapy," as used herein, refers to therapy administered after definitive surgery to reduce the risk of disease recurrence. The purpose of adjuvant therapy is to prevent cancer recurrence, thus reducing the likelihood of cancer-related death. Adjuvant therapy, as used herein, specifically excludes neoadjuvant therapy.

[0043] "Definitive surgery" is a term used in the medical community. Definitive surgery includes, for example, procedures, surgeries, or other procedures that result in the removal or resection of a tumor, including those that result in the removal or resection of all tumor visible to the naked eye. Definitive surgery includes, for example, total or curative resection or gross total resection of a tumor. Definitive surgery includes procedures that occur in one or more stages, including, for example, multistage surgical procedures in which one or more surgeries or other procedures occur before the removal of the tumor. Definitive surgery includes procedures to remove or resect a tumor, including associated organs, organ parts, and tissues, as well as surrounding organs, such as lymph nodes, organ parts, or tissues. Removal may be incomplete, and tumor cells may remain, even if undetected.

[0044] "Survival" refers to the patient remaining alive, and includes disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS). Survival can be estimated by the Kaplan-Meier method, and any difference in survival is calculated using the stratified log-rank test.

[0045] "Progression-free survival" (PFS) is 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.

[0046] "Disease-free survival (DFS)" refers to a patient remaining alive and free from cancer recurrence for a period of time, such as about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, or about 10 years, from the start of treatment or from initial diagnosis. In one embodiment of the present disclosure, DFS is analyzed according to the intention-to-treat principle, i.e., patients are evaluated based on their assigned therapy. Events used in analyzing DFS can include local, regional, and distant recurrence of cancer in patients without previous events, the occurrence of a second cancer, and death from any cause (e.g., breast cancer recurrence or second primary cancer).

[0047] "Invasive disease-free survival (IDFS)" refers to the time from patient randomization to the first of the following invasive disease events: ipsilateral invasive breast tumor recurrence, ipsilateral local invasive disease recurrence, distant disease recurrence, contralateral invasive breast cancer, or death from any cause.

[0048] "Overall survival (OS)," as used herein, refers to a patient remaining alive for a period of time from the start of treatment or from initial diagnosis, such as about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 10 years, etc. In the studies underlying this disclosure, the event used for survival analysis was death from any cause.

[0049] "Prolonged survival," as used herein, refers to an increase in DFS and / or OS in treated patients compared to untreated patients or compared to a control treatment protocol. Survival is monitored for at least about 6 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., after initiation of treatment or initial diagnosis.

[0050] "Hazard ratio" in survival analysis is the summary of the difference between two survival curves, and represents the reduction in the risk of death for treatment compared with control over the follow-up period. "Hazard ratio" is the statistical definition of event rate. For the purpose of this disclosure, hazard ratio is defined as the probability of an event in the experimental group divided by the probability of an event in the control group at any particular time point.

[0051] "Monotherapy," as used herein, refers to a treatment regimen that includes only a single therapeutic agent for the treatment of a cancer or tumor during the course of treatment.

[0052] "Maintenance therapy," as used herein, refers to a treatment regimen given to reduce the likelihood of disease recurrence or disease progression. Maintenance therapy can be provided for any length of time, including for the lifespan of the subject. Maintenance therapy can be provided after initial therapy or in combination with initial therapy or additional therapy. Dosages used for maintenance therapy can vary and can include reduced dosages compared to dosages used in other types of therapy.

[0053] As defined herein, the terms "trastuzumab," "HERCEPTIN®," and "huMAb4D5-8" are used interchangeably.

[0054] "Epitope 4D5" or "4D5 epitope" or "4D5" refers to the region within the extracellular domain of HER2 to which antibody 4D5 (ATCC CRL 10463) and trastuzumab bind. This epitope is adjacent to the transmembrane domain of HER2 and is within domain IV of HER2. To screen for antibodies that bind to the 4D5 epitope, routine cross-blocking assays, such as those described in *Antibodies, A Laboratory Manual*, Cold Spring Harbor Laboratory, Ed Harlow and David Lane (1988), can be performed. 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 within the region of HER2 from about residue 529 to about residue 625, inclusive).

[0055] As defined herein, the terms "T-DM1," "trastuzumab-MCC-DM1," "ado-trastuzumab emtansine," "trastuzumab emtansine," and "KADCYLA®" are used interchangeably and refer to trastuzumab linked to the maytansinoid drug moiety DM1 via the linker moiety MCC, and include all mixtures of variously loaded and conjugated antibody-drug conjugates in which 1, 2, 3, 4, 5, 6, 7, and 8 drug moieties are covalently attached to the antibody trastuzumab (see U.S. Pat. No. 7,097,840; U.S. Patent Application Publication Nos. 2005 / 0276812; and 2005 / 0166993, which are incorporated by reference in their entireties). Trastuzumab-MCC-DM1 contains an average of 3.5 DM1 molecules per antibody.

[0056] "Chemotherapy" is the use of chemotherapeutic agents useful in the treatment of cancer.

[0057] "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.

[0058] Pertuzumab (also known as recombinant humanized monoclonal antibody 2C4, rhuMAb 2C4, PERJETA®, Genentech, Inc., South San Francisco) is another antibody therapy that targets Her2. Pertuzumab is a Her dimerization inhibitor (HDI) that functions to inhibit the ability of Her2 to form active heterodimers or homodimers with other Her receptors (such as EGFR / Her 1, Her 2, Her 3, and Her 4). 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); U.S. Patent No. 7,560,111.

[0059] Lapatinib, neratinib, dacomitinib, and afatinib are small molecule HER2 kinase inhibitors. Lapatinib (CAS 231277-92-2), used in the form of lapatinib ditosylate (Tyverb / Tykerb®), inhibits the tyrosine kinase activity of HER2 / neu and EGFR (epidermal growth factor receptor). Additional dual inhibitors of HER2 / neu and EGFR are neratinib (CAS 698387-09-6, Nerlynx®) and afatinib (CAS 850140-72-6, Gilotrif®), while dacomitinib (CAS 1110813-31-4, Vizimpro®) is an inhibitor of EGFR, HER2, and HER4 tyrosine kinases, i.e., a pan-HER inhibitor.

[0060] The term "effective amount" refers to an amount of drug effective to treat cancer in a patient. An effective amount of drug may reduce the number of cancer cells, reduce tumor size, inhibit (i.e., slow to some extent and preferably stop) cancer cell invasion into peripheral organs, inhibit (i.e., slow to some extent and preferably stop) tumor metastasis, inhibit tumor growth to some extent, and / or alleviate to some extent one or more symptoms associated with cancer. To the extent that a drug can prevent the growth of and / or kill existing cancer cells, the drug may be cytostatic and / or cytotoxic. An effective amount may extend progression-free survival (e.g., as measured by Response Evaluation Criteria in Solid Tumors (RECIST) or CA-125 change), result in an objective response (including partial response (PR) or complete response (CR)), increase overall survival, and / or improve one or more symptoms of cancer (e.g., as assessed by FOSI). The term "effective amount" specifically includes an amount suitable for achieving either the primary or secondary endpoints of the clinical trial described in Example 1.

[0061] "Taxanes" are chemotherapy agents that inhibit mitosis and disrupt microtubules. Examples of taxanes include paclitaxel (TAXOL®; Bristol-Myers Squibb Oncology, Princeton, NJ); a cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel or nab-paclitaxel (ABRAXANE™; American Pharmaceutical Partners, Schaumberg, Illinois); and docetaxel (TAXOTERE®; Rhone-Poulenc Rorer, Antony, France). "Taxane-based" therapy or "taxane-containing" therapy are used interchangeably herein and refer to a therapy that includes a taxane.

[0062] "Chemoresistant" cancer, as used herein, means that the cancer has progressed while the patient is receiving a chemotherapy regimen (i.e., the patient is "chemoresistant"), or has progressed within 12 months (e.g., within 6 months) after the patient has completed a chemotherapy regimen.

[0063] A "fixed" or "constant" dose of a therapeutic agent, as used herein, refers to a dose administered to a human patient without regard to the patient's body weight (WT) or body surface area (BSA). Thus, this fixed or constant dose may be expressed as a mg / kg dose or a mg / m 2 It is not provided as a dose, but rather as an absolute amount of therapeutic agent.

[0064] A "loading" dose, as used herein, generally comprises an initial dose of a therapeutic agent administered to a patient, followed by one or more maintenance dose(s) thereof. Generally, a single loading dose is administered, although multiple loading doses are contemplated herein. Typically, the amount of the loading dose(s) administered exceeds the amount of the maintenance dose(s) administered, and / or the loading dose(s) are administered more frequently than the maintenance dose(s) so as to achieve the desired steady-state concentration of the therapeutic agent more quickly than can be achieved with the maintenance dose(s).

[0065] A "maintenance" dose, as used herein, refers to one or more doses of a therapeutic agent administered to a patient over a treatment period. Typically, maintenance doses are administered at spaced treatment intervals, such as about every week, about every two weeks, about every three weeks, or about every four weeks, preferably every three weeks.

[0066] "Infusion" or "infuse," as used herein, refers to the introduction of a drug-containing solution into the body intravenously for therapeutic purposes. Typically, this is accomplished via an intravenous (IV) bag.

[0067] An "intravenous bag" or "IV bag," as used herein, is a bag capable of holding a solution that can be administered via a patient's vein. In certain embodiments, the solution is saline (e.g., about 0.9% or about 0.45% NaCl). Optionally, the IV bag is formed from polyolefin or polyvinyl chloride.

[0068] "Co-administer" or "co-administration," as used herein, refers to the intravenous administration of two (or more) drugs in the same administration, rather than sequential infusion of the two or more drugs. Generally, this involves mixing the two (or more) agents in the same IV bag prior to their simultaneous administration.

[0069] A drug that is administered "concurrently" with one or more other drugs is a drug that is administered on the same treatment day and, optionally, at the same time as one or more other drugs during the same treatment cycle. For example, in the case of a cancer therapy given every three weeks, each of the concurrently administered drugs is administered on day 1 of the three-week cycle.

[0070] A "vial" is a container suitable for holding a liquid or lyophilized preparation. In certain embodiments, the vial is a single-use vial, for example, a 20 cc single-use vial with a stopper.

[0071] The term "package insert" is used to refer to instructions customarily included in commercial packaging of therapeutic products that contain information about the indications, uses, dosage, administration, contraindications, and / or warnings regarding the use of such therapeutic product.

