Methods of treating her2-positive metastatic breast cancer

Abstract

To provide a method for treating patients having HER2-positive metastatic or locally advanced breast cancer in first-line therapy.SOLUTION: A method comprising administering a therapeutically effective amount of an anti-HER2 maytansinoid conjugate to a patient having breast cancer who has received prior treatment with a taxane.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application claims the benefit under 35 U.S.C. § 119 of U.S. Provisional Application No. 62 / 168,809, filed May 30, 2015, the disclosure of which is incorporated herein by reference in its entirety.

[0002] Sequence Listing

[0001] This application contains a Sequence Listing in ASCII format, which is incorporated herein by reference in its entirety. The ASCII text file was created on May 20, 2016, is named GNE-0423R1-WO Sequence_Listing.txt, and is 30,476 bytes in size.

[0003] The present invention relates to methods of using anti-HER2-maytansinoid conjugates, such as trastuzumab-MCC-DM1, for the treatment of HER2-positive advanced or recurrent locally advanced or previously untreated metastatic breast cancer, in patients who have received prior treatment with a taxane. [Background technology]

[0004] Breast cancer and HER2 targeted therapy Breast cancer is a significant cause of morbidity and mortality worldwide. Each year, more than 1.3 million cases of breast cancer are diagnosed worldwide, with more than 450,000 disease-related deaths (Jemal A, Bray F, Center M, et al. Global cancer statistics. CA Cancer J Clin, 2011;61(2):69-90).

[0005] HER2 (ErbB2) receptor tyrosine kinase is a member of the epidermal growth factor receptor (EGFR) family of transmembrane receptors. HER2 overexpression is observed in approximately 20% of human breast cancers (hereinafter referred to as HER2-positive breast cancer), and is associated with the aggressive growth and poor clinical outcome 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).

[0006] Trastuzumab (CAS 180288-69-1, HERCEPTIN®, huMAb4D5-8, rhuMAb HER2, Genentech) is a recombinant DNA-derived IgG1κ monoclonal antibody that is a humanized version of the murine anti-HER2 antibody (4D5) that selectively binds with high affinity (Kd=5 nM) to the extracellular domain of HER2 in cell-based assays (see 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 (Hudziak et al (1989) Science 244:707-12; Slamon et al (2001) New Engl. J. Med. 344:783-792). Trastuzumab has been shown to inhibit the growth of HER2-overexpressing human tumor cells in both in vitro assays and in animals (Hudziak et al (1989) Mol Cell Biol 9:1165-72; Lewis et al (1993) Cancer Immunol Immunother;37:255-63; Baselga et al (1998) Cancer Res. 58:2825-2831).Trastuzumab is a mediator of antibody-dependent cellular cytotoxicity, ADCC (Lewis et al (1993) Cancer Immunol Immunother 37(4):255-263; Hotaling et al (1996) [abstract]. Proc. Annual Meeting Am Assoc Cancer Res; 37:471; Pegram MD, et al (1997) [abstract]. 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).

[0007] 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. [abstract]. Breast Cancer Res Treat 2006,100(Suppl 1):52). In 2006, the FDA approved HERCEPTIN® (trastuzumab, Genentech Inc.) as part of a treatment regimen including doxorubicin, cyclophosphamide, and paclitaxel for the adjuvant treatment of patients with HER2-positive, node-positive breast cancer.

[0008] An alternative approach to antibody-targeted therapy is to use antibodies to specifically deliver cytotoxic drugs to antigen-expressing cancer cells. Antibody-drug conjugates, or ADCs, are monoclonal antibodies to which highly potent cytotoxic agents are attached. ADCs represent a novel approach to confer tumor selectivity to systemically administered anti-tumor therapeutics. By utilizing tumor-specific and / or overexpressed surface antigens, ADCs are designed to focus the delivery of highly potent cytotoxic agents to tumor cells. This approach may create a more favorable therapeutic window for such agents than can be achieved by their administration as free drugs.

[0009] Maytansinoids, derivatives of the antimitotic drug maytansine, bind to microtubules in a manner similar to that of 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 naturally occurring 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 tested as a chemotherapy agent in approximately 800 patients at a dose of 2.0 mg / m2 given as a single dose every 3 weeks or on 3 consecutive days (Issell BF, Crooke ST. (1978) Maytansine. Cancer Treat Rev. 5:199-207). Despite preclinical activity, maytansine's activity in clinical settings was modest at doses that could be safely delivered. Dose-limiting toxicities (DLTs) were gastrointestinal, consisting of nausea, vomiting, and diarrhea (often followed by constipation). These toxicities were dose-dependent, not schedule-dependent. Peripheral neuropathy (primarily sensory) was reported and was most evident in patients with preexisting neuropathy. Subclinical transient evaluation of hepatic transaminases, alkaline phosphatase, and total bilirubin has been reported. Systemic toxicities, including weakness, lethargy, dysphoria, and insomnia, were common. Less common toxicities included infusion-site phlebitis and mild myelosuppression. A narrow therapeutic window led to the abandonment of further drug development in the 1980s.

[0010] Trastuzumab-MCC-DM1 (T-DM1, trastuzumab emtansine, ado-trastuzumab emtansine, KADCYLA®), a novel antibody-drug conjugate (ADC) for the treatment of HER2-positive breast cancer, is composed of the cytotoxic agent DM1 (a thiol-containing maytansinoid anti-microtubule agent) linked to trastuzumab at a lysine side chain via an MCC linker, and has 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.

[0011] In a phase I study of T-DM1 (TDM3569g), the maximum tolerated dose (MTD) of T-DM1 administered by IV infusion every 3 weeks (q3w) was 3.6 mg / kg. The dose-limiting toxicity consisted of transient thrombocytopenia in a patient treated with 4.8 mg / kg. Treatment with 3.6 mg / kg q3w was well tolerated and associated with significant clinical activity (Krop (2010) J. Clin. Oncol. 28(16):2698-2704). This same study also showed that weekly administration of 2.4 mg / kg was well tolerated and had antitumor activity (Beeram (2012) Cancer 118(23):5733-5740).

