Methods of treating residual breast cancer with trastuzumab emtansine

Abstract

Methods of treating patients with HER2-positive early-stage breast cancer with the antibody-drug conjugate trastuzumab emtansine (T-DM1) are provided.

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. Over 1.3 million cases of breast cancer are diagnosed worldwide each year, with over 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. Overexpression of HER2 is observed in approximately 20% of human breast cancers (hereafter referred to as HER2-positive breast cancers) and is associated with 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 with high affinity (Kd=5 nM) to the extracellular domain of HER2 in cell-based assays. 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. (1986) 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 human tumor cells that overexpress HER2 in both in vitro assays and in animals (Hudziak et al(1989) Mol Cell Biol 9:1165-72; Lewis et al(1993) Cancer Immunol Immunother;37:255-63; Baselga et al(1998) Cancer Res.58:2825-2831). Trastuzumab is a mediator of antibody-dependent cellular cytotoxicity (ADCC) (Lewis et al (1993) Cancer Immunol Immunother 37(4):255-263; Hotaling et al (1996) Proc. Annual Meeting Am Assoc Cancer Res;37:471; Pegram MD,et al (1997) [Proc Am Assoc Cancer Res;38:602; Sliwkowski et al (1999) Seminars in Oncology 26(4),Suppl 12:60-70; Yarden Y.and Sliwkowski,M.(2001)Nature Reviews:Molecular Cell Biology,Macmillan Magazines,Ltd.,Vol.2:127-137).

[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.) for the adjuvant treatment of patients with HER2-positive, node-positive breast cancer as part of a treatment regimen containing doxorubicin, cyclophosphamide, and paclitaxel.

[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 that are already conjugated with highly potent cytotoxic drugs. ADCs represent a novel approach to impart tumor selectivity to systemically administered antitumor therapy. Using tumor-specific and / or overexpressed surface antigens, ADCs are designed with a focus on delivering highly potent cytotoxic drugs to tumor cells. The potential of this approach is to create 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 the 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 treatment at a dose of 2.0 mg / m2 every 3 weeks, either as a single dose or on 3 consecutive days. 2 (Issell BF, Crooke ST. (1978) Maytansine. Cancer Treat Rev 5:199-207). Despite preclinical activity, the activity of maytansine in the clinic has been modest at doses that could be safely delivered. Dose-limiting toxicities (DLTs) were gastrointestinal toxicities consisting of nausea, vomiting, and diarrhea (often followed by constipation). These toxicities were dose-dependent but not schedule-dependent. Peripheral neuropathy (mainly sensory) has been reported, most often in patients with pre-existing neuropathy. Asymptomatic transient elevations of hepatic transaminases, alkaline phosphatase, and total bilirubin have been reported. Constitutional toxicities including weakness, lethargy, dysphoria, and insomnia were 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, ado-trastuzumab 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 anti-microtubule 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 breast cancer who do not achieve pathological 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 than patients who achieve pathological complete remission. In HER2-positive patients, achieving pathological 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 after 3 years (Schneeweiss 2018, de Azambuja Lancet Oncol 2014, Gianni Lancet Oncol 2014). However, pathological 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 therapy. In certain embodiments, the residual disease is present in the breast, in the lymph nodes, or in the breast and lymph nodes. In certain embodiments, the preoperative systemic therapy 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 prior to 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, where the adjuvant therapy is monotherapy and the patient has residual disease after preoperative systemic therapy. In certain embodiments, the residual disease is in the breast, in the lymph nodes, or in the breast and lymph nodes. In certain embodiments, the preoperative systemic therapy 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 includes trastuzumab and further includes an agent selected from the group consisting of lapatinib, neratinib, dacomitinib, and afatinib. In certain embodiments, the preoperative systemic therapy further includes a taxane. In certain embodiments, the patient is an adult patient. In certain embodiments, the patient undergoes definitive surgery prior to 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 trastuzumab.

[0014] In one aspect, the 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 therapy. In certain embodiments, the residual disease is in the breast, in the lymph nodes, or in the breast and the lymph nodes. In certain embodiments, the preoperative systemic therapy 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 includes trastuzumab and further includes an agent selected from the group consisting of lapatinib, neratinib, dacomitinib, and afatinib. In certain embodiments, the preoperative systemic therapy further includes a taxane. In certain embodiments, the patient is an adult patient. In certain embodiments, the patient undergoes definitive surgery prior to 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 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, the patient has residual disease in the breast or axillary lymph nodes after neoadjuvant therapy with chemotherapy and HER2-targeted therapy, the method comprising (i) removing all clinically 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 taxane and HER2-targeted therapy. In certain embodiments, the patient has completed at least 16 weeks of a taxane-containing chemotherapy regimen and neoadjuvant therapy with HER2-targeted therapy. In certain embodiments, the patient has completed at least 6 cycles of a taxane-containing chemotherapy regimen. In certain embodiments, the patient receives adjuvant treatment with T-DM1 within 12 weeks after definitive surgery. In certain embodiments, the definitive surgery is performed at least 14 days after the completion of neoadjuvant therapy. In certain embodiments, the definitive surgery is performed within 9 weeks after the completion of neoadjuvant therapy. In certain embodiments, the patient receives adjuvant therapy with T-DM1 at a dose of 3.6 mg / kg infused every 3 weeks. In certain embodiments, the patient receives adjuvant therapy with T-DM1 at a dose of 3.6 mg / kg infused every 3 weeks for 14 cycles. In certain embodiments, the treatment substantially increases invasive disease-free survival (IDFS) compared to adjuvant therapy with trastuzumab. In certain embodiments, the treatment results in a reduction in distant recurrence 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 40% reduction in the risk of distant recurrence compared to adjuvant trastuzumab.