[0072] An "adverse event" is any untoward and unintended sign, symptom, or illness, regardless of attribution, that is temporally associated with the use of an investigational (medicinal) product or other protocol-imposed intervention, including: an AE not previously observed in a patient that appears during the protocol-specified AE reporting period, including signs or symptoms associated with breast cancer that were not present prior to the AE reporting period; a complication arising as a result of a protocol-mandated intervention (e.g., an invasive procedure such as a biopsy); an AE occurring prior to the assignment of study treatment that is associated with drug washout, no treatment lead-in, or other protocol-mandated intervention, if applicable; or a pre-existing medical condition (other than the condition being studied) that is determined by the investigator to have worsened in severity or frequency or changed in character during the protocol-specified AE reporting period.

[0073] An adverse event is classified as a "serious adverse event" (SAE) if it meets the following criteria: results in death (i.e., the AE actually causes or leads to death); is life-threatening (i.e., the AE places the patient at risk of immediate death, in the investigator's opinion, but does not include AEs that would have caused death if they had occurred in a more severe form); requires or prolongs hospitalization of the patient; results in persistent or significant disability / incapacity (i.e., the AE results in a significant impairment of the patient's ability to perform normal life functions); results in congenital anomalies / birth defects in newborns / infants born to mothers exposed to the investigational drug; or is considered a serious medical event by the investigator based on medical judgment (e.g., may endanger the patient or require medical / surgical intervention to prevent one of the outcomes listed above). All AEs that do not meet any of the criteria for seriousness are considered non-serious AEs. The terms "severe" and "serious" are not synonymous. Severity (or intensity) refers to the grade of a particular AE, e.g., mild (Grade 1), moderate (Grade 2), or severe (Grade 3) myocardial infarction. "Severe" is a regulatory definition (see definitions above) based on patient or event outcomes or action criteria typically associated with an event that poses a threat to the patient's life or vital function. Severity (not severity) serves as a guide for defining regulatory reporting obligations from the sponsor to applicable regulatory agencies. Severity and severity should be assessed independently when recording AEs and SAEs in the eCRF.

[0074] II. Trastuzumab Emtansine

[0075] The present disclosure relates to trastuzumab emtansine (T-DM1), an antibody-drug conjugate (CAS Registry Number 139504-50-0, trastuzumab-MCC-DM1, N 2’ -(3-{1-[4-(trastuzumab)~1 / 3.5carbamoylcyclohexylmethy]-2,5-dioxo-pyrrolidin-3-ylsulfanyl}-propionyl)-deacetylmaytansine), having the structure: TIFF2026021340000002.tif91170, where Tr is trastuzumab linked to the maytansinoid drug moiety DM1 via the linker moiety MCC (U.S. Pat. Nos. 5,208,020 and 6,441,163). The microtubule inhibitor maytansinoid DM1 is synthesized from the maytansinoid maytansinol and linked primarily to lysine residues on an antibody using the heterobifunctional reagent SMCC. The drug-to-antibody ratio, or drug loading, is represented by p in the above structure of trastuzumab emtansine (trastuzumab-MCC-DM1), which ranges from an integer value of 1 to about 8. Trastuzumab-MCC-DM1 includes a mixture of all variably loaded and conjugated antibody-drug conjugates in which 1, 2, 3, 4, 5, 6, 7, and 8 drug moieties are covalently attached to the antibody trastuzumab (U.S. Patent No. 7,097,840; U.S. Patent Application Publication Nos. 2005 / 0276812 and 2005 / 0166993). On average, trastuzumab emtansine contains 3.5 DM1 molecules per antibody.

[0076] 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 structurally related to the epidermal growth factor receptor. Trastuzumab is an anti-HER2 antibody that contains the antigen-binding residues of, or is derived from, the murine 4D5 antibody (ATCC CRL 10463, deposited under the Budapest Treaty on 1990, Can. 24, with the American Type Culture Collection, 12301 Parklawn Drive, Rockville, Md. 20852). Exemplary humanized 4D5 antibodies include huMAb4D5-1, huMAb4D5-2, huMAb4D5-3, huMAb4D5-4, huMAb4D5-5, huMAb4D5-6, huMAb4D5-7, and huMAb4D5-8 (HERCEPTIN®), as described in U.S. Pat. No. 5,821,337.

[0077] Trastuzumab emtansine can be prepared, for example, according to Example 1 of U.S. Patent Application Publication No. 20110165155, which is incorporated by reference herein in its entirety.

[0078] III. Trastuzumab Emtansine Formulations

[0079] Trastuzumab emtansine (adotrastuzumab emtansine, T-DM1) can be formulated according to standard pharmaceutical practice. 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 water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, and water. The particular carrier, diluent, or excipient used will depend on the means and purpose for which the compounds of the present disclosure are being applied. Solvents are generally selected based on solvents recognized by those skilled in the art as safe (GRAS) for mammalian administration. Generally, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), and the like, 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, fragrances, flavoring agents, and other known additives to provide proper presentation of the drug (i.e., a compound of the present disclosure or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (i.e., a medicament).

[0080] 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 stabilized form of the 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 typically formulated into pharmaceutical dosage forms to provide an easily controllable drug dose and enable patient compliance with a prescribed regimen.

[0081] Pharmaceutical compositions (or formulations) for application may be packaged in a variety of ways depending on the method used to administer the drug. Generally, an article for distribution includes a container having disposed therein the pharmaceutical formulation in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-evident assembly to prevent unintentional access to the contents of the package. In addition, the container has disposed thereon a label that describes the contents of the container. The label may also include appropriate warnings.

[0082] Pharmaceutical formulations can be prepared for various routes and types of administration in the form of lyophilized preparations, crushed powders, or aqueous solutions with pharmaceutically acceptable diluents, carriers, excipients, or stabilizers (Remington's Pharmaceutical Sciences (1995) 18th edition, Mack Publishing Co., Easton, PA). Formulations may be made by mixing at ambient temperature, at an appropriate pH, and to the desired degree of purity with a physiologically acceptable carrier, i.e., a carrier that is nontoxic to recipients at the dosages and concentrations employed. The pH of the formulation will depend primarily on the specific application and concentration of compound, but may range from about 3 to about 8.

[0083] Pharmaceutical formulations are preferably sterile. In particular, formulations to be used for in vivo administration must be sterile. Such sterilization is readily accomplished by filtration through sterile filtration membranes.

[0084] Pharmaceutical formulations may typically be stored as solid compositions, lyophilized formulations, or aqueous solutions.

[0085] The pharmaceutical formulations of the present disclosure are formulated and administered in a manner consistent with good medical practice, i.e., in amounts, concentrations, schedules, courses, vehicles, and routes of administration. Factors to consider in this regard include the particular disorder being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the administration schedule, and other factors known to medical practitioners.

[0086] Acceptable diluents, carriers, excipients, and stabilizers are nontoxic to recipients at the dosages and concentrations employed and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl alcohol, ethanol, or benzyl alcohol; alkyl parabens such as methyl paraben or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol, etc.); 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 dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as TWEEN™, including Tween 80, PLURONICS™, or polyethylene glycols (PEG), including PEG400. The active pharmaceutical ingredient may also be incorporated into microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, e.g., hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively, colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences, 18th edition, (1995) Mack Publishing Co., Easton, PA.Other examples of drug formulations can be found in Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, Vol 3, 2nd Ed., New York, NY.

[0087] Pharmaceutical formulations include those suitable for the routes of administration detailed herein. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations are generally described in Remington's Pharmaceutical Sciences 18 th Ed. (1995) Mack Publishing Co., Easton, PA. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0088] The pharmaceutical compositions may be in the form of a sterile injectable preparation, such as an aqueous or oily sterile injectable suspension. This suspension can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as described above. Sterile injectable preparations can be solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol, or prepared from lyophilized powders. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils can be conventionally used as solvents or suspending media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid can also be used in the preparation of injectables.

[0089] The amount of active ingredient that can be combined with carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. For example, a sustained-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of the active ingredient compound, with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 95% (weight to weight) of the total composition. Pharmaceutical compositions may be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain about 3 to 500 μg of active ingredient per milliliter of solution to result in infusion of a suitable volume at a rate of about 30 mL / hour.

[0090] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which 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.

[0091] The formulations may be packaged in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example, water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind described above. Preferred unit dosage formulations are those containing a daily dose or daily sub-dose, as herein above recited, of the active ingredient, or an appropriate fraction thereof.

[0092] As a general proposition, the initial pharmaceutically effective amount of T-DM1 administered per dose ranges from about 0.3 to 15 mg / kg / day of patient body weight.

[0093] The commercially available T-DM1 formulation (KADCYLA®, trastuzumab emtansine) is a sterile, white to off-white, preservative-free, lyophilized powder in single-use vials. Each vial contains 100 mg or 160 mg of trastuzumab emtansine. After reconstitution, each single-use vial contains trastuzumab emtansine (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. The resulting solution, containing 20 mg / mL of trastuzumab emtansine, is administered by intravenous infusion after dilution.

[0094] IV. Trastuzumab Emtansine Administration

[0095] The present disclosure relates to the use of trastuzumab emtansine (T-DM1) as adjuvant therapy. In certain embodiments, T-DM1 is used as adjuvant therapy to treat HER2-positive early breast cancer in patients, e.g., adult patients. In certain embodiments, T-DM1 is used as adjuvant therapy to treat patients with HER2-positive non-metastatic invasive breast cancer. In certain embodiments, T-DM1 can be administered as monotherapy in individuals with residual disease, for example, after preoperative systemic treatment.

[0096] 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, the adjuvant therapy results in about a 40%, about a 50%, or about a 60% reduction in the risk of invasive disease recurrence compared to adjuvant therapy with trastuzumab. For example, but not limited to, the adjuvant therapy described herein results in a 50% reduction in the risk of invasive disease recurrence compared to adjuvant therapy with trastuzumab. In certain embodiments, the adjuvant therapy results in a reduction in distant recurrence compared to adjuvant therapy with trastuzumab. For example, but not limited to, the adjuvant therapy described herein results in a 40% reduction in the risk of distant recurrence compared to adjuvant therapy with trastuzumab.

[0097] The present disclosure provides methods for adjuvant therapy comprising administering T-DM1. For example, but not limited to, the adjuvant therapy method comprises administering an effective amount of T-DM1 as monotherapy to a patient with HER2-positive early breast cancer, the patient having residual disease after preoperative systemic treatment.

[0098] 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 lymph nodes, e.g., axillary lymph nodes. In certain embodiments, the residual disease is in the breast and in lymph nodes.