[0012] A phase II study (TDM4374g) demonstrated single-agent antitumor activity of T-DM1 administered at 3.6 mg / kg q3w in a heavily pretreated patient population with HER2-positive metastatic breast cancer (Krop (2012) 30(26):3234-3241). A phase III study (TDM4370g, "EMILIA") demonstrated that T-DM1 administered at 3.6 mg / kg q3w significantly extended progression-free survival and overall survival, with less toxicity, compared with lapatinib and capecitabine in patients with HER2-positive advanced breast cancer (second- and third-line metastatic breast cancer) previously treated with trastuzumab and a taxane (Verma (2012) New England Journal of Medicine 367:1783-1791).

[0013] On February 22, 2013, the U.S. Food and Drug Administration approved ado-trastuzumab emtansine, marketed under the trade name KADCYLA®, for the treatment of patients with HER2-positive metastatic breast cancer who have previously been treated with trastuzumab and a taxane.

[0014] Pertuzumab (recombinant humanized monoclonal antibody 2C4, rhuMAb 2C4, also known as PERJETA® (Genentech, Inc., South San Francisco)) is the first of a new class of drugs known as HER dimerization inhibitors (HDIs), which function by inhibiting the ability of HER2 to form active heterodimers or homodimers with other HER receptors (e.g., EGFR / HER1, HER2, HER3, and HER4). See, e.g., Harari and Yarden Oncogene 19:6102-14 (2000), Yarden and Sliwkowski. Nat Rev Mol Cell Biol 2:127-37 (2001), Sliwkowski Nat Struct Biol 10:158-9 (2003), Cho et al. Nature 421:756-60 (2003), and Malik et al. Pro Am Soc Cancer Res 44:176-7 (2003).

[0015] It has been demonstrated that blocking the formation of HER2-HER3 heterodimers in tumor cells by pertuzumab inhibits critical cell signaling, resulting in reduced tumor growth and survival (Agus et al. Cancer Cell 2:127-37 (2002)).

[0016] Pertuzumab has been tested as a single agent in clinical settings, with a Phase Ia clinical trial in patients with advanced cancer and a Phase II clinical trial in patients with ovarian and breast cancer, as well as lung and prostate cancer. In the Phase I trial, patients with untreatable locally advanced, recurrent, or metastatic solid tumors that had progressed on or after standard therapy were treated with pertuzumab administered intravenously every 3 weeks. Pertuzumab was generally well tolerated. Tumor regression was achieved in 3 of 20 patients evaluable for response. Two patients had confirmed partial responses. Stable disease lasting more than 2.5 months was observed in 6 of 21 patients (Agus et al. Pro Am Soc Clin Oncol 22:192 (2003)). At doses of 2.0 to 15 mg / kg, the pharmacokinetics of pertuzumab was linear, with mean clearance ranging from 2.69 to 3.74 mL / day / kg and a mean terminal elimination half-life of 15.3 to 27.6 days. No antibodies to pertuzumab were detected (Allison et al. Pro Am Soc Clin Oncol 22:197 (2003)).

[0017] US2006 / 0034842 describes a method for treating ErbB-expressing cancers in combination with an anti-ErbB2 antibody. US2008 / 0102069 describes the use of trastuzumab and pertuzumab in the treatment of HER2-positive metastatic cancers, such as breast cancer. Baselga et al., J Clin Oncol, 2007 ASCO Annual Meeting Proceedings Part I, Col. 25, No. 18S (June 20 Supplement), 2007:1004, reports the treatment of patients with pretreated HER2-positive breast cancer that progressed during treatment with trastuzumab and a combination of trastuzumab and pertuzumab. Portera et al., J Clin Oncol, 2007 ASCO Annual Meeting Proceedings Part I, Vol. 25, No. 18S (June 20 Supplement), 2007:1028, evaluated the efficacy and safety of trastuzumab plus pertuzumab combination therapy in patients with HER2-positive breast cancer who had progressed on trastuzumab-based therapy. The authors concluded that further evaluation of the efficacy of the combination therapy is needed to define the overall risks and benefits of this treatment regimen.

[0018] Pertuzumab has been evaluated in phase II trials in conjunction with trastuzumab in patients with HER2-positive metastatic breast cancer who had previously received trastuzumab for metastatic disease. One trial, conducted by the National Cancer Institute (NCI), enrolled 11 patients with previously treated, HER2-positive metastatic breast cancer. Two of the 11 patients had a partial response (PR) (Baselga et al., J Clin Oncol 2007 ASCO Annual Meeting Proceedings;25:18 S(June 20 Supplement):1004). Results of a phase II neoadjuvant trial evaluating the effect of a novel combination regimen of pertuzumab and trastuzumab plus chemotherapy (docetaxel) in women with early-stage HER2-positive breast cancer, presented at the CTRC-AACR San Antonio Breast Cancer Symposium (SABCS), December 8-12, 2010, showed that the two HER2 antibodies plus docetaxel administered in neoadjuvant therapy prior to surgery significantly improved the rate of complete tumor disappearance in the breast by more than half (45.8 percent pathological complete response, pCR), compared with trastuzumab plus docetaxel (29.0 percent pCR), p=0.014).

[0019] Pertuzumab, marketed under the trade name PERJETA®, was approved in 2012 for the treatment of patients with advanced or late-stage (metastatic) HER2-positive breast cancer, which has increased amounts of the HER2 protein, which contributes to cancer cell growth and survival.

[0020] On September 30, 2013, the U.S. Food and Drug Administration granted accelerated approval to PERJETA® (pertuzumab) as part of a complete treatment regimen before surgery (neoadjuvant therapy) for patients with early-stage breast cancer (EBC). PERJETA® is the first FDA-approved drug for the neoadjuvant treatment of breast cancer.