[0016] In one aspect, the disclosure relates to a method for the treatment of HER2-positive early breast cancer in a patient with residual disease after neoadjuvant therapy, the method comprising administering to the patient an effective amount of T-DM1 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 6 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 the completion of neoadjuvant therapy. In certain embodiments, the definitive surgery is performed within 9 weeks after the 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 disclosure relates to a method for reducing the risk of cancer recurrence in a patient with HER2-positive early breast cancer, the method comprising administering to the patient an effective amount of T-DM1, 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 6 cycles of taxane-containing neoadjuvant therapy. In certain embodiments, the patient is treated with T-DM1 within 12 weeks after 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 the 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 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 description of the drawings]

[0018] [Figure 1] FIG. 1 is a schematic diagram of the KATHERINE study design. [Figure 2A] FIG. 1 shows an overview of baseline characteristics of the KATHERINE Clinical Trial treatment arms. [Figure 2B] FIG. 1 shows an overview of baseline characteristics of the KATHERINE Clinical Trial treatment arms. [Figure 2C] FIG. 1 shows an overview of baseline characteristics of the KATHERINE Clinical Trial treatment arms. [Diagram 3] Kaplan-Meier plot of invasive disease-free survival. Invasive disease-free survival was defined as the time from random assignment 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, 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 first invasive lesion event in patients. [Diagram 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 PREFERRED EMBODIMENTS

[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. It will be understood that although the present disclosure will be described in conjunction with the enumerated embodiments, they are not intended to limit the present disclosure to these 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. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein that can be used to implement 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 down (alleviate) undesired physiological changes or diseases (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, reduction in the extent of disease, stabilization (i.e., not worsening) of disease pathology, delay or slowing of disease progression, amelioration or alleviation of disease pathology, 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 a condition or disease, as well as those prone to having a condition or disease, or those in need of preventing a condition or disease.

[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 (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, salivary gland cancer, kidney 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 stage 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 stage 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 cancer 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 the skilled clinician.

[0028] The term "metastatic breast cancer" means a form of breast cancer in which 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 antitumor agents such as chemotherapy being administered to a cancer patient. An example of a resistant cancer is a platinum-resistant cancer.

[0031] A "recurrent" cancer is one that has regrown, either at the initial site or at a distant site, after responding to initial treatment 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 (surgery).

[0035] "HER2 positive" cancer comprises cancer cells with higher than normal levels of HER2. Examples of HER2 positive cancer include HER2 positive breast cancer and HER2 positive gastric cancer. Optionally, HER2 positive cancer has 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" is 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 therapy" 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 the size of tumors, allowing for complete resection of initially unresectable tumors, or preserving parts of organs and their functions. Additionally, 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 given after definitive surgery to reduce the risk of disease recurrence. The purpose of adjuvant therapy is to prevent cancer recurrence, thus reducing the possibility of cancer-related death. Adjuvant therapy in this specification expressly excludes neoadjuvant therapy.

[0043] "Definitive surgery" is used as a term in the medical community. Definitive surgery includes procedures, surgeries, or other that result in the removal or resection of a tumor, including, for example, those that result in the removal or resection of all tumors visible to the naked eye. Definitive surgery includes, for example, complete or curative resection or gross total resection of a tumor. Definitive surgery includes procedures that occur in one or more stages, including, for example, multi-stage surgical procedures in which one or more surgeries or other procedures are performed before the resection of the tumor. Definitive surgery includes procedures to remove or resect a tumor, including associated organs, organ parts and tissues, and 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 differences in survival are 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 the study, whichever occurs first.

[0046] "Disease-free survival (DFS)" refers to a patient remaining alive and free of cancer recurrence for a period of time, such as about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 10 years, etc., from the start of treatment or from initial diagnosis. In one aspect 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 the analysis of DFS can include local, regional, and distant recurrence of cancer in patients without previous events, occurrence of 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 date of first occurrence of an invasive disease event, including 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, such as about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 10 years, etc., from the start of treatment or from initial diagnosis. In the studies underlying this disclosure, the event used for survival analysis was death from any cause.

[0049] "Extended survival," as used herein, refers to increased 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 to control over the follow-up period. "Hazard ratio" is the statistical definition of the occurrence rate of an event. 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 for 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" is the region within the extracellular domain of HER2 to which antibody 4D5 (ATCC CRL 10463) and trastuzumab bind. This epitope is proximal 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, including 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; 2005 / 0166993, which are incorporated by reference in their entireties). Trastuzumab-MCC-DM1 contains an average of 3.5 DM1 molecules / 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 hetero- 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 HER2 / neu and EGFR (epidermal growth factor receptor). Further 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 down to some extent and preferably stop) cancer cell invasion into peripheral organs, inhibit (i.e., slow down 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 the drug can prevent the growth of existing cancer cells and / or kill them, 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); cremophor-free, albumin engineered nanoparticle formulations 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 was undergoing a chemotherapy regimen (i.e., the patient is "chemoresistant") or has progressed within 12 months (e.g., within 6 months) after the patient 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). The fixed or constant dose may therefore 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 includes 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 a 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 via a vein 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 a 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 injecting the two or more drugs sequentially. 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 a 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, e.g., 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 a therapeutic agent that contain information about the indications, usage, dosage, administration, contraindications, and / or warnings regarding the use of such therapeutic agent.