[0099] In certain embodiments, the preoperative systemic treatment comprises a HER2-targeted therapy, for example, one or more HER2-targeted therapies. Non-limiting examples of HER2-targeted therapies include trastuzumab, pertuzumab, lapatinib, neratinib, dacomitinib, and / or afatinib. In certain embodiments, the HER2-targeted therapy is trastuzumab. In certain embodiments, the HER2-targeted therapy is pertuzumab. In certain embodiments, the HER2-targeted therapy is lapatinib. In certain embodiments, the HER2-targeted therapy is neratinib. In certain embodiments, the HER2-targeted therapy is dacomitinib. In certain embodiments, the HER2-targeted therapy is afatinib.

[0100] In certain embodiments, the preoperative systemic treatment can 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.

[0101] In certain embodiments, the method can 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, for example, prior to treatment with T-DM1. In certain embodiments, the patient has completed at least six cycles of taxane-containing chemotherapy.

[0102] In certain embodiments, the methods of the present disclosure can further include definitive surgery. For example, but not limited to, the patient undergoes definitive surgery before administration of T-DM1. In certain embodiments, the patient is administered T-DM1 within 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks after the definitive surgery. In certain embodiments, the patient is administered T-DM1 within 12 weeks after the definitive surgery.

[0103] The presently disclosed subject matter further provides methods for treating breast cancer in patients with HER2-positive early-stage breast cancer, where the patient has residual disease in the breast or axillary lymph nodes after neoadjuvant therapy with chemotherapy and a HER2-targeted therapy. In certain embodiments, the method includes removing all clinically evident tumor cells in the breast and axillary lymph nodes by definitive surgery and administering to the patient adjuvant monotherapy with T-DM1.

[0104] In certain embodiments, the patient has residual disease in the breast or axillary lymph nodes after neoadjuvant therapy with a taxane and a 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 receives adjuvant treatment with T-DM1 within 12 weeks of definitive surgery.

[0105] The presently disclosed subject matter further provides methods for treating HER2-positive early breast cancer in patients with residual disease after neoadjuvant therapy. In certain embodiments, the method comprises administering an effective amount of T-DM1 to a patient after the patient has undergone 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 a lymph node. 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 both the lymph node and the breast.

[0106] The presently disclosed subject matter provides methods for reducing the risk of cancer recurrence in patients with HER2-positive early-stage breast cancer. In certain embodiments, the method comprises administering an effective amount of T-DM1 to the patient, wherein the patient has not achieved pathological complete remission with neoadjuvant therapy and the patient has undergone curative surgery prior to administration of T-DM1.

[0107] In certain embodiments, the neoadjuvant therapy includes a taxane and / or a HER2-targeted therapy. In certain embodiments, the neoadjuvant therapy includes a taxane and a HER2-targeted therapy. For example, but not limited to, the neoadjuvant therapy includes a taxane 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 taxane-containing neoadjuvant therapy. In certain embodiments, patients are treated with T-DM1 within 12 weeks of definitive surgery.

[0108] In certain embodiments, the methods of the present disclosure do not include prior or concurrent adjuvant treatment with chemotherapy.

[0109] In certain embodiments, the methods of the present disclosure can include administering T-DM1 at a dose of 3.6 mg / kg every three weeks. For example, and without limitation, a patient can be administered T-DM1 at a dose of 3.6 mg / kg every three weeks for 14 cycles.

[0110] The present disclosure further provides trastuzumab emtansine (T-DM1) and pharmaceutical compositions thereof for use as adjuvant therapy for HER2-positive early breast cancer in patients. In certain embodiments, T-DM1 is administered as 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 the lymph nodes. In certain embodiments, the preoperative systemic treatment includes a HER2-targeted therapy, such as trastuzumab or trastuzumab and pertuzumab, lapatinib, neratinib, dacomitinib, and / or afatinib. In certain embodiments, the preoperative systemic treatment further includes a taxane. In certain embodiments, the patient undergoes definitive surgery before administration of T-DM1.

[0111] In a further aspect, the presently disclosed subject matter provides use of T-DM1 in the manufacture of a medicament for use in adjuvant therapy of HER2-positive early breast cancer in a patient, wherein the adjuvant is 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 the lymph nodes. In certain embodiments, the preoperative systemic treatment includes a HER2-targeted therapy, such as trastuzumab or trastuzumab and pertuzumab, lapatinib, neratinib, dacomitinib, and / or afatinib. In certain embodiments, the preoperative systemic treatment further includes a taxane. In certain embodiments, the patient undergoes definitive surgery before administration of T-DM1.

[0112] Trastuzumab emtansine (T-DM1) and pharmaceutical compositions thereof can be administered in the methods of the present disclosure by any route appropriate to the condition being treated. For example, but not limited to, 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), intravaginal, intraperitoneal, intrapulmonary, and intranasal. Local administration can also include the use of transdermal administration, such as transdermal patches or iontophoresis devices. For localized immunosuppressive treatment, the compound can be administered intralesionally, including by perfusing or otherwise contacting the graft with an inhibitor prior to transplantation. It will be understood that the preferred route may vary, for example, with the condition of the recipient. When the compound is administered orally, it may be formulated as a pill, capsule, tablet, etc., along with a pharmaceutically acceptable carrier, glidant, or excipient. Where the compound is administered parenterally, it may be formulated in a unit dosage form for injection with a pharmaceutically acceptable parenteral vehicle or diluent, as detailed below.

[0113] V.Product

[0114] Articles of manufacture or "kits" containing T-DM1 useful in the therapeutic 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, including information about the indications, usage, dosage, administration, contraindications, and / or warnings regarding the use of such therapeutic products. Suitable containers include, for example, bottles, vials, syringes, blister packs, and the like. The container may be formed from a variety of materials, such as glass or plastic. The container may hold T-DM1 or a formulation thereof effective for use in the therapeutic methods herein and may have a sterile access port (e.g., the container may be an intravenous solution bag or a vial with a stopper pierceable by a hypodermic injection needle). The label or package insert indicates that the composition is for use in the therapeutic methods described and claimed herein. The article of manufacture may also include an additional container containing a pharmaceutically acceptable 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 standpoint, including other buffers, diluents, filters, needles, and syringes.

[0115] The kit can further include instructions for administering T-DM1. For example, if the kit includes a first composition comprising T-DM1 and a second pharmaceutical formulation, the kit can further include instructions for administering the first and second pharmaceutical compositions simultaneously, sequentially, or separately to a patient in need thereof.

[0116] In certain embodiments, the kit is suitable for delivery of a solid oral form of T-DM1, such as a tablet or capsule. Such a kit preferably includes several unit dosages. Such a kit may include a card with the dosages arranged 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, for example, in the form of numbers, letters, or other markings or with a calendar insert, can be provided that designates the days in the treatment schedule on which the dosages can be administered.

[0117] In certain embodiments, the articles of manufacture herein include an intravenous infusion (IV) bag containing a stable mixture of T-DM1 suitable for administration to cancer patients. Optionally, the mixture is in saline, e.g., containing about 0.9% NaCl or about 0.45% NaCl. An exemplary IV bag is a polyolefin or polyvinyl chloride infusion bag, e.g., a 250 mL IV bag. According to certain embodiments of the present disclosure, the bag contains about 100 mg to about 160 mg of T-DM1.

[0118] Optionally, the mixture in the IV bag is stable for up to 24 hours at 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, particulate analysis, size exclusion chromatography (SEC), ion exchange chromatography (IEC), capillary zone electrophoresis (CZE), image capillary isoelectric focusing (iCIEF), and potency assays.

[0119] VI. Illustrative Embodiments

[0120] 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 (T-DM1) as monotherapy to a patient with HER2-positive early stage breast cancer, wherein the patient has residual disease following neoadjuvant systemic treatment.

[0121] A1. The method according to A, wherein the residual disease is present in the breast.

[0122] A2. The method of claim A, wherein the residual disease is present in a lymph node.

[0123] A3. The method according to A, wherein the residual disease is present in the breast and lymph nodes.

[0124] A4. The method of any one of A to A3, wherein the preoperative systemic treatment comprises a HER2-targeted therapy.

[0125] A5. The method according to A4, wherein the HER2 targeted therapy comprises trastuzumab.

[0126] A6. The method according to A5, wherein the HER2 targeted therapy further comprises pertuzumab.

[0127] A7. The above method of A4 or A5, wherein the HER2 targeted therapy further comprises an agent selected from the group consisting of lapatinib, neratinib, dacomitinib, afatinib, and combinations thereof.

[0128] A8. The method of any one of A-A7, wherein the preoperative systemic treatment further comprises a taxane. A9. The method according to any one of A to A8, wherein the patient is an adult patient.

[0129] A10. The aforementioned method of any one of A-A9, wherein the patient undergoes curative surgery prior to administration of T-DM1.

[0130] A11. The above method of A10, wherein the patient is administered T-DM1 within 12 weeks after radical surgery.

[0131] A12. The method of 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.

[0132] A13. The method of any one of A-A12, wherein the patient has completed at least six cycles of taxane-containing chemotherapy.

[0133] A14. The aforementioned method of any one of A-A13, wherein the patient is administered T-DM1 at a dose of 3.6 mg / kg every 3 weeks.

[0134] A15. The aforementioned method of any one of A-A14, wherein the patient is administered T-DM1 at a dose of 3.6 mg / kg every 3 weeks for 14 cycles.

[0135] A16. The method according to any one of A to A15, wherein the adjuvant therapy substantially increases invasive disease-free survival (IDFS) compared to adjuvant therapy using trastuzumab.

[0136] A17. The method of any one of A-A16, wherein the adjuvant therapy results in a 50% reduction in the risk of invasive disease recurrence compared to adjuvant therapy with trastuzumab.

[0137] A18. The method according to any one of A to A17, wherein the adjuvant therapy results in a reduction in distant recurrence compared to adjuvant therapy using trastuzumab.

[0138] A19. The method of any one of A-A18, wherein the adjuvant therapy results in a 40% reduction in the risk of distant recurrence compared to adjuvant trastuzumab.

[0139] B. In certain embodiments, the presently disclosed subject matter provides trastuzumab emtansine (T-DM1) for use in the adjuvant treatment of HER2-positive early breast cancer in a patient, wherein the adjuvant is monotherapy and the patient has residual disease after neoadjuvant systemic treatment.

[0140] B1. The above use of T-DM1 according to B, wherein the residual disease is present in the breast, present in the lymph nodes, or present in the breast and lymph nodes.

[0141] B2. The above-mentioned use of T-DM1 according to B or B1, wherein the preoperative systemic treatment comprises a HER2-targeted therapy.

[0142] 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.

[0143] B4. The aforementioned use of T-DM1 according to any one of B-B3, wherein the preoperative systemic treatment further comprises a taxane.