[0021] Patent publications relating to HER2 antibodies include U.S. Patent Nos. 5,677,171; 5,720,937; 5,720,954; 5,725,856; 5,770,195; 5,772,997; 6,165,464; 6,387,371; 6,399,063; 6,015,567; 6,333,169; 4,968,603; 5,821,337; 6,054,297; 6,407,213; 6,639,055; 6,719,971; 6,800, No. 738; No. 8,075,890; No. 5,648,237; No. 7,018,809; No. 6,267,958; No. 6,6 85,940; 6,821,515; 7,060,268; 7,682,609; 7,371,376; No. 6,127,526; No. 6,333,398; No. 6,797,814; No. 6,339,142; No. 6,417,335 ; Same No. 6,489,447; Same No. 7,074,404; Same No. 7,531,645; Same No. 7,846,441; Same No. 7,892,5 No. 49; No. 8,075,892; No. 6,573,043; No. 6,905,830; No. 7,129,051; No. 7,3 44,840; 7,468,252; 7,674,589; 7,919,254; 6,949,245; No. 7,485,302; No. 7,498,030; No. 7,501,122; No. 7,537,931; No. 7,618,631 ; Same No. 7,862,817; Same No. 7,041,292; Same No. 6,627,196; Same No. 7,371,379; Same No. 6,632,9 No. 79; No. 7,097,840; No. 7,575,748; No. 6,984,494; No. 7,279,287; No. 7,81 No. 1,773; No. 7,993,834; No. 8,076,066; No. 8,044,017; No. 7,435,797; No. 7 , 850,966; 7,485,704; 7,807,799; 8,142,784; 7,560,111; 7 , No. 879,325; No. 8,241,630; No. 7,449,184; No. 8,163,287; No. 7,700,299;Nos. 7,981,418; 8,247,397; and US2010 / 0016556; US2005 / 0244929; US2001 / 0014326; US2003 / 0202972; US2006 / 0099201; US2010 / 0158899; US2011 / 0236383; US2011 / 0033460; US2008 / 0286280; US2005 / 0063972; US2006 / 0182739; US2009 / 0220492; US2003 / 0147884; US2004 / 0037823; US2005 / 00 02928;US2007 / 0292419;US2008 / 0187533;US2011 / 0250194;US2012 / 0034213;US2003 / 0152987;US2005 / 0100944;US2006 / 0183150;US2008 / 00507 48;US2009 / 0155803;US2010 / 0120053;US2005 / 0244417;US2007 / 0026001 ;US2008 / 0160026;US2008 / 0241146;US2005 / 0208043;US2005 / 0238640;U S2006 / 0034842;US2006 / 0073143;US2006 / 0193854;US2006 / 0198843;US2011 / 0129464;US2007 / 0184055;US2007 / 0269429;US2008 / 0050373;US20 06 / 0083739;US2009 / 0087432;US2006 / 0210561;US2002 / 0035736;US2002 / 0001587;US2008 / 0226659;US2002 / 0090662;US2006 / 0046270;US2008 / 0 108096;US2007 / 0166753;US2008 / 0112958;US2009 / 0239236;US2012 / 0034609;US2012 / 0093838;US2004 / 0082047;US2012 / 0065381;US2009 / 0187 007;US2011 / 0159014;US2004 / 0106161;US2011 / 0117096;US2004 / 025868 5;US2009 / 0148402;US2009 / 0099344;US2006 / 0034840;US2011 / 0064737;US2005 / 0276812;US2008 / 0171040;US2009 / 0202536;US2006 / 0013819;US2012 / 0107391;US2006 / 0018899; US2009 / 0285837;US2011 / 0117097;US2006 / 0088523;US2010 / 0015157;US2006 / 0121044;US2008 / 0317753;U S2006 / 0165702;US2009 / 0081223;US2006 / 0188509;US2009 / 0155259;US2011 / 0165157;US2006 / 0204505;US 2006 / 0212956;US2006 / 0275305;US2012 / 0003217;US2007 / 0009976;US2007 / 0020261;US2007 / 0037228;US2 010 / 0112603;US2006 / 0067930;US2007 / 0224203;US2011 / 0064736;US2008 / 0038271;US2008 / 0050385;US2 010 / 0285010;US2011 / 0223159;US2008 / 0102069;US2010 / 0008975;US2011 / 0245103;US2011 / 0246399;US20 11 / 0027190;US2010 / 0298156;US2011 / 0151454;US2011 / 0223619;US2012 / 0107302;US2009 / 0098135;US2009 / 0148435;US2009 / 0202546;US2009 / 0226455;US2009 / 0317387;US2011 / 0044977;US2012 / 0121586. Summary of the Invention

[0022] The present invention relates to methods of using an anti-HER2-maytansinoid conjugate, such as trastuzumab-MCC-DM1, for the treatment of HER2-positive advanced or recurrent locally advanced or untreated metastatic breast cancer (first-line metastatic breast cancer), where the patient has been pre-treated with a taxane. Although treatment options exist for patients with HER2-positive cancer in the adjuvant, neoadjuvant, and metastatic breast cancer settings, there is a need for further options, including metastatic breast cancer in the "first-line" setting, i.e., for patients with untreated metastatic breast cancer or locally advanced breast cancer.

[0023] The present invention is based, in part, on the observation that trastuzumab-MCC-DM1 was unexpectedly effective in treating patients with metastatic HER2-positive breast cancer in the first-line setting who had received prior taxane therapy compared with patients who had not previously received a taxane.

[0024] In one aspect, the invention provides a method for treating HER2-positive locally advanced or untreated metastatic breast cancer, comprising administering a therapeutically effective amount of an anti-HER2-maytansinoid conjugate to a patient having said breast cancer, wherein the patient has received prior treatment with a taxane.

[0025] In another aspect, the present invention provides the use of a therapeutically effective amount of an anti-HER2-maytansinoid conjugate in the manufacture of a medicament for the treatment of HER2-positive locally advanced or untreated metastatic breast cancer in a subject, wherein the subject has received prior treatment with a taxane.

[0026] In certain embodiments, the administration occurs six months or more after prior treatment with a taxane. In some embodiments, the patient has received prior treatment with a taxane and at least one HER2-targeted therapy. In one embodiment, the patient has received prior treatment with a taxane and trastuzumab. In another embodiment, the patient has received prior treatment with a taxane, trastuzumab, and pertuzumab. In some embodiments, the prior treatment is administered in the adjuvant setting. In yet other embodiments, the prior treatment is administered in the neoadjuvant setting.

[0027] In certain other aspects, the present invention provides methods for treating HER2-positive locally advanced or previously untreated metastatic breast cancer, comprising: (1) determining whether the patient has received prior taxane treatment; and (2) if the patient has received prior taxane treatment, administering a therapeutically effective amount of an anti-HER2-maytansinoid conjugate to the patient. In certain embodiments, the administration occurs six months or more after the prior taxane treatment. In some embodiments, the patient has received prior taxane treatment and at least one HER2-targeted therapy. In one embodiment, the patient has received prior treatment with a taxane and trastuzumab. In another embodiment, the patient has received prior treatment with a taxane, trastuzumab, and pertuzumab. In one embodiment, the prior treatment is administered in the adjuvant setting. In another embodiment, the prior treatment is administered in the neoadjuvant setting.