[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 assignment of study treatment that is associated with drug washout, no treatment induction, or other protocol-mandated intervention, if applicable; 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, in the investigator's opinion, places the patient at risk of immediate death, 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 substantial 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 product; or is considered a serious medical event by the investigator based on medical judgment (e.g., may endanger the patient or may 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 definition 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 functions. Severity (not severity) serves as a guide to define regulatory reporting obligations from the sponsor to the applicable regulatory agency. 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: TIFF0007627210000001.tif91170, where Tr is trastuzumab linked to a maytansinoid drug moiety DM1 via the linker moiety MCC (US Pat. Nos. 5,208,020 and 6,441,163). The microtubule inhibitor maytansinoid DM1 is synthesized from the maytansinoid maytansinol and is primarily linked to lysine residues of 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) and ranges from an integer value of 1 to about 8. Trastuzumab-MCC-DM1 includes a mixture of all the 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 (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 / 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 that is structurally related to the epidermal growth factor receptor. Trastuzumab is an anti-HER2 antibody that has the antigen-binding residues of, or is derived from, the murine 4D5 antibody (ATCC CRL 10463, deposited under the Budapest Treaty on Can 24, 1990 at 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 (ado-trastuzumab 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, water, and the like. The particular carrier, diluent, or excipient used will depend on the means and purpose for which the compounds of the present disclosure are applied. Solvents are generally selected based on solvents recognized by those skilled in the art as safe (GRAS) to be administered to mammals. In general, 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 glycol (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, flavorings, 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 dissolving and mixing procedures. For example, the drug substance (i.e., the 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 allow patient compliance with a given regimen.

[0081] The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending on the method used to administer the drug. Generally, the article for distribution includes a container having disposed therein the pharmaceutical formulation in a suitable 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 pharma- ceutically acceptable diluents, carriers, excipients, or stabilizers (Remington's Pharmaceutical Sciences (1995) 18th edition, Mack Publ. Co., Easton, PA). Formulation may be carried out by mixing with a physiologically acceptable carrier, i.e., a carrier that is non-toxic to the recipient at the dosage and concentration employed, at ambient temperature, at an appropriate pH, and with the desired degree of purity. The pH of the formulation will depend primarily on the particular application and the concentration of the 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., amounts, concentrations, schedules, courses, vehicles, and routes of administration. Factors to be considered in this regard include the particular disorder being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the drug, 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 phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (octadecyldimethylbenzyl ammonium 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); 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 (PEGs), including PEG400. The active pharmaceutical ingredient may also be incorporated into microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, 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 Publ. 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 composition may be in the form of a sterile injectable preparation, such as an aqueous or oily sterile injectable suspension. This suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable preparation may be a solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol, or may be prepared from a lyophilized powder. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils may be conventionally used as a solvent or suspending medium. For this purpose, any mild fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables as well.

[0089] The amount of active ingredient that can be combined with carrier materials to produce a single dosage form varies 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 1-1000 mg of active ingredient compound, together 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 3-500 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, immediately prior to use for injection. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or daily unit sub-dose of the active ingredient, as herein above recited, or an appropriate fraction thereof.

[0092] As a general proposition, the initial pharmacologic 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 a single-use vial. 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, for example, 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 40%, about 50%, or about 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 results in a 40% reduction in the risk of distant recurrence compared to adjuvant trastuzumab.

[0097] The present disclosure provides a method for adjuvant therapy comprising administering T-DM1. For example, but not limited to, the method of adjuvant therapy 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, such as 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 therapy 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, before treatment with T-DM1.In certain embodiments, the patient has completed at least 6 cycles of taxane-containing chemotherapy.

[0102] In certain embodiments, the method 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 definitive surgery. In certain embodiments, the patient is administered T-DM1 within 12 weeks after definitive surgery.

[0103] The subject matter of the present disclosure further provides a method for treating breast cancer in a patient with HER2-positive early stage breast cancer, where the patient has residual disease in the breast or axillary lymph nodes following chemotherapy and neoadjuvant therapy with 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 therapy with T-DM1.

[0104] In certain embodiments, the patient has residual disease in the breast or axillary lymph nodes after neoadjuvant therapy with taxane and HER2 targeted therapy. In certain embodiments, the patient has completed at least 16 weeks of neoadjuvant therapy with 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 after definitive surgery.

[0105] The subject matter of the present disclosure further provides a method 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 the 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 lymph nodes. In certain embodiments, the residual disease is pathological residual invasive disease in the breast. In certain embodiments, the residual disease is pathological residual invasive disease in lymph nodes and in the breast.

[0106] The subject matter of the present disclosure provides a method for reducing the risk of cancer recurrence in a patient with HER2-positive early breast cancer. In certain embodiments, the method comprises administering an effective amount of T-DM1 to the patient, 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, the patient treated according to the method of the present disclosure has completed at least 16 weeks of neoadjuvant therapy. In certain embodiments, the patient has completed at least 6 cycles of taxane-containing neoadjuvant therapy. In certain embodiments, the patient is treated with T-DM1 within 12 weeks after 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 disclosed methods can include administration of T-DM1 at a dose of 3.6 mg / kg every 3 weeks. For example, but not limited to, a patient can be administered T-DM1 at a dose of 3.6 mg / kg every 3 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, present in lymph nodes, or present in the breast and 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 prior to administration of T-DM1.