[0144] B5. The above-mentioned use of T-DM1 according to any one of B-B4, wherein the patient is an adult patient.

[0145] B6. The above-mentioned use of T-DM1 according to any one of B-B5, wherein the patient undergoes curative surgery prior to administration of T-DM1.

[0146] B7. The aforementioned use of T-DM1 of any one of B-B6, wherein the adjuvant therapy substantially increases invasive disease-free survival (IDFS) compared to adjuvant therapy with trastuzumab.

[0147] B8. The aforementioned use of T-DM1 of any one of B-B7, wherein the adjuvant therapy results in a 50% reduction in the risk of invasive disease recurrence compared to adjuvant therapy with trastuzumab.

[0148] B9. The aforementioned use of T-DM1 of any one of B-B8, wherein the adjuvant therapy results in a reduction in distant recurrence compared to adjuvant therapy with trastuzumab.

[0149] B10. The aforementioned use of T-DM1 of any one of B-B9, wherein the adjuvant therapy results in a 40% reduction in the risk of distant recurrence compared to adjuvant trastuzumab.

[0150] C. In certain embodiments, the presently disclosed subject matter provides the use of trastuzumab emtansine (T-DM1) in the manufacture of a medicament for use in the adjuvant treatment of HER2-positive early breast cancer in a patient, wherein the adjuvant is monotherapy and the patient has residual disease after neoadjuvant systemic treatment.

[0151] C1. The use according to C, wherein the residual disease is present in the breast, in the lymph nodes, or in the breast and the lymph nodes.

[0152] C2. The use of any one of C or C1 above, wherein the preoperative systemic treatment comprises a HER2-targeted therapy.

[0153] C3. The use as described in C2, wherein the HER2 targeted therapy comprises trastuzumab or trastuzumab and pertuzumab, lapatinib, neratinib, dacomitinib and / or afatinib.

[0154] C4. The use of any one of C-C3, wherein the preoperative systemic treatment further comprises a taxane.

[0155] C5. The use of any one of C-C4, wherein the patient is an adult patient.

[0156] C6. The use of any one of C-C5, wherein the patient undergoes curative surgery prior to administration of T-DM1.

[0157] C7. The use of any one of C-C6, wherein the adjuvant therapy substantially increases invasive disease-free survival (IDFS) compared to adjuvant therapy with trastuzumab.

[0158] C8. The use of any one of C-C7, wherein the adjuvant therapy results in a 50% reduction in the risk of invasive disease recurrence compared to adjuvant therapy with trastuzumab.

[0159] C9. The use of any one of C-C8, wherein the adjuvant therapy results in a reduction in distant recurrence compared to adjuvant therapy with trastuzumab.

[0160] C10. The use of any one of C-C9, wherein the adjuvant therapy results in a 40% reduction in the risk of distant recurrence compared to adjuvant trastuzumab.

[0161] D. In certain non-limiting embodiments, the presently disclosed subject matter is a method for treating breast cancer in a patient with HER2-positive early stage breast cancer, wherein the patient has residual disease in the breast or axillary lymph nodes after neoadjuvant therapy with chemotherapy and a HER2-targeted therapy, the method comprising: (i) radical surgery to remove all clinically evident tumor cells in the breast and axillary lymph nodes; and (ii) administering to the patient adjuvant monotherapy with trastuzumab emtansine (T-DM1).

[0162] D1. The above method of 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.

[0163] D2. The method of any one of D or D1, wherein the patient has completed at least 16 weeks of neoadjuvant therapy with taxane-containing chemotherapy.

[0164] D3. The method of any one of D-D2, wherein the patient has completed at least six cycles of taxane-containing chemotherapy.

[0165] D4. The aforementioned method of any one of D-D3, wherein the patient receives adjuvant treatment with T-DM1 within 12 weeks after definitive surgery.

[0166] D5. The aforementioned method of any one of D-D4, wherein the patient receives adjuvant treatment with T-DM1 at a dose of 3.6 mg / kg infused every 3 weeks.

[0167] D6. The aforementioned method of any one of D-D5, wherein the patient receives adjuvant treatment with T-DM1 infused at a dose of 3.6 mg / kg every 3 weeks for 14 cycles.

[0168] D7. The aforementioned method of any one of D-D6, wherein said treatment substantially increases invasive disease-free survival (IDFS) compared to adjuvant treatment with trastuzumab.

[0169] D8. The aforementioned method of any one of D-D7, wherein the treatment results in a reduction in distant recurrence compared to adjuvant treatment with trastuzumab.

[0170] E. In certain non-limiting embodiments, the presently disclosed subject matter provides methods for treating HER2-positive early breast cancer in patients with residual disease after neoadjuvant therapy, the method comprising administering to the patient an effective amount of trastuzumab emtansine (T-DM1) after the patient has undergone curative surgery.

[0171] E1. The method of E above, wherein the residual disease is pathological residual invasive disease.

[0172] E2. The method of E or E1, wherein the residual disease is pathological residual invasive disease in a lymph node.

[0173] E3. The aforementioned method of any one of E-E2, wherein the residual disease is pathological residual invasive disease in the breast.

[0174] E4. The aforementioned method of any one of E-E3, wherein the method does not include prior or concurrent adjuvant treatment with chemotherapy.

[0175] E5. The aforementioned method of any one of E-E4, wherein the neoadjuvant therapy comprises a taxane and a HER2-targeted therapy.

[0176] E6. The aforementioned method of any one of E-E5, wherein the neoadjuvant therapy comprises a taxane and trastuzumab.

[0177] E7. The aforementioned method of any one of E-E6, wherein the patient has completed at least 16 weeks of neoadjuvant therapy.

[0178] E8. The aforementioned method of any one of E-E7, wherein the patient has completed at least six cycles of taxane-containing neoadjuvant therapy.

[0179] E9. The aforementioned method of any one of E-E8, wherein the patient is treated with T-DM1 within 12 weeks of definitive surgery.

[0180] E10. The aforementioned method of any one of E-E9, wherein the patient is treated with T-DM1 at a dose of 3.6 mg / kg infusion every three weeks.

[0181] E11. The aforementioned method of any one of E-E10, wherein the patient is treated with T-DM1 infusions at a dose of 3.6 mg / kg every three weeks for 14 cycles.

[0182] E12. The aforementioned method of any one of E-E11, wherein said treatment substantially increases invasive disease-free survival (IDFS) compared to adjuvant treatment with trastuzumab.

[0183] E13. The aforementioned method of any one of E-E12, wherein said treatment results in a reduction in distant recurrence compared to adjuvant treatment with trastuzumab.

[0184] 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-stage breast cancer, the method comprising administering to the patient an effective amount of trastuzumab emtansine (T-DM1), wherein the patient has not achieved a pathological complete remission with neoadjuvant therapy and the patient has undergone curative surgery prior to administration of T-DM1.

[0185] F1. The method as described above in F, wherein the method does not include prior or concurrent adjuvant treatment with chemotherapy.

[0186] F2. The method of any one of F or F1, wherein the neoadjuvant therapy comprises a taxane and a HER2-targeted therapy.

[0187] F3. The aforementioned method of any one of F-F2, wherein the neoadjuvant therapy comprises a taxane-containing chemotherapy regimen and trastuzumab.

[0188] F4. The aforementioned method of any one of F-F3, wherein the patient has completed at least 16 weeks of neoadjuvant therapy.

[0189] F5. The aforementioned method of any one of F-F4, wherein the patient has completed at least six cycles of taxane-containing neoadjuvant therapy.

[0190] F6. The aforementioned method of any one of F-F5, wherein the patient is treated with T-DM1 within 12 weeks after definitive surgery.

[0191] F7. The aforementioned method of any one of F-F6, wherein the patient is treated with T-DM1 infusions at a dose of 3.6 mg / kg every three weeks.

[0192] F8. The aforementioned method of any one of F-F7, wherein the patient is treated with T-DM1 infusions at a dose of 3.6 mg / kg every three weeks for 14 cycles.

[0193] F9. The aforementioned method of any one of F-F8, wherein said treatment substantially increases invasive disease-free survival (IDFS) compared to adjuvant treatment with trastuzumab.

[0194] F10. The aforementioned method of any one of F-F9, wherein the treatment results in a reduction in distant recurrence compared to adjuvant treatment with trastuzumab.

[0195] F11. The aforementioned method of any one of D-F10, wherein said adjuvant therapy results in a 50% reduction in the risk of invasive disease recurrence compared to adjuvant therapy with trastuzumab.

[0196] F12. The aforementioned method of any one of D-F11, wherein said adjuvant therapy results in a 40% reduction in the risk of distant recurrence compared to adjuvant trastuzumab. [Example]

[0197] The following examples are included to illustrate the present disclosure, however, it should be understood that these examples do not limit the disclosure and are only meant to suggest exemplary methods of practicing the disclosure.

[0198] Example 1 - Clinical Trial Design

[0199] Phase III clinical trial

[0200] This phase 3, open-label trial (NCT01772472 / BO27938 / NSABPB-50-I / GBG 77; KATHERINE) enrolled patients with HER2-positive early-stage breast cancer who had received neoadjuvant taxane-containing chemotherapy plus trastuzumab-containing HER2-targeted therapy and had pathologically residual invasive disease in the breast and / or axillary lymph nodes. Patients were randomized to receive 14 cycles of adjuvant T-DM1 or trastuzumab. The primary endpoint was invasive disease-free survival (IDFS). The efficacy stopping boundary for this single prespecified interim analysis of IDFS was P<0.0124 or a hazard ratio of 0.732 or less.

[0201] patient

[0202] The patient population for this study is patients with primary, non-metastatic, HER2-positive breast cancer.

[0203] Selection Criteria

[0204] Patients must meet the following study entry criteria: 1. HER2-positive breast cancer. HER2-positive status is defined as an immunohistochemistry (IHC) score of 3+ based on pretreatment biopsy material and / or positive in situ hybridization (ISH) confirmed prospectively by a central laboratory prior to study enrollment. ISH positivity is defined as a ratio of HER2 gene copy number to chromosome 17 copy signal number of ≥ 2.0. Formalin-fixed, paraffin-embedded tumor tissue blocks or partial blocks must be available for central adjudication of HER2 expression. If a site is unable to send tissue blocks due to local regulations, at least eight unstained slides should be sent for HER2 testing and up to five additional slides should be sent for exploratory biomarker studies. The central laboratory will perform both IHC and ISH assays, but only one positive result is required for eligibility. If sufficient material from a pretreatment biopsy is not available for application, central HER2 adjudication for eligibility can be performed on residual tumor tissue from the time of definitive surgery. Patients with synchronous bilateral invasive disease are eligible if both lesions are HER2 positive.