[0028] In certain embodiments of the above aspects, the taxane is paclitaxel. In some embodiments, paclitaxel is administered intravenously weekly at 80 mg / m. In certain embodiments, paclitaxel is administered for a minimum of 18 weeks.

[0029] In other embodiments, the taxane is docetaxel. In some embodiments, docetaxel is administered intravenously at 75 mg / m² or 100 mg / m² every 3 weeks. In certain embodiments, docetaxel is administered for a minimum of 6 cycles.

[0030] In embodiments where the patient has been pretreated with a taxane and trastuzumab, and in one embodiment, trastuzumab may be or was administered intravenously at 8 mg / kg in cycle 1 followed by 6 mg / kg in subsequent cycles every three weeks. In another embodiment, trastuzumab was administered intravenously at 4 mg / kg on day 1 of cycle 1 followed by 2 mg / kg weekly starting on day 8 of cycle 1.

[0031] In embodiments where the patient has been pretreated with a taxane, trastuzumab, and pertuzumab, and in one embodiment, pertuzumab may be or was administered intravenously at 840 mg / kg on day 1 of cycle 1, followed by 420 mg every 3 weeks in subsequent cycles.

[0032] In all embodiments, the anti-HER2 maytansinoid conjugate may be a trastuzumab-maytansinoid conjugate. In certain embodiments, the trastuzumab-maytansinoid conjugate is a trastuzumab-DM1 conjugate. In certain embodiments, the trastuzumab-DM1 conjugate is a trastuzumab-MCC-DM1 conjugate. In some embodiments, the trastuzumab-MCC-DM1 is administered at 3.6 mg / kg every three weeks. In other embodiments, the trastuzumab-MCC-DM1 is administered at 2.4 mg / kg weekly.

[0033] In certain embodiments of the invention, the breast cancer is untreated metastatic breast cancer. [Brief explanation of the drawings]

[0034] [Figure 1] A schematic diagram of the HER2 protein structure and the amino acid sequences for domains I to IV of its extracellular domain (SEQ ID NOs: 1 to 4, respectively) are provided. [Figure 2A]Figures 2A and 2B depict alignments of the amino acid sequences of the variable light (VL) (Figure 2A) and variable heavy (VH) (Figure 2B) domains of murine monoclonal antibody 2C4 (SEQ ID NOs: 5 and 6, respectively); the VL and VH domains of variant 574 / Pertuzumab (SEQ ID NOs: 7 and 8, respectively), and the human VL and VH consensus frameworks (hum id, light chain kappa subgroup I; hum III, heavy chain subgroup III) (SEQ ID NOs: 9 and 10, respectively). Asterisks identify differences between the variable domains of Pertuzumab and monoclonal antibody 2C4, and between the variable domains of Pertuzumab and the human frameworks. Complementarity-determining regions (CDRs) are indicated in brackets. [Figure 2B] Figures 2A and 2B depict alignments of the amino acid sequences of the variable light (VL) (Figure 2A) and variable heavy (VH) (Figure 2B) domains of murine monoclonal antibody 2C4 (SEQ ID NOs: 5 and 6, respectively); the VL and VH domains of variant 574 / Pertuzumab (SEQ ID NOs: 7 and 8, respectively), and the human VL and VH consensus frameworks (hum id, light chain kappa subgroup I; hum III, heavy chain subgroup III) (SEQ ID NOs: 9 and 10, respectively). Asterisks identify differences between the variable domains of Pertuzumab and monoclonal antibody 2C4, and between the variable domains of Pertuzumab and the human frameworks. Complementarity-determining regions (CDRs) are indicated in brackets. [Figure 3A] Figures 3A and 3B show the amino acid sequences of the pertuzumab light chain (Figure 3A; SEQ ID NO: 11) and heavy chain (Figure 3B; SEQ ID NO: 12). The CDRs are shown in bold. The calculated molecular masses of the light and heavy chains are 23,526.22 Da and 49,216.56 Da (reduced cysteines). A carbohydrate moiety is attached to Asn299 of the heavy chain. [Figure 3B]Figures 3A and 3B show the amino acid sequences of the pertuzumab light chain (Figure 3A; SEQ ID NO: 11) and heavy chain (Figure 3B; SEQ ID NO: 12). The CDRs are shown in bold. The calculated molecular masses of the light and heavy chains are 23,526.22 Da and 49,216.56 Da (reduced cysteines). A carbohydrate moiety is attached to Asn299 of the heavy chain. [Figure 4A] Figures 4A and 4B show the amino acid sequences of the trastuzumab light chain (Figure 4A; SEQ ID NO: 13) and heavy chain (Figure 4B; SEQ ID NO: 14), respectively. The boundaries of the variable light and variable heavy chain domains are indicated by arrows. [Figure 4B] Figures 4A and 4B show the amino acid sequences of the trastuzumab light chain (Figure 4A; SEQ ID NO: 13) and heavy chain (Figure 4B; SEQ ID NO: 14), respectively. The boundaries of the variable light and variable heavy chain domains are indicated by arrows. [Figure 5A] Figures 5A and 5B depict the variant pertuzumab light chain sequence (Figure 5A; SEQ ID NO: 15) and variant pertuzumab heavy chain sequence (Figure 5B; SEQ ID NO: 16), respectively. [Figure 5B] Figures 5A and 5B depict the variant pertuzumab light chain sequence (Figure 5A; SEQ ID NO: 15) and variant pertuzumab heavy chain sequence (Figure 5B; SEQ ID NO: 16), respectively. [Figure 6] 1 depicts a schema of the MARIANNE clinical trial design described in Example 1. a Locally advanced or recurrent disease and not undergoing resection with curative intent; b Pertuzumab placebo. LD, loading dose. [Figure 7]1 shows results from the MARIANNE clinical trial described in Example 1. Overall, T-DM1 (KADCYLA®) demonstrated non-inferior progression-free survival (PFS) compared with standard-of-care trastuzumab (HERCEPTIN®) plus taxane (HT), but it was not superior to HT. However, the data (shaded box) suggest a superior effect of KADCYLA® over HT for patients who have previously received taxane therapy, indicating that KADCYLA® should be the treatment of choice for these patients with locally advanced and metastatic Her2-positive breast cancer in the first-line setting. DETAILED DESCRIPTION OF THE INVENTION

[0035] Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents which may be included within the scope of the present invention as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described.

[0036] 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.