[0111] In a further aspect, the subject matter of the present disclosure provides the 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 a monotherapy and the patient has residual disease after preoperative systemic treatment. In certain embodiments, the residual disease is present in the breast, present in the lymph nodes, or present in the breast and 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 its pharmaceutical compositions can be administered in the methods of the present disclosure by any route appropriate to the condition to be treated. For example, but not limited to, suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, inhalation, intradermal, intrathecal, epidural, and injection techniques), transdermal, rectal, nasal, topical (including buccal and sublingual), intravaginal, intraperitoneal, pulmonary, 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 by intralesional administration, including 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 disease state of the recipient. When the compound is administered orally, it may be formulated as a pill, capsule, tablet, etc., 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 pharma- ceutically acceptable parenteral vehicle or diluent, as detailed below.

[0113] V.Product

[0114] An article of manufacture or "kit" is provided that contains T-DM1 useful in the therapeutic methods herein. In certain embodiments, the kit includes a container that contains T-DM1. The kit can 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 packages of therapeutics that contain information about the indications, usage, dosage, administration, contraindications, and / or warnings regarding the use of such therapeutics. Suitable containers include, for example, bottles, vials, syringes, blister packs, and the like. The container can be formed from a variety of materials, such as glass or plastic. The container can hold T-DM1 or a formulation thereof effective for use in the therapeutic methods herein and can have a sterile access port (e.g., the container can 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 additional containers containing pharma- ceutically acceptable buffers, 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 administration of 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 solid oral forms of T-DM1, such as tablets or capsules. Such kits preferably include several unit dosages. Such kits 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 to package pharmaceutical unit dosage forms. If desired, a memory aid can be provided, for example in the form of numbers, letters, or other markings, or with a calendar insert, designating the days in the treatment schedule on which the dosages may be administered.

[0117] In certain embodiments, the article of manufacture herein comprises an intravenous infusion (IV) bag containing a stable mixture of T-DM1 suitable for administration to a cancer patient. 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, where the patient has residual disease following preoperative systemic treatment.

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

[0122] A2. The method according to 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 according to 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 above method according to A5, wherein the HER2 targeted therapy further comprises pertuzumab.

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

[0128] A8. The method according to 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 above method according to any one of A-A9, wherein the patient undergoes curative surgery prior to administration of T-DM1.

[0130] A11. The method of claim 10, wherein the patient is administered T-DM1 within 12 weeks after definitive surgery.

[0131] A12. The method according to any one of A-A11, wherein the patient has completed at least 16 weeks of preoperative systemic treatment with a taxane-containing chemotherapy regimen and a HER2-targeted therapy.

[0132] A13. The method according to any one of A-A12, wherein the patient has completed at least 6 cycles of taxane-containing chemotherapy.

[0133] A14. The 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 above 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-A15, wherein the adjuvant therapy substantially increases invasive disease-free survival (IDFS) compared to adjuvant therapy with trastuzumab.

[0136] A17. The method according to 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 according to 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 subject matter of the present disclosure provides trastuzumab emtansine (T-DM1) for use in the adjuvant treatment of HER2-positive early breast cancer in a patient, where the adjuvant is monotherapy and the patient has residual disease following preoperative systemic treatment.

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

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

[0142] B3. The above 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 above-mentioned 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 to 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 above-mentioned use of T-DM1 according to 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 above-mentioned use of T-DM1 according to any one of B-B7, wherein said 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 according to 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 above-mentioned use of T-DM1 according to any one of B-B9, wherein said adjuvant therapy results in a 40% reduction in the risk of distant recurrence compared to adjuvant trastuzumab.

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

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

[0152] C2. The use according to C or C1 above, wherein the preoperative systemic treatment comprises a HER2 targeted therapy.

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

[0154] C4. The use of any one of C-C3 above, 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 above, 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 above, 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 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, the patient having residual disease in the breast or axillary lymph nodes following chemotherapy and neoadjuvant therapy with a HER2 targeted therapy, the method comprising: (i) definitive surgery to remove all clinically evident tumor cells in the breast and axillary lymph nodes; and (ii) administering to the patient an adjuvant monotherapy regimen with trastuzumab emtansine (T-DM1).

[0162] D1. The above method according to D, wherein the patient has residual disease in the breast or axillary lymph nodes after neoadjuvant therapy with a taxane and a HER2 targeted therapy.

[0163] D2. The method of any one of D or D1 above, wherein the patient has completed at least 16 weeks of neoadjuvant therapy with a 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 above 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 infused at a dose of 3.6 mg / kg 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 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 said 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 a method for the treatment of HER2-positive early breast cancer in a patient with residual disease after neoadjuvant therapy, the method comprising administering to the patient an effective amount of trastuzumab emtansine (T-DM1) after the patient has undergone curative surgery.

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

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

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

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

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

[0176] E6. The 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 above method of any one of E-E7, wherein the patient has completed at least six cycles of a taxane-containing neoadjuvant therapy.

[0179] E9. The above 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 3 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 3 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) as compared to adjuvant treatment with trastuzumab.