[0205] 2. Histologically confirmed invasive breast cancer.

[0206] 3. Clinical stage at presentation: T1-4, N0-3, M0 (Note: Patients with T1a / bN0 tumors are not eligible).

[0207] 4. Completion of preoperative systemic chemotherapy and HER2-targeted therapy. Systemic therapy must consist of 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-based chemotherapy. Patients may have received an anthracycline as part of their preoperative treatment in addition to taxane chemotherapy. Patients receiving dose-intensive chemotherapy regimens are eligible if they have received at least 8 weeks of taxane-based therapy and at least 8 weeks of trastuzumab. Patients receiving dose-escalating paclitaxel (225 mg / m) over 6 weeks are eligible. 2q2w) Dose-intensive regimens are permitted. Patients may receive two or more HER2-targeted therapies. Note: A period of HER2-targeted therapy alone does not fulfill the requirement for a cycle of preoperative systemic chemotherapy. All systemic chemotherapy should be completed preoperatively.

[0208] 5. Adequate resection: Surgical removal of all clinically evident lesions in the breast and lymph nodes, including:

[0209] Breast Surgery: Total mastectomy with no gross residual disease at the excision periphery, or breast-conserving surgery with a histologically negative excision periphery. For patients undergoing breast-conserving surgery, the periphery of the excision specimen must be histologically free of invasive tumor and DCIS as determined by an on-site pathologist. If pathology shows tumor at the excision line, additional surgical procedures can be performed to obtain a clear periphery. If tumor is still present at the excision periphery after re-excision(s), the patient must undergo total mastectomy to be eligible. Patients with a positive periphery for lobular carcinoma in situ (LCIS) are eligible without additional excision.

[0210] Lymph Node Surgery: If a positive result from fine-needle aspiration, core biopsy, or sentinel lymph node biopsy performed before preoperative therapy is present, additional surgical evaluation of the axilla is necessary following preoperative therapy. If only micrometastases are present in the sentinel lymph node preoperatively (i.e., lymph node metastases in the sentinel lymph node are 0.2 mm or less in greatest diameter), additional surgical evaluation of the axilla is not necessary. If the sentinel lymph node biopsy performed before preoperative therapy is negative, additional surgical evaluation of the axilla is not necessary after preoperative therapy. If the only sentinel lymph nodes identified by isotope scan are in the internal mammary chain, surgical evaluation of the axilla is recommended.

[0211] If a sentinel lymph node biopsy performed after preoperative therapy is positive, further surgical evaluation of the axilla is recommended. If a sentinel lymph node evaluation performed after preoperative therapy is negative, further surgical evaluation of the axilla is not necessary. Axillary dissection without sentinel lymph node evaluation is permitted after preoperative therapy.

[0212] 6. Pathologic evidence of residual invasive carcinoma in the breast or axillary lymph nodes after completion of preoperative therapy. If invasive disease is present in both breasts, residual invasive carcinoma must be present in at least one breast or axillary lymph node after surgery.

[0213] 7. The interval between the date of primary surgery and the date of randomization is 12 weeks or less.

[0214] 8. Known Hormone Receptor Status. Hormone receptor-positive status can be determined by either known positive ER status or known positive PgR status, and hormone receptor-negative status must be determined by both known negative ER and known negative PgR.

[0215] 9. Signed written informed consent approved by the study site's Institutional Review Board (IRB) / Ethics Committee (EC).

[0216] 10. Age 18 or older

[0217] 11. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

[0218] 12. Life expectancy of 6 months or more

[0219] 13. Adequate organ function during screening, defined as: Absolute neutrophil count ≥ 1200 cells / mm 3 b. Platelet count ≧100000 cells / mm 3 c. Hemoglobin ≥ 9.0 g / dL. Patients may receive red blood cell transfusions to achieve this level. d. Serum creatinine < 1.5 × upper limit of normal (ULN) e. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≦ 1.5 × ULN f. Serum AST and ALT ≤ 1.5 x ULN g. Serum total bilirubin (TBILI) ≦1.0 × ULN (within the normal range), except for patients with Gilbert syndrome, for which direct bilirubin must be within the normal range. h. Serum alkaline phosphatase (ALK) ≤ 1.5 × ULN i. Screening LVEF ≥ 50% for ECHO or MUGA after receiving neoadjuvant chemotherapy, with no decline in LVEF to an absolute point of > 15% from pre-chemotherapy LVEF. Or, if pre-chemotherapy LVEF was not assessed, screening LVEF must be ≥ 55% after completion of neoadjuvant chemotherapy.

[0220] i.LVEF assessment may be repeated once up to 3 weeks following the initial screening assessment to assess suitability.

[0221] 14. For women who are not postmenopausal (non-treatment-induced amenorrhea for ≥ 12 months) or surgically sterile (absence of ovaries and / or uterus): Agreement to remain abstinent during treatment and for at least 7 months after the last dose of study drug, or to use a single or combined method of contraception that results in a failure rate of less than 1% per year. a. Abstinence is acceptable only if it is consistent with the patient's preferred, normal lifestyle. Periodic abstinence (e.g., calendar, ovulation, symptomatic-thermal, or postovulatory methods) and abortive intercourse are not acceptable methods of contraception. Examples of contraceptive methods with failure rates of less than 1% per year include tubal ligation, male sterilization, hormonal implants, established and appropriate use of combined oral or injectable hormonal contraceptives, and certain intrauterine devices. Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) can be combined to achieve a failure rate of less than 1% per year. Barrier methods always require the addition of spermicide. b. Male patients whose partners are pregnant should use condoms or strictly abstain from sexual activity for the duration of the pregnancy.

[0222] 15. A negative serum pregnancy test for premenopausal women, including those who have had a tubal ligation, and women who are less than 12 months past the onset of menopause.

[0223] 16. Documentation of hepatitis B virus (HBV) and hepatitis C virus (HCV) serology is required: this includes HB surface antigen (HBsAg) and / or total HB core antibody (anti-HBc) in addition to HCV antibody testing. The most recent serology test must have been performed within 3 months prior to the start of neoadjuvant therapy. If such testing has not been performed, it should be performed during screening.

[0224] Exclusion criteria

[0225] Patients who meet any of the following criteria will be excluded from study enrollment: Disease-related exclusion criteria:

[0226] 1. Stage IV (metastatic) breast cancer.

[0227] 2. History of any previous (ipsilateral or contralateral) breast cancer except lobular carcinoma in situ

[0228] 3. Evidence of clinically evident gross residual or recurrent disease after preoperative therapy and surgery.

[0229] 4. Overall response to PD according to the investigator at the time of completion of preoperative systemic therapy.

[0230] 5. Treatment with any anti-cancer investigational drug within 28 days prior to initiation of study treatment.

[0231] 6. History of other malignancies within the past 5 years, excluding adequately treated CIS of the cervix, non-melanoma skin cancer, stage I uterine cancer, or other non-breast malignancies with outcomes similar to those mentioned above.

[0232] 7. Patients for whom radiation therapy would be recommended for breast cancer treatment but is contraindicated for medical reasons (e.g., connective tissue disease or previous ipsilateral breast irradiation).

[0233] 8. Current NCI CTCAE (version 4.0) grade ≥ 2 peripheral neuropathy.

[0234] 9. History of exposure to the following cumulative doses of anthracyclines: Doxorubicin > 240 mg / m 2 . Epirubicin or doxorubicin hydrochloride-encapsulated liposomes (Myocet®) >480 mg / m 2 . For other anthracyclines, doxorubicin >240 mg / m 2 and equivalent exposure.

[0235] 10. Cardiopulmonary insufficiency as defined by any of the following: a. History of symptomatic CHF of NCI CTCAE (Version 4.0) grade ≥ 3 or NYHA diagnostic criteria classification ≥ II. b. Angina requiring antianginal medication, serious cardiac arrhythmias not controlled by adequate medication, severe conduction abnormalities, or clinically significant valvular disease. c. High-risk uncontrolled arrhythmias, i.e., atrial tachycardia with a resting heart rate greater than 100 beats per minute, significant ventricular arrhythmias (ventricular tachycardia), or high-degree atrioventricular block (second-degree atrioventricular block type 2 [Mobitz2] or third-degree atrioventricular block). d. Significant symptoms (grade ≥ 2) related to left ventricular dysfunction, cardiac arrhythmia, or cardiac ischemia during or since receiving preoperative therapy. e. History of LVEF decline to <40% with prior trastuzumab treatment (e.g., during preoperative therapy) f. Uncontrolled hypertension (systolic blood pressure >180mmHg and / or diastolic blood pressure >100mmHg). g. Evidence of transmural infarction on ECG requirement for continuous oxygen therapy

[0236] 11. Prior treatment with trastuzumab emtansine

[0237] General exclusion criteria

[0238] 12. Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease, impaired wound healing, ulcers).

[0239] 13. For female patients, current pregnancy and / or lactation

[0240] 14. Major surgical procedure unrelated to breast cancer or major trauma within approximately 28 days prior to randomization, or anticipated need for major surgery during the course of study treatment.

[0241] 15. Any known active liver disease, e.g., disease due to HBV, HCV, autoimmune hepatitis, or sclerosing cholangitis. Patients without known active disease and with a positive HBV or HCV serology test must meet the eligibility criteria for ALT, AST, TBILI, INR, aPTT, and alkaline phosphatase (ALK) on at least two consecutive occasions, separated by at least one week, within the 30-day screening period.

[0242] 16. Concurrent, severe, uncontrolled infection or known infection with HI.

[0243] 17. History of intolerance, including grade 3-4 infusion reaction or hypersensitivity, to trastuzumab or the mouse protein or any component of the product.

[0244] 18. Ongoing unresolved infection at screening requiring treatment

[0245] 19. Unable or unwilling to comply with the requirements of the protocol as assessed by the investigator

[0246] Study design

[0247] Patients who consent and qualify for the study will be randomized in a 1:1 ratio to one of the following treatment groups: Arm A: Trastuzumab emtansine 3.6 mg / kg IV q3w for 14 cycles. Arm B: Trastuzumab 6 mg / kg IV q3w for 14 cycles (if there has been an interval of more than 6 weeks since the last dose of trastuzumab, an 8 mg / kg loading dose should be administered).

[0248] The trial will enroll approximately 1,484 patients with pathologically documented residual invasive disease in either the breast or axillary lymph nodes after completion of preoperative therapy. Patients must have completed preoperative systemic treatment, consisting of at least six cycles with a total duration of at least 16 weeks, including at least nine weeks of trastuzumab and at least nine weeks of taxane-based chemotherapy (or, if receiving a dose-intensive chemotherapy regimen, at least six to eight weeks of taxane-based therapy and at least eight weeks of trastuzumab).