[0037] definition The terms "comprise," "comprising," "include," "including," and "includes," when used in the present specification and claims, are intended to specify the presence of stated features, integers, components, or steps, but do not exclude the presence or addition of one or more other features, integers, components, steps, or groups thereof.

[0038] The terms "treat" and "treatment" refer to both therapeutic treatment and / or prophylactic or preventative measures, the purpose of which is to prevent or slow down (alleviate) an undesirable physiological change or disorder, such as, for example, the growth, progression, or spread of a hyperproliferative condition such as cancer. In the present invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, attenuation of the extent of the disease, stabilization of the disease state (i.e., not worsening), delay or slowing of disease progression, palliation or palliative treatment of the disease state, and remission (either partial or complete), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder, as well as those prone to have the condition or disorder, or those in whom the condition or disorder is to be prevented.

[0039] The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. A "tumor" comprises one or more cancerous cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphatic malignancies. More specific examples of such cancers include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), small cell lung cancer, non-small cell lung cancer (NSCLC), lung cancer, including 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, hepatic cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, and head and neck cancer.

[0040] References to "Stage 0," "Stage I," "Stage II," "Stage III," or "Stage IV," and various substages of a tumor or cancer within this classification, refer to the classification of the tumor or cancer using either the overall stage grouping or Roman numeral staging methods known in the art. Generally, the actual stage of a cancer is determined by the type of cancer, with Stage 0 cancers being epithelial lesions, Stage I cancers being small, localized tumors, Stage II and III cancers being locally advanced tumors showing regional lymph node involvement, and Stage IV cancers representing metastatic cancer. The specific stages for each type of tumor are known to skilled clinicians.

[0041] The term "metastatic breast cancer" refers to a condition of breast cancer in which cancer cells spread from the original site by blood vessels or lymph nodes to one or more other sites in the body and form one or more secondary tumors in one or more organs other than the breast.

[0042] The terms "first line" metastatic breast cancer or "untreated" metastatic breast cancer refer to metastatic breast cancer that has not been treated in the metastatic setting.

[0043] As used herein, the term "locally advanced" breast cancer refers to locally advanced breast cancer that is progressive or recurrent.

[0044] The term "prior treatment" in reference to taxanes refers to treatment that occurs prior to first-line metastatic or locally advanced breast cancer treatment. For example, "prior treatment" may refer to neoadjuvant, adjuvant, or other treatment prior to first-line metastatic or locally advanced breast cancer treatment.

[0045] 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.

[0046] A "refractory" cancer is one that progresses even when anti-tumor agents such as chemotherapy are administered to the cancer patient. An example of a refractory cancer is one that is platinum-refractory.

[0047] A "recurrent" cancer is one that has regrown, either at the original site or at a distant site, after responding to initial therapy such as surgery.

[0048] A "locally recurrent" cancer is one that returns after treatment in the same place as the previously treated cancer.

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

[0050] "Non-resectable" or "unresectable" cancer cannot be removed (resected) by surgery.

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

[0052] As used herein, a "patient" or "subject" is a human patient. The patient may be a "cancer patient," i.e., one who is suffering from or at risk of suffering from one or more symptoms of cancer, particularly gastric cancer or breast cancer.

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

[0054] A "relapsed" patient is one who has signs or symptoms of cancer after remission. Optionally, the patient has relapsed after adjuvant or neoadjuvant therapy.

[0055] A cancer or biological sample that "exhibits HER expression, amplification, or activation" is one that, in a diagnostic test, expresses (including overexpression) a HER receptor, the HER gene is amplified, and / or otherwise demonstrates activation or phosphorylation of a HER receptor.

[0056] "Neoadjuvant therapy" or "preoperative therapy," as used herein, refers to therapy administered before surgery. The goal of neoadjuvant therapy is to provide immediate systemic treatment, potentially eradicating micrometastases that would otherwise grow if the standard sequence of surgery followed by systemic therapy were followed. Neoadjuvant therapy may also reduce tumor size, thereby helping to completely remove initially unresectable tumors or preserve some of the organs and their functions. Furthermore, neoadjuvant therapy allows for in vivo evaluation of drug efficacy, which can guide subsequent treatment selection.

[0057] "Adjuvant therapy" as used herein refers to therapy administered after definitive surgery in which no evidence of residual disease can be detected, in order to reduce the risk of disease recurrence. The goal of adjuvant therapy is to prevent cancer recurrence, thus reducing the likelihood of cancer-related death. As used herein, adjuvant therapy specifically excludes neoadjuvant therapy.

[0058] "Survival" refers to whether a patient is still 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.

[0059] "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.

[0060] "Disease-free survival (DFS)" refers to a patient remaining alive for a defined period of time, for example, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, or about 10 years, from the start of treatment or from the initial diagnosis without cancer recurrence. In one embodiment of the present invention, DFS is analyzed according to the intent-to-treat principle. That is, patients are evaluated based on the assigned therapy. Events used in analyzing DFS can include local, regional, and distant recurrence of cancer, the occurrence of a second cancer, and death from any cause in patients without a preceding event (e.g., breast cancer recurrence or second primary cancer).

[0061] "Overall survival" refers to a patient still being alive for a defined 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 the present invention, the event used for survival analysis was death from any cause.

[0062] "Prolonging survival" means increasing 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.

[0063] " Hazard ratio " in survival analysis is the summary of the difference between two survival curves, and represents the reduction in the risk of death during follow-up period when treatment is compared with control.Hazard ratio is the statistical definition of event rate.In the present invention, hazard ratio is defined as the probability of event in experimental group divided by the probability of event in control group at any specific time point.

[0064] "Monotherapy" means a treatment regimen that includes only a single therapeutic agent for the treatment of a cancer or tumor during a course of treatment.

[0065] "Maintenance therapy" refers to a treatment regimen that is administered to reduce the likelihood of disease recurrence or progression.Maintenance therapy can be administered for any period of time, including for the lifespan of the patient.Maintenance therapy can be administered after initial therapy, or in conjunction with initial therapy or additional therapy.The dosage used in maintenance therapy can vary and can include reduced dosages compared to the dosages used in other types of therapy.