[0183] E13. The 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), where 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 under 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 method of any one of F-F2, wherein the neoadjuvant therapy comprises a taxane-containing chemotherapy regimen and trastuzumab.

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

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

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

[0191] F7. The above 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 3 weeks.

[0192] F8. The above 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 3 weeks for 14 cycles.

[0193] F9. The 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 method according to any one of F-F9, wherein said treatment results in a reduction in distant recurrence compared to adjuvant treatment with trastuzumab.

[0195] F11. The method according to 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 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. EXAMPLES

[0197] To illustrate the present disclosure, the following examples are included. 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 Trials

[0200] This phase 3, open-label trial (NCT01772472 / BO27938 / NSABPB-50-I / GBG 77; KATHERINE) enrolled patients with HER2-positive early breast cancer who had received neoadjuvant taxane-containing chemotherapy plus trastuzumab-containing HER2-targeted therapy and had pathologic 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 was 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 by in situ hybridization (ISH) prospectively confirmed by a central laboratory prior to study enrollment. ISH positivity is defined as a ratio of ≥2.0 for HER2 gene copy number to chromosome 17 copy signal number. 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 carcinoma.

[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 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. Dose escalation of paclitaxel (225 mg / m2) over 6 weeks is required. 2q2w) Dose-intensive regimens are permitted. Patients may receive ≥2 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 disease within 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 histologically negative excision periphery. For patients undergoing breast-conserving surgery, the periphery of the resection specimen must be histologically free of invasive tumor and DCIS as determined by an on-site pathologist. If pathology shows tumor at the resection line, additional surgical procedures can be performed to obtain a clear periphery. If tumor is still present at the resection 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 resection.

[0210] Lymph node surgery: If a positive result from fine needle aspiration, core biopsy, or sentinel lymph node biopsy performed before preoperative therapy, additional operative evaluation of the axilla is necessary following preoperative therapy. If only micrometastases are present in the sentinel lymph node preoperatively (i.e., no nodal metastases in the sentinel lymph node are greater than 0.2 mm in maximum diameter), no additional operative evaluation of the axilla is necessary. If the sentinel lymph node biopsy performed before preoperative therapy is negative, no additional operative evaluation of the axilla is necessary after preoperative therapy. If the only sentinel lymph nodes identified by isotope scan are in the internal mammary chain, operative evaluation of the axilla is recommended.

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

[0212] 6. Pathological evidence of residual invasive carcinoma in the breast or axillary lymph nodes following 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 nodes following 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, while 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 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. Patient may receive red blood cell transfusions to achieve this level. d. Serum creatinine < 1.5 x 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 × ULN g. Serum total bilirubin (TBILI) ≦1.0×ULN (within the normal range), except for patients with Gilbert's syndrome, for which direct bilirubin should 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 from pre-chemotherapy LVEF to an absolute point of > 15%. 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 resulting in a failure rate of less than 1% per year. a. Abstinence is acceptable only if it is compatible with the patient's preferred normal lifestyle. Periodic abstinence (e.g., calendar, ovulation, symptomatic temperature, or postovulation) and abortive intercourse are not acceptable contraceptive methods. 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 injected hormonal contraceptives, and certain intrauterine devices. Alternatively, two methods (e.g., two barrier methods such as condoms and cervical caps) can be combined to achieve a failure rate of less than 1% per year. Barrier methods always require the addition of spermicide use. b. Male patients whose partners are pregnant should either use condoms or 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. Hepatitis B virus (HBV) serology and Hepatitis C virus (HCV) serology must be documented: 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, testing 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 significant gross residual or recurrent disease following preoperative therapy and surgery.

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

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

[0231] 6. History of other malignancies within the past 5 years, except for 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 the treatment of breast cancer but is contraindicated for medical reasons (e.g., connective tissue disease or prior 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 Equivalent exposure.

[0235] 10. Cardiopulmonary insufficiency as defined by any of the following: History of symptomatic CHF of NCI CTCAE (Version 4.0) grade ≥ 3 or NYHA classification ≥ II. b. Angina requiring antianginal medication, severe 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 (type 2 atrioventricular block [Mobitz2] or type 3 atrioventricular block). d. Significant symptoms (grade ≧2) related to left ventricular dysfunction, cardiac arrhythmias, or cardiac ischemia during or since receiving preoperative therapy. e. History of decline in LVEF 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 requirements 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 positive HBV or HCV serology must meet eligibility criteria for ALT, AST, TBILI, INR, aPTT, and alkaline phosphatase (ALK) on at least two consecutive occasions, at least one week apart, within a 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 this study will be randomized in a 1:1 ratio to one of the following treatment arms: 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 >6 weeks since the last dose of trastuzumab, a loading dose of 8 mg / kg should be administered).

[0248] The study 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 two or more HER2 targeted therapies. Patients may have received anthracyclines as part of preoperative treatment.

[0250] Patients will receive study treatment for up to 14 cycles. Treatment will be discontinued prior to the 14th cycle 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. 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 when 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 nodal irradiation is required if patients are found to have clinical T3 (except T3N0) or T4 disease and / or clinical N2 or N3 disease at initial diagnosis. Regional nodal irradiation is recommended in cases of T3N0 or residual disease in lymph nodes. For post-mastectomy patients, chest wall and LNLRT are required if the patient is found to have clinical T3 (except T3N0) or T4 disease and / or clinical N2 or N3 disease at initial diagnosis. Chest wall and LNLRT are recommended for T3N0 disease or if there is residual disease in the lymph nodes. For post-mastectomy patients not meeting these criteria, radiation therapy will be at the investigator's discretion based on institutional standards.