[0249] HER2-targeted therapy and chemotherapy can be administered simultaneously. Patients may have received more than one HER2-targeted therapy. Patients may have received an anthracycline as part of their preoperative treatment.

[0250] Patients will receive study treatment for up to 14 cycles. Treatment will be discontinued prior to 14 cycles in the event of disease recurrence, unacceptable toxicity, or termination of the study by the sponsor. Patients who discontinue trastuzumab emtansine will be allowed to complete the study therapy period with trastuzumab if appropriate, given toxicity considerations. After discontinuation or completion of study treatment, patients will continue to be followed for efficacy and safety purposes until the end of the study.

[0251] Concurrent radiation therapy (for patients with hormone receptor-positive tumors) and / or hormone therapy should be administered to patients with study treatment if indicated based on the following guidelines: In patients with hormone receptor-positive disease at presentation, hormone therapy (e.g., aromatase inhibitors, tamoxifen) should be initiated. For patients undergoing breast-conserving surgery, whole-breast irradiation is required. Primary tumor bed boost may be performed according to local policy. Regional lymph node irradiation is required if patients are found to have clinical T3 (excluding T3N0) or T4 disease and / or clinical N2 or N3 disease at initial diagnosis. Regional lymph node irradiation is recommended in cases of T3N0 or if there is residual disease in the lymph nodes. For post-mastectomy patients, chest wall and regional lymph node irradiation are required if the patient is found to have clinical T3 (excluding T3N0) or T4 disease and / or clinical N2 or N3 disease at initial diagnosis. Chest wall and regional lymph node irradiation are recommended for T3N0 disease or if there is residual disease in the lymph nodes. For post-mastectomy patients who do not meet these criteria, radiation therapy will be administered at the investigator's discretion based on institutional standards.

[0252] A permuted block randomization scheme will be used to ensure that patients receive trastuzumab emtansine or trastuzumab, with an approximately 1:1 allocation, for the following stratification factors: Clinical stage at presentation: inoperable (stage T4NxM0 or TxN2-3M0) vs. operable (stage T1-3N0-1M0) Hormone receptor status: estrogen receptor (ER) or progesterone receptor (PgR) positive vs. ER and PgR negative / unknown Preoperative HER2-targeted therapy: trastuzumab vs. trastuzumab plus additional HER2-targeted agent(s) Pathological lymph node status assessed after preoperative therapy: node-positive vs. node-negative / not performed

[0253] Efficacy endpoints

[0254] Primary efficacy endpoint

[0255] The primary efficacy endpoints of this study were:

[0256] The primary efficacy endpoint was IDFS, defined as the time from randomization to the first occurrence of any of the following events: · Ipsilateral invasive breast tumor recurrence (i.e., invasive breast cancer involving the same breast parenchyma as the original primary tumor). · Ipsilateral localized-regionally invasive breast cancer recurrence (i.e., invasive breast cancer in the axilla, regional lymph nodes, chest wall, and / or skin of the ipsilateral breast). Distant recurrence (i.e., evidence of histologically confirmed or clinically diagnosed recurrent invasive breast cancer at any anatomical site other than the two sites mentioned above). Contralateral invasive breast cancer. Breast cancer, non-breast cancer, or Death from any cause, including unknown causes (however, whenever possible, the cause of death should be identified).

[0257] Secondary efficacy endpoints

[0258] Secondary efficacy endpoints include: IDFS including second primary non-breast cancers, defined as the same as IDFS for the primary endpoint but including second primary non-breast invasive cancers as events (excluding non-melanoma skin cancer at any site and carcinoma in situ [CIS]). DFS: defined as the time between randomization and the date of the first occurrence of an IDFS event, including a second primary non-breast cancer event, or contralateral or ipsilateral ductal carcinoma in situ (DCIS) OS: defined as the time from randomization to death from any cause DRFI: defined as the time between randomization and the date of distant breast cancer recurrence

[0259] Safety evaluation items

[0260] Clinical and laboratory AEs will be reported according to the NCI CTCAE (version 4.0). LVEF will be assessed using either echocardiogram (ECHO) or multi-gated acquisition (MUGA).

[0261] Safety will be assessed by determining the incidence, nature, and severity of AEs. Safety endpoints will be the following protocol-specific AEs: Incidence, type, and severity of all AEs based on NCI CTCAE (Version 4.0). · Incidence, type, and severity of SAEs. The incidence and type of AEs leading to treatment interruptions, modifications, or delays. Causes of death in the study. · Abnormal laboratory test values. ·Decreased LVEF. · Severe CHF (NYHA class III or IV) defined as a cardiac event, death from cardiac causes, or a decrease in LVEF of ≥ 10 percent from baseline to < 50% LVEF.

[0262] Patient-reported outcome (PRO) items

[0263] The PRO items for this study were as follows: The incidence of treatment-related symptoms and assessment of health-related quality of life (HRQOL) assessed using the EORTC QLQ-C30 questionnaire and the QLQBR23 module. Assessment of health status, assessed using the EuroQol EQ-5D™ questionnaire for health economic modelling.

[0264] Dosage, Administration, and Compliance

[0265] Trastuzumab emtansine

[0266] Trastuzumab emtansine (T-DM1) will be administered at a dose of 3.6 mg / kg IV on day 1 of a 3-week cycle q3w. If the administration falls on a non-administrative holiday, it should be administered within 5 business days after the scheduled date. The total dose will be calculated based on the patient's weight on day 1 of each cycle (or up to 3 days prior) with no upper limit. A weight change of <10% from baseline does not require a dose recalculation.

[0267] The trastuzumab emtansine dose may be reduced to 2.4 mg / kg per dose modification guidelines. Administration may be delayed up to 42 days after the last dose.

[0268] The first infusion of trastuzumab emtansine will be administered over 90 minutes (± 10 minutes). The infusion may be slowed or interrupted for patients with infusion-related symptoms. Vital signs should be assessed before and after administration. After the first administration, patients will be observed for at least 90 minutes for fever, chills, or other infusion-related symptoms. If the previous infusion is well tolerated (without any signs or symptoms of an infusion reaction), subsequent doses of trastuzumab emtansine may be administered over 30 minutes (± 10 minutes), with a minimum 30-minute observation period following the infusion. Further observation and monitoring should follow local health authority guidelines, if applicable. Premedication 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.

[0269] Trastuzumab

[0270] Trastuzumab is administered at a maintenance dose of 6 mg / kg IV on day 1 of a 3-week cycle. If >6 weeks have passed since the previous trastuzumab dose, an 8 mg / kg loading dose is required. If the timing falls on a non-administrative holiday, the dose should be administered within 5 business days after the scheduled date.

[0271] Trastuzumab infusions should be administered according to local guidelines and / or package insert.

[0272] Example 2 - Clinical Trial Results

[0273] This example provides results from the KATHERINE (NCT01772472 / BO27938 / NSABPB-50-I / GBG77) phase 3 trial, which compared adjuvant trastuzumab emtansine (T-DM1) with trastuzumab in patients with HER2-positive early-stage breast cancer and residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy.

[0274] Study design

[0275] KATHERINE was a randomized, multicenter, open-label phase 3 trial in which eligible patients were randomized to receive either adjuvant T-DM1 or trastuzumab (Figure 1).

[0276] Exam proctoring

[0277] This study was designed by a steering committee consisting of members from 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 was conducted under the guidance of an Independent Data Monitoring Committee (IDMC). Data were collected by the sponsor using a platform maintained and managed by the NSABP Foundation. Prespecified interim analyses were reviewed by the IDMC, which recommended reporting of the results. The recommendations and interim analysis results were reviewed by the sponsor in collaboration with the agreed-upon steering committee. The steering committee vouched for the completeness and accuracy of the data and analyses, as well as fidelity to the study protocol. The study was conducted in accordance with the revised Declaration of Helsinki and protocol and was approved by the Institutional Review Boards of each participating center. All patients provided written informed consent.

[0278] patient

[0279] Eligible patients had histologically confirmed, HER2-positive, non-metastatic, 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 before study enrollment. Patients were required to have completed at least six cycles (16 weeks) of neoadjuvant chemotherapy with at least nine weeks of taxane-based therapy and at least nine weeks of trastuzumab therapy (shorter treatment durations were permitted for dose-intensive regimens). Anthracyclines and additional HER2-targeted agents were permitted. Exclusion criteria included early clinical stage T1a / bN0; gross residual disease at the periphery of the resection; recurrent or progressive disease after preoperative systemic therapy; cardiopulmonary insufficiency, including New York Heart Association class II or greater heart failure or a history of reduced left ventricular ejection fraction to less than 40% due to prior trastuzumab; and doxorubicin 240 mg / m 2 More than equivalent amounts of prior cumulative exposure were included.

[0280] HER2-positive status was defined as an immunohistochemistry score of 3+ and / or HER2 amplification by in situ hybridization, defined as a ratio of 2.0 or greater for HER2 gene copy number to chromosome 17 copy signal number based on local pathology of the primary tumor, according to American Society of Clinical Oncology / College of American Pathologists guidelines.

[0281] treatment

[0282] Patients were randomized in a 1:1 ratio using an interactive voice or web-based response system within 12 weeks of surgery. A permuted block randomization scheme was used, stratified by clinical stage at presentation (inoperable [tumor stage T4 or lymph node stage N2 or N3 and metastatic stage M0] vs. operable [tumor stage T1-T3, lymph node stage N0 or N1, and metastatic stage M0]), hormone receptor status by local laboratory (positive vs. negative or unknown), preoperative HER2-targeted therapy (trastuzumab vs. trastuzumab plus additional HER2-targeted agent(s)), and pathological lymph node status assessed after neoadjuvant therapy (node-positive vs. node-negative / not performed).

[0283] Patients received either 3.6 mg of T-DM1 per kilogram of body weight or 6 mg of trastuzumab per kilogram intravenously every 3 weeks for 14 cycles. If more than 6 weeks had passed since the last trastuzumab dose, trastuzumab was administered at a loading dose of 8 mg per kilogram. Patients who discontinued T-DM1 due to toxicity were allowed to complete 14 cycles of study treatment with trastuzumab at the investigator's discretion. Endocrine therapy and radiation therapy were administered according to institutional standards and protocols.

[0284] evaluation

[0285] Reassessment of metastatic disease after neoadjuvant therapy and surgery before randomization was not required. Evaluation for disease recurrence occurred every 3 months for up to 2 years, every 6 months for years 3 to 5, and annually for years 6 to 10. Patients were assessed for toxicity before each dose of study drug. Left ventricular ejection fraction was assessed during the last week of cycle 2, then every 4 cycles, at study drug completion, 3, 6, 12, 18, and 24 months, and annually thereafter until year 5.