[0066] "Definitive surgery" is used as the term is used within the medical community. Definitive surgery includes, for example, procedures, surgeries, or otherwise that result in the removal or resection of a tumor, e.g., that result in the removal or resection of all macroscopically visible tumor. Definitive surgery includes, for example, complete or curative resection of a tumor, or macroscopically total resection. Definitive surgery includes procedures that occur in one or more stages, e.g., multi-stage surgical procedures in which one or more surgeries or other procedures are performed before the tumor is removed. Definitive surgery includes procedures that remove or resect a tumor, including involved organs, parts of organs and tissues, and surrounding organs, e.g., lymph nodes, parts of organs, or tissues.

[0067] As defined herein, the terms "trastuzumab," "HERCEPTIN®," and "huMAb4D5-8" are used interchangeably. Such antibodies preferably comprise the light and heavy chain amino acid sequences shown in Figure 4A (SEQ ID NO: 13) and Figure 4B (SEQ ID NO: 14), respectively.

[0068] "Epitope 4D5" or "4D5 epitope" or "4D5" refers to the region within the extracellular domain of HER2 to which antibody 4D5 (ATCC CRL 10463) and trastuzumab bind. This epitope is located near the transmembrane domain of HER2, 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 from about residue 529 to about residue 625, including HER2).

[0069] "Epitope 2C4" or "2C4 epitope" is the region in the extracellular domain of HER2 to which antibody 2C4 binds. To screen for antibodies that bind to the 2C4 epitope, a routine cross-blocking assay such as that 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 2C4 epitope of HER2. Epitope 2C4 includes residues from domain II in the extracellular domain of HER2. The 2C4 antibody and pertuzumab bind to the extracellular domain of HER2 at the junction of domains I, II, and III (Franklin et al. Cancer Cell 5:317-328 (2004)).

[0070] As used herein, "pertuzumab," "PERJETA®," and "rhuMAb 2C4" are used interchangeably. Such antibodies preferably comprise the light chain and heavy chain amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 8, respectively. When pertuzumab is a whole antibody, it preferably comprises an IgG1 antibody, which in one embodiment comprises the light chain amino acid sequence of SEQ ID NO: 11 or 15 and the heavy chain amino acid sequence of SEQ ID NO: 12 or 16. The antibody is optionally produced by recombinant Chinese hamster ovary (CHO) cells.

[0071] As defined herein, the terms "T-DM1," "trastuzumab-MCC-DM1," "ado-trastuzumab emtansine," "trastuzumab emtansine," and "KADCYLA®" are used interchangeably and refer to trastuzumab conjugated to the maytansinoid drug moiety DM1 by the linker moiety MCC, and include all mixtures of variously loaded and conjugated antibody-drug conjugates in which 1, 2, 3, 4, 5, 6, 7, and 8 drug moieties are covalently attached to the antibody trastuzumab (US 7097840, US 2005 / 0276812, US 2005 / 0166993).

[0072] As used herein, "anti-tumor agents" refer to drugs used to treat cancer. Non-limiting examples of anti-tumor agents include chemotherapeutic agents, HER dimerization inhibitors, HER antibodies, antibodies directed against tumor-associated antigens, anti-hormonal compounds, cytokines, EGFR-targeting drugs, anti-angiogenic agents, tyrosine kinase inhibitors, growth inhibitors and antibodies, cytotoxic agents, apoptosis-inducing antibodies, COX inhibitors, farnesyltransferase inhibitors, antibodies binding to the oncofetal protein CA 125, HER2 vaccines, Raf or ras inhibitors, liposomal doxorubicin, topotecan, taxanes, dual tyrosine kinase inhibitors, TLK286, EMD-7200, pertuzumab, trastuzumab, erlotinib, and bevacizumab.

[0073] "Chemotherapy" is the use of chemotherapeutic agents useful in the treatment of cancer.

[0074] A "chemotherapeutic agent" is a chemical compound useful in the treatment of cancer, regardless of mechanism of action. Classes of chemotherapeutic agents include, but are not limited to, alkylating agents, antimetabolites, spindle poison plant alkaloids, cytotoxic / antitumor antibiotics, topoisomerase inhibitors, antibodies, photosensitizers, and kinase inhibitors. Examples of chemotherapeutic agents include erlotinib (TARCEVA®, Genentech / OSI Pharm.), docetaxel (TAXOTERE®, Sanofi-Aventis), 5-FU (fluorouracil, 5-fluorouracil, CAS number 51-21-8), gemcitabine (GEMZAR®, Lilly), PD-0325901 (CAS number 391210-10-9, Pfizer), cisplatin (cis-diammine, dichloroplatinum(II), CAS number 15663-27-1), carboplatin (CAS number 41575-94-4), paclitaxel (TAXOL®, Bristol-Myers Squibb), and others. Oncology, Princeton, NJ), temozolomide (4-methyl-5-oxo-2,3,4,6,8-pentazabicyclo[4.3.0]nona-2,7,9-triene-9-carboxamide, CAS number 85622-93-1, TEMODAR®, TEMODAL®, Schering Plough), tamoxifen ((Z)-2-[4-(1,2-diphenylbut-1-enyl)phenoxy]-N,N-dimethyl-ethanamine, NOLVADEX®, ISTUBAL®, VALODEX®), and doxorubicin (ADRIAMYCIN®), Akti-1 / 2, HPPD, and rapamycin.