[0252] A permutation block randomization scheme will be used to ensure that, with an approximate 1:1 allocation, patients receive trastuzumab emtansine or trastuzumab 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 + additional HER2-targeted agent(s) Pathologic 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 outcome was IDFS, defined as the time from randomization to the date of the first occurrence of any of the following events: · Ipsilateral invasive breast tumour recurrence (i.e. invasive breast cancer involving the same breast parenchyma as the original primary tumour). · Ipsilateral localized-regional 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 included the following: IDFS including second primary non-breast cancers, defined 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 a contralateral or ipsilateral ductal intraepithelial carcinoma (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 interruption, modification, or delay of dosing. Causes of death in the study. · Abnormal laboratory 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 an LVEF of < 50%.

[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) is administered at a dose of 3.6 mg / kg IV on day 1 of a 3-week cycle q3w. If the timing falls on a non-dosing holiday, the dose should be administered within 5 business days after the scheduled date. Total dose is calculated based on the patient's weight on day 1 of each cycle (or up to 3 days prior) with no upper limit. No dose recalculation is required for weight changes of <10% from baseline.

[0267] The trastuzumab emtansine dose may be reduced to 2.4 mg / kg per dose modification guidelines. Dosing 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). For patients with infusion-related symptoms, the infusion may be slowed or interrupted. Vital signs must 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 observation period of 30 minutes 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 pain relievers, 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, a loading dose of 8 mg / kg 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 comparing adjuvant trastuzumab emtansine (T-DM1) with trastuzumab in patients with HER2-positive early 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 Supervision

[0277] The 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 steering committee. The steering committee ensures the completeness and accuracy of the data and analysis, and 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 center involved. 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 was confirmed centrally prior to study enrollment. Patients were required to have completed at least six cycles (16 weeks) of preoperative 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 <40% with prior trastuzumab; and doxorubicin 240 mg / m 2 More than equal amounts of prior cumulative exposure were included.

[0280] HER2-positive status was defined as an immunohistochemistry score of 3+ and / or amplification of HER2 by in situ hybridization, defined as a ratio of ≥2.0 for HER2 gene copy number to chromosome 17 copy signal number based on local pathology of the primary tumor according to the 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 response system within 12 weeks of surgery.A permutation block randomization scheme was used with stratification according to clinical stage at presentation (inoperable [tumor stage T4 or nodal stage N2 or N3 and metastatic stage M0] vs. operable [tumor stage T1-T3, nodal 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 T-DM1 at 3.6 mg per kilogram of body weight or trastuzumab at 6 mg per kilogram, each administered intravenously every 3 weeks for 14 cycles. If >6 weeks had elapsed 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] Reevaluation of metastatic disease after neoadjuvant therapy and surgery prior to randomization was not required. Patients were evaluated for disease recurrence 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 evaluated for toxicity before each dose of study drug. Left ventricular ejection fraction was assessed during the last week of cycle 2, every 4 cycles thereafter, at completion of study drug, 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 date of 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. Standardized definitions of efficacy endpoints (STEEP) include 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] A sample size of 1484 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% for the primary analysis. This calculation assumes 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 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 were beyond the early reporting boundary.

[0289] Primary analyses were performed on the intent-to-treat population. The proportion of invasive disease-free survival was compared between groups using a stratified log-rank test. Hazard ratios and their 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. 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 overall type I error was adjusted to 0.05 for the overall survival analysis using O'Brien-Fleming boundaries and the Lan-DeMets alpha-spending function.

[0291] result

[0292] 1486 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 to 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 a first invasive disease event occurred in 78 patients (10.5%) who received T-DM1 and in 118 patients (15.9%) who received trastuzumab (Figures 4A, 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 to 0.79 (Figure 5)). The hazard ratio of 0.60 indicates that T-DM1 monovalent adjuvant 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 < .0001) (Figure 5).

[0298] Subgroup analyses of invasive disease-free survival included 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), pathologic 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, 0.26; 95% CI, 0.11-0.26) The benefit of T-DM1 was 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 for patients with HER2-targeted disease. The benefit of adjuvant T-DM1 over adjuvant trastuzumab was observed independent of neoadjuvant HER2-targeted therapy. Among patients who received 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 to 0.65). Among patients who received ER2-targeted therapy, invasive disease events occurred in 13 patients in the T-DM1 group and in 24 patients in the adjuvant trastuzumab group (hazard ratio, 0.54; 95% CI, 0.27 to 1.06). In 93.8% of patients who received 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 in 24 patients in the adjuvant trastuzumab group (hazard ratio, 0.50; 95% CI, 0.25 to 1.00) (Figure 7).Other HER2-targeted therapies used as second-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 1460 patients were analyzed for safety (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 of treatment. The most common grade ≥3 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%) who received T-DM1 and in 59 patients (8.2%) who received 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 in 5 patients (0.7%) treated with trastuzumab. Elevations of aminotransferase levels of any grade 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% (alanine aminotransferase) and 1.6% (aspartate aminotransferase) patients. No patients in the trastuzumab group had treatment discontinued 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 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 showed consistent benefit independent of hormone receptor status, extent of residual disease at surgery, single or dual HER2-targeted therapy in the neoadjuvant regimen, and baseline patient characteristics. Importantly, fewer patients receiving T-DM1 (10.5%) had 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 treatment 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 to 1.00; P = 0.045) of adjuvant chemotherapy plus dual HER2 blockade with pertuzumab and trastuzumab compared with chemotherapy plus trastuzumab alone in node-positive or high-risk node-negative patients (von Minckwitz NEJM 2017). Despite these data, the benefit of additional dual-blockade adjuvant therapy after neoadjuvant dual blockade plus chemotherapy remains unclear. Subgroup analyses 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), a benefit 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 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 deemed to be within the scope of the disclosure as defined by the following claims.