[0286] statistical analysis

[0287] The primary endpoint was invasive disease-free survival, defined as the time from randomization to the first occurrence of an invasive disease event: ipsilateral invasive breast tumor recurrence, ipsilateral local invasive disease recurrence, distant disease recurrence, contralateral invasive breast cancer, or death from any cause. The standardized definition of efficacy endpoints (STEEP) includes second primary non-breast cancer as an event for invasive disease-free survival (Hudis JCO2007), and this definition was included as a secondary endpoint. Other secondary endpoints included disease-free survival, overall survival, distant recurrence-free survival, and safety.

[0288] For the primary analysis, a sample size of 1,484 patients was planned based on the need for 384 invasive disease events to provide 80% power to detect a hazard ratio of 0.75 at a two-sided significance level of 5%. This calculation assumed 3-year invasive disease-free survival rates of 75.6% (T-DM1) and 70.0% (trastuzumab). An interim analysis of invasive disease-free survival was planned when approximately 267 (67%) subjects had experienced an invasive disease event, with an efficacy stopping boundary of P<0.0124 or an observed hazard ratio of 0.732 or less. The results of the interim analysis exceeded the early reporting boundary.

[0289] The primary analysis was performed on the intention-to-treat population. The stratified log-rank test was used to compare the rates of invasive disease-free survival between groups. Hazard ratios and their 95% confidence intervals (CIs) were estimated using the Cox proportional hazards model. The 3-year event-free rate for each treatment group was estimated using the Kaplan-Meier method. Data from patients without a recorded event were censored at the date the patient was last known to be alive and event-free.

[0290] A first interim overall survival analysis was planned at the time of the interim invasive-disease-free survival analysis if it crossed a prespecified boundary. The O'Brien-Fleming boundary and the Lan-DeMets alpha-spending function were used to adjust the overall type I error to 0.05 for the overall survival analysis.

[0291] result

[0292] A total of 1,486 patients were enrolled and randomized (T-DM1, n=743; trastuzumab, n=743). In the intent-to-treat population, median follow-up was approximately 41 months. Baseline characteristics were well balanced between treatment arms (Figure 2). Hormone receptor-positive disease was present in 72.3% of patients. 76.9% of patients received an anthracycline, and 19.5% of patients received additional HER2-targeted therapy (usually pertuzumab) as a component of neoadjuvant therapy.

[0293] Effectiveness

[0294] 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, 0.39-0.64; P < 0.0001 (Figure 3A)). A hazard ratio of 0.50 indicates that adjuvant T-DM1 monovalent therapy reduced the risk of invasive disease recurrence by 50% compared with adjuvant therapy with trastuzumab.

[0295] 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 estimated 3-year invasive disease-free survival was 88.3% (T-DM1) and 77.0% (trastuzumab). Distant recurrence as the first invasive disease event occurred in 78 patients (10.5%) who received T-DM1 and 118 patients (15.9%) who received trastuzumab (Figures 4A and 4B).

[0296] The risk of distant recurrence was lower in the T-DM1 group than in the trastuzumab group (hazard ratio, 0.60; 95% CI, 0.45-0.79 (Figure 5)). A hazard ratio of 0.60 indicates that adjuvant T-DM1 monovalent therapy reduced the risk of distant recurrence by 40% compared with adjuvant trastuzumab.

[0297] When second primary non-breast cancers were included as invasive disease events, the number of patients with events increased to 95 (12.8%) in the T-DM1 group and 167 (22.5%) in the trastuzumab group, and the difference in invasive disease-free survival remained in favor of T-DM1 (hazard ratio, 0.51; 95% CI, 0.40 to 0.66; P < 0.0001) (Figure 5).

[0298] Subgroup analyses of invasive disease-free survival revealed significant differences in patients with hormone receptor-positive disease (hazard ratio, 0.48; 95% CI, 0.35-0.67), hormone receptor-negative disease (hazard ratio, 0.50; 95% CI, 0.33-0.74), pathologically node-positive status assessed after preoperative therapy (hazard ratio, 0.52; 95% CI, 0.38-0.71), node-negative status (hazard ratio, 0.44; 95% CI, 0.28-0.68), and those with small residual disease (ypT0 / ypT1a / ypT1b / ypTmic / ypTis) (hazard ratio, 0.49; 95% CI, 0.28-0.68). The benefit of T-DM1 was found to be consistent across patient subgroups, including those receiving neoadjuvant trastuzumab alone (hazard ratio, 0.66; 95% CI, 0.44-1.00), neoadjuvant trastuzumab alone (hazard ratio, 0.49; 95% CI, 0.37-0.65), and neoadjuvant trastuzumab plus any additional HER2-targeted therapy (hazard ratio, 0.54; 95% CI, 0.27-1.06) (Figures 6A and 6B). Similar results were observed when comparing T-DM1 with trastuzumab in patients with adjuvant T-DM1. The benefit of adjuvant T-DM1 over adjuvant trastuzumab was observed independent of neoadjuvant HER2-targeted therapy. Among patients receiving chemotherapy and neoadjuvant trastuzumab, invasive disease events occurred in 78 patients in the T-DM1 group and in 141 patients in the adjuvant trastuzumab group (hazard ratio, 0.49; 95% CI, 0.37-0.65). Among patients receiving HER2-targeted therapy, 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, 0.27-1.06). In 93.8% of patients receiving a second neoadjuvant HER2-targeted agent, pertuzumab was the second therapy; in this group, invasive disease events occurred in 12 patients in the T-DM1 group and 24 patients in the adjuvant trastuzumab group (hazard ratio, 0.50; 95% CI, 0.25-1.00) (Figure 7).Other HER2-targeted therapies used as second-line therapy included lapatinib, neratinib, dacomitinib, and afatinib.

[0299] Ninety-eight patients died (42 patients (5.7%), T-DM1; 56 patients (7.5%), trastuzumab), and were not sufficient for overall survival analysis, which did not cross the border (hazard ratio 0.70; 95% CI, 0.47 to 1.05; P = 0.08) (Figures 5 and 8). The number of patients who died without a prior invasive disease event was 2 (T-DM1) and 3 (trastuzumab).

[0300] safety

[0301] A total of 1,460 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 with trastuzumab to complete all 14 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-related skin damage 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 patients treated with T-DM1 and 2.1% of patients treated with trastuzumab. Two fatal adverse events occurred, one in each group: intracranial hemorrhage and encephalitis.

[0302] Radiation pneumonitis of any grade occurred in 11 patients (1.5%) treated with T-DM1 and 5 patients (0.7%) treated with trastuzumab. Elevations of any grade in aminotransferase levels were more frequent 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 patients in the trastuzumab group discontinued treatment due to aminotransferase increases. Two cases of adjudicated nodular regenerative hyperplasia occurred, both in the T-DM1 group.

[0303] Consideration

[0304] In the KATHERINE trial, in patients with HER2-positive early-stage breast cancer and residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy, adjuvant treatment with T-DM1 reduced the risk of invasive disease recurrence or death by 50% compared with adjuvant trastuzumab. Subgroup analyses demonstrated consistent benefit regardless of hormone receptor status, extent of residual disease at surgery, single or dual HER2-targeted therapy in the neoadjuvant regimen, and patient baseline characteristics. Importantly, fewer patients receiving T-DM1 (10.5%) experienced distant recurrence as their first invasive disease event compared with trastuzumab (15.9%). These results represent a major therapeutic advance in this high-risk population.

[0305] Currently, the choice of adjuvant treatment for patients with residual invasive disease after neoadjuvant therapy is based on extrapolated data from trials in other settings. APHINITY demonstrated a disease-free survival advantage (hazard ratio, 0.81; 95% CI, 0.66-1.00; P=0.045) for adjuvant chemotherapy plus dual HER2 blockade with pertuzumab and trastuzumab compared with chemotherapy plus trastuzumab alone in patients with node-positive or high-risk node-negative disease (von Minckwitz, NEJM 2017). Despite these data, the benefit of additional adjuvant dual-blockade therapy after neoadjuvant dual-blockade plus chemotherapy remains unclear. A subgroup analysis from KATHERINE suggested that T-DM1 may be an appropriate option for patients with residual disease and provided evidence that switching to T-DM1 conferred benefit in such patients who received dual HER2 blockade plus trastuzumab and a neoadjuvant chemotherapy regimen (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).

[0306] The overall safety profile of T-DM1 was generally consistent with that observed in the metastatic setting, with the expected increase in adverse events associated with T-DM1 compared with trastuzumab alone.

[0307] References Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014;384:164-72. 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. Dieras 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. Dieras 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. Egloff H,Kidwell KM,Schott A.Ado-trastuzumab emtansine-induced pulmonary toxicity:a single-institution retrospective review.Case Rep Oncol.2018 11:527-533. 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. 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. 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. Hudis CA,Barlow WE,Costantino JP,et al.Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials:the STEEP system.J Clin Oncol 2007;25:2127-32. 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. 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. Kadcyla (Package Insert). South San Francisco, CA: Genentech, Inc.; September 2018. Krop IE, Kim SB, Gonzalez-Martin A, et al. Trastuzumab emtansine versus treatment of physician’s choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol 2014;15:689-99. 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. 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. 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. Lindstrom LS,Karlsson E,Wilking UM,et al.Clinically used breast cancer markers such as estrogen receptor,progesterone receptor,and human epidermal growth factor receptor 2 are unstable throughout tumor progression.J Clin Oncol 2012;30:2601-2608. 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. Masuda N,Lee SJ,Ohtani S,et al.Adjuvant capecitabine for breast cancer after preoperative chemotherapy.N Engl J Med 2017;376:2147-2159. National Comprehensive Cancer Network.NCCN clinical practice guidelines in oncology:breast cancer version 1.2018. Perez EA,Barrios C,Eiermann W,et al.Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive,advanced breast cancer:primary results from the phase III MARIANNE study.J Clin Oncol 2017;35:141-148. Promberger R,Dubsky P,Mittlbock M,et al.Postoperative CMF does not ameliorate poor outcomes in women with residual invasive breast cancer after neoadjuvant epirubicin / docetaxel chemotherapy.Clin Breast Cancer 2015;15:505-11. Schneeweiss A,Chia S,Hickish T,et al.Long-term efficacy analysis of the randomised,phase II TRYPHAENA cardiac safety study:Evaluating pertuzumab and trastuzumab plus standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer.Eur J Cancer 2018;89:27-35. Senkus E,Kyriakides S,Ohno S,et al.Primary breast cancer:ESMO clinical practice guidelines for diagnosis,treatment and follow-up.Ann Oncol 2015;26(Suppl 5):v8-30. 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. Verma S,Miles D,Gianni L,et al.Trastuzumab emtansine for HER2-positive advanced breast cancer.N Engl J Med 2012;367:1783-91. von Minckwitz G,Procter M,de Azambuja E,et al.Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer.N Engl J Med 2017;377:122-131. Yoshida A,Hayashi N,Suzuki K,Takimoto M,Nakamura S,Yamauchi H.Change in HER2 status after neoadjuvant chemotherapy and the prognostic impact in patients with primary breast cancer.J Surg Oncol 2017;116:1021-1028. von Minckwitz G,et al.,Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer.N Engl J Med 2019:380:617-628.