[0075] Further examples of chemotherapeutic agents include oxaliplatin (ELOXATIN®, Sanofi), bortezomib (VELCADE®, Millennium Pharm.), sutent (SUNITINIB®, SU11248, Pfizer), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), XL-518 (MEK inhibitor, Exelixis, WO2007 / 044515), ARRY-886 (MEK inhibitor, AZD6244, Array BioPharma, Astra Zeneca), SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235 (PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis), PTK787 / ZK 222584 (Novartis), fulvestrant (FASLODEX®, AstraZeneca), leucovorin (folinic acid), rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, GSK572016, GlaxoSmithKline), lonafarnib (SARASAR™, SCH 66336, Schering Plough), sorafenib (NEXAVAR®, BAY43-9006, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), irinotecan (CAMPTOSAR®, CPT-11, Pfizer), tipifarnib (ZARNESTRA™, Johnson & Johnson), ABRAXANE™ (without Cremophor),Albumin-photoengineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), vandetanib (rINN, ZD6474, ZACTIMA®, AstraZeneca), chlorambucil, AG1478, AG1571 (SU 5271; Sugen), temsirolimus (TORISEL®, Wyeth), pazopanib (GlaxoSmithKline), canfosfamide (TELCYTA®, Telik), thiotepa, and cyclosphosphamide (CYTOXAN®, NEOSAR®); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines, including and the methylamelamines: altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; the acetogenins (especially bullatacin and bullatacinone); camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its synthetic analogues adozelesin, carzelesin and bizelesin); the cryptophycins (especiallyincluding cryptophycin 1 and cryptophycin 8; dolastatin; duocarmycin (including synthetic analogs KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyins; spongistatin; nitrogen mustards, e.g., chlorambucil, chlornaphazine phazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard mustard; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics, such as enediyne antibiotics (e.g., calicheamicin, calicheamicin gamma 1I, calicheamicin omega 1I (Angew Chem. Intl. Ed. Engl. (1994) 33:183-186); dynemicin, dynemicin A; bisphosphonates such as clodronate; esperamicins; and neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores, aclacinomycins, actinomycin, autramycin, azaserine, bleomycins,Cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin, epirubicin, esorubicin, idarubicin, nemorubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites, e.g., metronidazole, methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine,Dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; antiadrenergics such as aminoglutethimide, mitotane, trilostane; folate replenishers such as folic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid acid); eniluracil; amsacrine; bestrabucil; bisantrene; edatrexate; defofamine; democolcine; diaziquone; elfornithine; elliptinium acetate; epothilones; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids,For example, maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, Roridin A and anguidine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs, such as cisplatin and carboplatin ; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine (NAVELBINE®); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®, Roche); ibandronate; CPT-11; the topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; and pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0076] The term "therapeutically effective amount" refers to an amount of a drug effective to treat cancer in a patient. An effective amount of a drug can reduce the number of cancer cells; reduce tumor size; inhibit (i.e., delay to some extent and preferably stop) cancer cell invasion into peripheral organs; inhibit (i.e., delay to some extent and preferably stop) tumor metastasis; inhibit tumor growth to some extent; and / or alleviate to some extent one or more symptoms associated with cancer. To the extent that a drug can prevent the growth of and / or kill existing cancer cells, the drug can be cytostatic and / or cytotoxic. An effective amount increases progression-free survival (e.g., as measured by Response Evaluation Criteria in Solid Tumors (RECIST) or CA-125 change), results in an objective response (partial response (PR) or complete response (CR)), prolongs overall survival, and / or improves one or more symptoms of cancer (e.g., as assessed by FOSI). The term "effective amount" specifically includes an amount appropriate for achieving any of the primary or secondary endpoints of the clinical trial described in Example 1.

[0077] "Taxanes" are chemotherapy drugs that inhibit mitosis and disrupt microtubules. Examples of taxanes include paclitaxel (TAXOL®; Bristol-Myers Squibb Oncology, Princeton, NL); a cremophor-free albumin engineered nanoparticle formulation of paclitaxel or nab-paclitaxel (ABRAXANE™; American Pharmaceutical Partners, Schaumberg, Illinois); and docetaxel (TAXOTERE®; Rhone-Poulenc Rorer, Antony, France).

[0078] "Anthracyclines" are a type of antibiotic derived from the fungus Streptococcus peucetius, and examples include daunorubicin, doxorubicin, and epirubicin.

[0079] "Anthracycline-based chemotherapy" refers to a chemotherapy regimen consisting of or including one or more anthracyclines. Examples include 5-FU, epirubicin, and cyclophosphamide (FEC); 5-FU, doxorubicin, and cyclophosphamide (FAC); doxorubicin and cyclophosphamide (AC); epirubicin and cyclophosphamide (EC), etc.

[0080] As used herein, "carboplatin-based chemotherapy" refers to a chemotherapy regimen consisting of or including one or more carboplatins. Examples are TCH (docetaxel / TAXOL®, carboplatin, and trastuzumab / HERCEPTIN®).

[0081] An "aromatase inhibitor" inhibits the enzyme aromatase, which regulates estrogen production in the adrenal gland. Examples of aromatase inhibitors include 4(5)-imidazole, aminoglutethimide, MEGASE® megestrol acetate, AROMASIN® exemestane, formestane, fadrozole, RIVISOR® vorozole, FEMARA® letrozole, and ARIMIDEX® anastrozole. In one embodiment, the aromatase inhibitor herein is letrozole or anastrozole.

[0082] "Antimetabolite chemotherapy" is the use of drugs that are structurally similar to metabolites but cannot be used in a productive manner by the body. Many antimetabolite chemotherapeutic agents interfere with the production of nucleic acids, RNA, and DNA. Examples of antimetabolite chemotherapeutic agents include gemcitabine (GEMZAR®), 5-fluorouracil (5-FU), capecitabine (XELODA™), 6-mercaptopurine, methotrexate, 6-thioguanine, pemetrexed, raltitrexed, arabinosylcytosine ARA-C cytarabine (CYTOSAR-U®), dacarbazine (DTIC-DOME®), azacytosine, deoxycytosine, pyridmidene, fludarabine (FLUDARA®), cladrabine, 2-deoxy-D-glucose, and the like.

[0083] A cancer is "chemoresistant" if the patient's cancer progressed while receiving a chemotherapy regimen (i.e., the patient is "chemorefractory") or if the patient's cancer progressed within 12 months (e.g., within 6 months) of completing a chemotherapy regimen.

[0084] The term "platin" refers to platinum-based chemotherapy, including, but not limited to, cisplatin, carboplatin, and oxaliplatin.

[0085] The term "fluoropyrimidine" refers to antimetabolite chemotherapy, including, but not limited to, capecitabine, floxuridine, and fluorouracil (5-FU).

[0086] A "fixed" or "constant" dose of a therapeutic agent herein refers to a dose administered to a human patient without regard to the patient's body weight (WT) or body surface area (BSA). Thus, the fixed or constant dose may be expressed as a mg / kg dose or a mg / m 2 It is not provided as a dose, but rather as an absolute amount of therapeutic agent.

[0087] A "loading" dose or "LD" herein generally comprises an initial dose of a therapeutic agent administered to a patient, followed by one or more maintenance dose(s). Generally, a single loading dose is administered, although multiple loading doses are contemplated herein. Typically, the amount of the administered loading dose(s) exceeds the amount of the administered maintenance dose(s), and / or the loading dose(s) are administered more frequently than the maintenance dose(s), so as to achieve the desired steady-state concentration of the therapeutic agent more quickly than can be achieved with the maintenance dose(s).