Claims

1. A compound comprising an effective amount of trastuzumab emtansine (T-DM1). A medicament for adjuvant therapy in patients with HER2-positive early breast cancer, comprising: the T-DM1 is administered as monotherapy; the patient has residual disease present in the breast and / or lymph nodes following preoperative systemic treatment; The preoperative systemic treatment includes a HER2 targeted therapy and a taxane.

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

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

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

5. The pharmaceutical agent of any one of claims 1 to 4, wherein the HER2 targeted therapy comprises trastuzumab.

6. The pharmaceutical composition of claim 5, wherein the HER2 targeted therapy further comprises pertuzumab.

7. The pharmaceutical agent of any one of claims 1 to 5, wherein the HER2 targeted therapy further comprises an agent selected from the group consisting of lapatinib, neratinib, dacomitinib, afatinib, and combinations thereof.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the patient is an adult patient.

9. The pharmaceutical agent of claim 8, wherein the patient is administered T-DM1 within 12 weeks after radical surgery.

10. The pharmaceutical agent of any one of claims 1 to 9, wherein the patient has completed at least 16 weeks of preoperative systemic treatment with a taxane-containing chemotherapy regimen and a HER2 targeted therapy.

11. The method of any one of claims 1 to 10, wherein the patient has completed at least six cycles of taxane-containing chemotherapy.

12. The medicament of any one of claims 1 to 11, wherein the patient is administered T-DM1 at a dose of 3.6 mg / kg every 3 weeks.

13. The medicament of any one of claims 1 to 12, wherein the patient is administered T-DM1 at a dose of 3.6 mg / kg every 3 weeks for 14 cycles.

14. The method of any one of claims 1 to 13, wherein the adjuvant therapy substantially increases invasive disease-free survival (IDFS) compared to adjuvant therapy with trastuzumab.

15. The method of any one of claims 1 to 14, wherein the adjuvant therapy results in a 50% reduction in the risk of invasive disease recurrence compared to adjuvant therapy with trastuzumab.

16. The pharmaceutical agent according to any one of claims 1 to 15, wherein the adjuvant therapy results in a reduction in distant recurrence compared to adjuvant therapy using trastuzumab.

17. The medicament of any one of claims 1 to 16, wherein the adjuvant therapy results in a 40% reduction in the risk of distant recurrence compared to adjuvant trastuzumab.

18. 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, comprising: The adjuvant is a monotherapy, and The patient has residual disease in the breast and / or lymph nodes following preoperative systemic therapy, and The use, wherein the preoperative systemic treatment comprises a HER2 targeted therapy and a taxane.

19. 19. The use of claim 18, wherein the residual disease is in the breast, in the lymph nodes, or in the breast and the lymph nodes.

20. 20. The use according to claim 18 or 19, wherein the preoperative systemic treatment comprises a HER2 targeted therapy.

21. 21. The use of claim 20, wherein the HER2 targeted therapy comprises trastuzumab, or trastuzumab and pertuzumab, lapatinib, neratinib, dacomitinib and / or afatinib.

22. The use according to any one of claims 18 to 21, wherein the preoperative systemic treatment further comprises a taxane.

23. The use according to any one of claims 18 to 22, wherein the patient is an adult patient.

24. The use according to any one of claims 18 to 23, wherein the adjuvant therapy substantially increases invasive disease free survival (IDFS) compared to adjuvant therapy with trastuzumab.

25. The use according to any one of claims 18 to 24, wherein the adjuvant therapy results in a 50% reduction in the risk of invasive disease recurrence compared to adjuvant therapy with trastuzumab.

26. The use according to any one of claims 18 to 25, wherein the adjuvant therapy results in a reduction in distant recurrence compared to adjuvant therapy with trastuzumab.

27. 27. The use according to any one of claims 18 to 26, wherein the adjuvant therapy results in a 40% reduction in the risk of distant recurrence compared to adjuvant trastuzumab.

28. A compound comprising trastuzumab emtansine (T-DM1).

1. A medicament for treating breast cancer in a patient with HER2-positive early stage breast cancer who has residual disease in the breast or axillary lymph nodes following chemotherapy and neoadjuvant therapy with a HER2-targeted therapy, comprising: The treatment comprises: (i) definitive surgery to remove all clinically evident tumor cells in the breast and axillary lymph nodes; (ii) administering to the patient adjuvant monotherapy with trastuzumab emtansine (T-DM1); Preoperative systemic treatment includes HER2 targeted therapy and taxanes.

29. The pharmaceutical agent of claim 28, wherein the patient has residual disease in the breast or axillary lymph nodes following neoadjuvant therapy with a taxane and a HER2 targeted therapy.

30. 30. The method of claim 28 or 29, wherein the patient has completed at least 16 weeks of neoadjuvant therapy with a taxane-containing chemotherapy.