[0308] The foregoing description is considered as illustrative only of the principles of the present disclosure. Moreover, since numerous modifications and changes will be readily apparent to those skilled in the art, it is not desired to limit the disclosure to the exact construction and process shown above. Accordingly, all suitable modifications and equivalents may be considered to be within the scope of the present disclosure as defined by the following claims.

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 neoadjuvant systemic treatment.

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

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

4. 10. 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 to 4, wherein the preoperative systemic treatment comprises a HER2 targeted therapy.

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

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

8. 7. 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 combinations thereof.

9. The method of any of claims 5 to 8, wherein the preoperative systemic treatment further comprises a taxane.

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

11. The method of any of claims 1-10, wherein the patient undergoes curative surgery prior to said administration of T-DM1.

12. 12. The method of claim 11, wherein the patient is administered T-DM1 within 12 weeks after the definitive surgery.

13. The method of any of claims 1 to 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.

14. The method of any one of claims 1 to 13, wherein the patient has completed at least six cycles of taxane-containing chemotherapy.

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

16. 16. The method of any one of claims 1-15, wherein the patient is administered T-DM1 at a dose of 3.6 mg / kg every three weeks for 14 cycles.

17. 17. The method of any one of claims 1 to 16, wherein the adjuvant therapy substantially increases invasive disease-free survival (IDFS) compared to adjuvant therapy with trastuzumab.

18. 18. The method of any one of claims 1 to 17, wherein the adjuvant therapy results in a 50% reduction in the risk of invasive disease recurrence compared to adjuvant therapy with trastuzumab.

19. 19. The method of any one of claims 1 to 18, wherein the adjuvant therapy results in a reduction in distant recurrence compared to adjuvant therapy with trastuzumab.

20. 20. The method of any one of claims 1-19, wherein the adjuvant therapy results in a 40% reduction in the risk of distant recurrence compared to adjuvant trastuzumab.

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

22. 22. The T-DM1 for use of claim 21, wherein the residual disease is in the breast, in the lymph nodes, or in the breast and the lymph nodes.

23. 23. The T-DM1 for use according to claim 21 or 22, wherein the preoperative systemic treatment comprises a HER2-targeted therapy.

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

25. 26. The T-DM1 for use according to any of claims 21-25, wherein the preoperative systemic treatment further comprises a taxane.

26. 26. The T-DM1 for use according to any of claims 21-25, wherein the patient is an adult patient.

27. 27. The T-DM1 for use according to any of claims 21-26, wherein the patient undergoes curative surgery prior to administration of T-DM1.

28. 28. The T-DM1 for use according to any of claims 21-27, wherein the adjuvant therapy substantially increases invasive disease-free survival (IDFS) compared to adjuvant therapy with trastuzumab.

29. 29. T-DM1 for use according to any of claims 21-28, wherein the adjuvant therapy results in a 50% reduction in the risk of invasive disease recurrence compared to adjuvant therapy with trastuzumab.

30. 30. The T-DM1 for use according to any of claims 21-29, wherein the adjuvant therapy results in a reduction in distant recurrence compared to adjuvant therapy with trastuzumab.

31. 31. The T-DM1 for use according to any of claims 21-30, wherein the adjuvant therapy results in a 40% reduction in the risk of distant recurrence compared to adjuvant trastuzumab.

32. 1. Use of trastuzumab emtansine (T-DM1) in the manufacture of a medicament for use in the adjuvant treatment of HER2-positive early breast cancer in a patient, wherein the adjuvant is monotherapy and the patient has residual disease after neoadjuvant systemic treatment.

33. 33. The use of claim 32, wherein the residual disease is present in the breast, in the lymph nodes, or in the breast and the lymph nodes.

34. 34. The use of claim 32 or 33, wherein the preoperative systemic treatment comprises a HER2 targeted therapy.

35. 35. The use of claim 34, wherein the HER2 targeted therapy comprises trastuzumab or trastuzumab and pertuzumab, lapatinib, neratinib, dacomitinib and / or afatinib.

36. The use according to any one of claims 32 to 35, wherein the preoperative systemic treatment further comprises a taxane.

37. The use according to any one of claims 32 to 36, wherein the patient is an adult patient.

38. 38. The use of any of claims 32-37, wherein the patient undergoes curative surgery prior to administration of T-DM1.

39. The use according to any of claims 32 to 38, wherein the adjuvant therapy substantially increases invasive disease-free survival (IDFS) compared to adjuvant therapy with trastuzumab.

40. 40. The use of any of claims 32 to 39, wherein the adjuvant therapy results in a 50% reduction in the risk of invasive disease recurrence compared to adjuvant therapy with trastuzumab.

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

42. 42. The use of any of claims 32 to 41, wherein the adjuvant therapy results in a 40% reduction in the risk of distant recurrence compared to adjuvant trastuzumab.

44. 1. A method for treating breast cancer in a patient with HER2-positive early stage breast cancer, wherein the patient has residual disease in the breast or axillary lymph nodes after neoadjuvant therapy with chemotherapy and a HER2-targeted therapy, comprising: (i) radical surgery to remove all clinically evident tumor cells in the breast and the axillary lymph nodes; (ii) administering to said patient adjuvant monotherapy with trastuzumab emtansine (T-DM1).

45. 45. The method of claim 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.

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

47. The method of any one of claims 44 to 46, wherein the patient has completed at least six cycles of taxane-containing chemotherapy.

48. 48. The method of any one of claims 44-47, wherein the patient receives adjuvant treatment with T-DM1 within 12 weeks after radical surgery.

49. 49. The method of any one of claims 44-48, wherein the patient receives adjuvant treatment with T-DM1 infused at a dose of 3.6 mg / kg every three weeks.

50. 50. The method of any one of claims 44-49, wherein the patient receives adjuvant treatment with T-DM1 infused every three weeks at a dose of 3.6 mg / kg for 14 cycles.

51. 51. The method of any one of claims 44 to 50, wherein the treatment substantially increases invasive disease-free survival (IDFS) compared to adjuvant treatment with trastuzumab.

52. 52. The method of any one of claims 44 to 51, wherein the treatment results in a reduction in distant recurrence compared to adjuvant treatment with trastuzumab.

53. 1. A method for the treatment of HER2-positive early breast cancer in patients with residual disease after neoadjuvant therapy, said method comprising administering to said patient an effective amount of trastuzumab emtansine (T-DM1) after said patient has undergone curative surgery.

54. 54. The method of claim 53, wherein the residual disease is pathological residual invasive disease.

55. 55. The method of claim 53 or 54, wherein the residual disease is pathological residual invasive disease in lymph nodes.

56. 56. The method of any one of claims 53 to 55, wherein the residual disease is pathological residual invasive disease in the breast.

57. 57. The method of any one of claims 53 to 56, wherein the method does not include prior or concurrent adjuvant treatment with chemotherapy.

58. 58. The method of any one of claims 53 to 57, wherein the neoadjuvant therapy comprises a taxane and a HER2 targeted therapy.

59. 59. The method of any one of claims 53 to 58, wherein the neoadjuvant therapy comprises a taxane and trastuzumab.

60. 60. The method of any one of claims 53 to 59, wherein the patient has completed at least 16 weeks of neoadjuvant therapy.

61. 61. The method of any one of claims 53 to 60, wherein the patient has completed at least six cycles of taxane-containing neoadjuvant therapy.

62. 62. The method of any one of claims 53-61, wherein the patient is treated with T-DM1 within 12 weeks after radical surgery.

63. 63. The method of any one of claims 53-62, wherein the patient is treated with T-DM1 infusions at a dose of 3.6 mg / kg every three weeks.

64. 64. The method of any one of claims 53-63, wherein the patient is treated with T-DM1 infusions at a dose of 3.6 mg / kg every three weeks for 14 cycles.

65. 65. The method of any one of claims 53 to 64, wherein said treatment substantially increases invasive disease-free survival (IDFS) compared to adjuvant treatment with trastuzumab.

66. 66. The method of any one of claims 53 to 65, wherein the treatment results in a reduction in distant recurrence compared to adjuvant treatment with trastuzumab.

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

68. 68. The method of claim 67, wherein the method does not include prior or concurrent adjuvant treatment with chemotherapy.

69. 69. The method of claim 67 or 68, wherein the neoadjuvant therapy comprises a taxane and a HER2 targeted therapy.

70. 70. The method of any one of claims 67-69, wherein the neoadjuvant therapy comprises a taxane-containing chemotherapy regimen and trastuzumab.

71. 71. The method of any one of claims 67 to 70, wherein the patient has completed at least 16 weeks of neoadjuvant therapy.

72. 72. The method of any one of claims 67 to 71, wherein the patient has completed at least six cycles of taxane-containing neoadjuvant therapy.

73. 73. The method of any one of claims 67-72, wherein the patient is treated with T-DM1 within 12 weeks after radical surgery.

74. 74. The method of any one of claims 67-73, wherein the patient is treated with T-DM1 infusions at a dose of 3.6 mg / kg every three weeks.

75. 75. The method of any one of claims 67-74, wherein the patient is treated with T-DM1 infusions at a dose of 3.6 mg / kg every three weeks for 14 cycles.

76. 76. The method of any one of claims 67 to 75, wherein said treatment substantially increases invasive disease-free survival (IDFS) compared to adjuvant treatment with trastuzumab.

77. 77. The method of any one of claims 67 to 76, wherein the treatment results in a reduction in distant recurrence compared to adjuvant treatment with trastuzumab.

78. 78. The method of any one of claims 44 to 77, wherein the adjuvant therapy results in a 50% reduction in the risk of invasive disease recurrence compared to adjuvant therapy with trastuzumab.

79. 79. The method of any one of claims 44-78, wherein the adjuvant therapy results in a 40% reduction in the risk of distant recurrence compared to adjuvant trastuzumab.

Images