31. The method of any one of claims 28 to 30, wherein the patient has completed at least six cycles of taxane-containing chemotherapy.

32. The medicament of any one of claims 28 to 31, wherein the patient receives adjuvant treatment with T-DM1 within 12 weeks after radical surgery.

33. The medicament of any one of claims 28 to 32, wherein the patient receives adjuvant treatment with T-DM1 infusions at a dose of 3.6 mg / kg every 3 weeks.

34. The medicament of any one of claims 28 to 33, wherein the patient receives adjuvant treatment with T-DM1 infusions at a dose of 3.6 mg / kg every 3 weeks for 14 cycles.

35. The method of any one of claims 28 to 34, wherein the treatment substantially increases invasive disease free survival (IDFS) compared to adjuvant treatment with trastuzumab.

36. The pharmaceutical agent of any one of claims 28 to 35, wherein the treatment results in a reduction in distant recurrence compared to adjuvant treatment with trastuzumab.

37. A composition comprising an effective amount of trastuzumab emtansine (T-DM1).

1. A medicament for the treatment of HER2-positive early breast cancer in patients with residual disease in the breast and / or lymph nodes following neoadjuvant therapy, comprising: T-DM1 is administered after the patient has undergone definitive surgery; and Preoperative systemic treatment includes HER2 targeted therapy and taxanes.

38. The method of claim 37, wherein the residual disease is pathological residual invasive disease.

39. The pharmaceutical of claim 37 or 38, wherein the residual disease is pathological residual invasive disease in a lymph node.

40. The pharmaceutical composition of any one of claims 37 to 39, wherein the residual lesion is pathological residual invasive disease in the breast.

41. The medicament according to any one of claims 37 to 40, wherein the medicament does not include prior or simultaneous adjuvant treatment with chemotherapy.

42. The pharmaceutical of any one of claims 37 to 41, wherein the neoadjuvant therapy comprises a taxane and a HER2 targeted therapy.

43. The method of any one of claims 37 to 42, wherein the neoadjuvant therapy comprises a taxane and trastuzumab.

44. The method of any one of claims 37 to 43, wherein the patient has completed at least 16 weeks of neoadjuvant therapy.

45. The method of any one of claims 37 to 44, wherein the patient has completed at least six cycles of taxane-containing neoadjuvant therapy.

46. The method of any one of claims 37 to 45, wherein the patient is treated with T-DM1 within 12 weeks after radical surgery.

47. The medicament of any one of claims 37 to 46, wherein the patient is treated with T-DM1 infusions at a dose of 3.6 mg / kg every 3 weeks.

48. The medicament of any one of claims 37 to 47, wherein the patient is treated with T-DM1 infusions at a dose of 3.6 mg / kg every 3 weeks for 14 cycles.

49. The method of any one of claims 37 to 48, wherein the treatment substantially increases invasive disease free survival (IDFS) compared to adjuvant treatment with trastuzumab.

50. The pharmaceutical agent of any one of claims 37 to 49, wherein the treatment results in a reduction in distant recurrence compared to adjuvant treatment with trastuzumab.

51. A pharmaceutical agent for reducing a risk of cancer recurrence in a patient with HER2-positive early breast cancer, comprising an effective amount of trastuzumab emtansine (T-DM1), the patient has not achieved complete pathological response with neoadjuvant therapy, and the patient has undergone curative surgery prior to said administration of T-DM1; The patient has residual disease in the breast and / or lymph nodes following preoperative systemic therapy, and The preoperative systemic treatment includes a HER2 targeted therapy and a taxane.

52. 52. The medicament of claim 51, wherein the medicament does not include prior or concurrent adjuvant treatment with chemotherapy.

53. 53. The pharmaceutical of claim 51 or 52, wherein the neoadjuvant therapy comprises a taxane and a HER2 targeted therapy.

54. The method of any one of claims 51 to 53, wherein the neoadjuvant therapy comprises a taxane-containing chemotherapy regimen and trastuzumab.

55. The pharmaceutical agent of any one of claims 51 to 54, wherein the patient has completed at least 16 weeks of neoadjuvant therapy.

56. The method of any one of claims 51 to 55, wherein the patient has completed at least six cycles of a taxane-containing neoadjuvant therapy.

57. The method of any one of claims 51 to 56, wherein the patient is treated with T-DM1 within 12 weeks after radical surgery.

58. The medicament of any one of claims 51-57, wherein the patient is treated with T-DM1 infusions at a dose of 3.6 mg / kg every 3 weeks.

59. The medicament of any one of claims 51-58, wherein the patient is treated with T-DM1 infusions at a dose of 3.6 mg / kg every 3 weeks for 14 cycles.

60. The medicament of any one of claims 51 to 59, wherein the treatment substantially increases invasive disease free survival (IDFS) compared to adjuvant treatment with trastuzumab.

61. The pharmaceutical of any one of claims 51 to 60, wherein the treatment results in a reduction in distant recurrence compared to adjuvant treatment with trastuzumab.

62. The method of any one of claims 28 to 61, wherein the adjuvant therapy results in a 50% reduction in the risk of invasive disease recurrence compared to adjuvant therapy with trastuzumab.

63. 63. The medicament of any one of claims 28 to 62, wherein the adjuvant therapy results in a 40% reduction in the risk of distant recurrence compared to adjuvant trastuzumab.

Images