[0088] As used herein, a "maintenance" dose refers to one or more doses of a therapeutic agent administered to a patient over a treatment period. Typically, the maintenance dose is administered at a treatment interval of about every week, about every two weeks, about every three weeks, or about every four weeks, but preferably every three weeks or the like.

[0089] "Infusion" or "infusion" refers to the introduction of a drug-containing solution into the body through a vein for therapeutic purposes. Typically, this is accomplished through an intravenous (IV) bag.

[0090] An "intravenous bag" or "IV bag" is a bag capable of holding a solution that can be administered via a patient's vein. In one embodiment, the solution is saline (e.g., about 0.9% or about 0.45% NaCl). Optionally, the IV bag is formed from polyolefin or polyvinyl chloride.

[0091] "Co-administration" means the intravenous administration of two (or more) drugs during the same administration, rather than sequential infusion of two (or more) drugs. Generally, this requires that the two (or more) drugs be combined in the same IV bag prior to their co-administration.

[0092] A drug that is administered "concurrently" with one or more other drugs is administered on the same treatment day as the one or more other drugs during the same treatment cycle, optionally simultaneously with the one or more other drugs. For example, in the case of cancer therapy administered every three weeks, each of the concurrently administered drugs is administered on day 1 of a three-week cycle.

[0093] "Cardiotoxicity" refers to any toxic side effect that affects the heart and results from drug or drug combination administration. Cardiotoxicity can be assessed based on any one or more of the following: the occurrence of symptomatic left ventricular systolic dysfunction (LVSD) or congestive heart failure (CHF), or a decrease in left ventricular drive fraction (LVEF).

[0094] The phrase "without increasing cardiac toxicity" in reference to drug combinations that include pertuzumab refers to the occurrence of cardiac toxicity that is equal to or less than that observed in patients treated with the combination of drugs other than pertuzumab (e.g., equal to or less than that resulting from the administration of trastuzumab and a chemotherapeutic agent, such as docetaxel).

[0095] A "vial" is a container suitable for holding a liquid or lyophilized preparation. In one embodiment, the vial is a single-use vial, for example, a 20 cc single-use vial with a stopper.

[0096] The term "package insert" is used to refer to instructions customarily included in commercial packaging of therapeutic products that contain information about the indications, uses, dosage, administration, contraindications, and / or warnings regarding the use of such therapeutic product.

[0097] "Adverse event" means any untoward and unintended sign, symptom, or illness, regardless of attribution, that is temporally related to the use of an investigational product (medicinal product) or other protocol-mandated intervention, and includes an AE not previously observed in a patient that emerges during the protocol-specified AE reporting period, including signs or symptoms related to 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 during a washout period, off-treatment period, or prior to assignment of study treatment related to another protocol-mandated intervention, if applicable; and a pre-existing medical condition (other than the condition being tested) that is determined by the investigator to have worsened in severity or frequency or changed in nature during the protocol-specified AE reporting period.

[0098] An adverse event will be classified as a "serious adverse event" (SAE) if it meets the following criteria: fatal (i.e., the AE actually causes or leads to death); life-threatening (i.e., in the investigator's view, the AE places the patient at imminent risk of death, but does not include AEs that could cause death if they occurred in a more severe form); requiring hospitalization or prolonged hospitalization; resulting in permanent or significant disability / incapacity (i.e., the AE results in a substantial interruption of the patient's ability to perform normal life functions); resulting in congenital anomalies / birth defects in the offspring of newborns / infants born to mothers exposed to the investigational drug; or deemed a significant medical event by the investigator based on medical judgment (e.g., that may endanger the patient or require medical / surgical intervention to prevent one of the outcomes listed above). All AEs that do not meet any of the criteria for severity are considered non-serious AEs. The terms "severe" and "serious" are not synonymous. Severity (or intensity) refers to the grade of a particular AE, i.e., mild (Grade 1), moderate (Grade 2), or severe (Grade 3) myocardial infarction (see Section 5.2.2). "Severe" is a regulatory definition (see previous definition) and is usually based on patient or event outcomes or behavioral criteria related to an event that poses a threat to the patient's life or function. Severity (rather than severity) serves as a guide for defining regulatory reporting obligations from sponsors to applicable regulatory authorities. When reporting AEs and SAEs in eCRFs (electronic case report forms), severity and seriousness should be assessed independently.

[0099] The present invention is based, in part, on the observation that trastuzumab-MCC-DM1 was unexpectedly effective in treating patients with metastatic HER2-positive breast cancer in the first-line setting who had been previously treated with a taxane, compared with patients who had not previously received a taxane. The present invention provides methods of using an anti-HER2-maytansinoid conjugate, such as trastuzumab-MCC-DM1, for the treatment of HER2-positive progressive or recurrent locally advanced or untreated metastatic breast cancer (first-line metastatic breast cancer), where the patient has been pretreated with a taxane. While treatment options exist for HER2-positive cancer patients in the adjuvant, neoadjuvant, and metastatic breast cancer settings, additional options are needed, including metastatic breast cancer settings in the "first-line" setting, i.e., for patients with untreated metastatic breast cancer or locally advanced breast cancer. Overall, T-DM1 demonstrated non-inferior progression-free survival (PFS) compared with standard-of-care HERCEPTIN plus taxane (HT), but it was not superior to HT. However, the data suggest a superior effect of T-DM1 over HT for patients who have previously received taxane therapy, indicating that treatment with an anti-HER2-maytansinoid conjugate, such as trastuzumab-MCC-DM1, should be selected for locally advanced and first-line metastatic Her2-positive breast cancer in these patients.

[0100] Trastuzumab-MCC-DM1 (T-DM1) The present invention relates to a compound having the structure: Therapeutic treatment with trastuzumab-MCC-DM1 (T-DM1), an antibody-drug conjugate (Cas Reg. No. 139504-50-0) having the formula JPEG2025157247000001.jpg63127, where Tr is trastuzumab conjugated to the maytansinoid drug moiety DM1 via the linker moiety MCC (US Pat. No. 5,208,020, US Pat. No. 6,441,163). The drug-to-antibody ratio, or drug loading, is represented by p in the above structure of trastuzumab-MCC-DM1, and ranges from 1 to about 8 integer values. Trastuzumab-MCC-DM1 includes a mixture of all variably loaded and conjugated antibody-drug conjugates, where 1, 2, 3, 4, 5, 6, 7, and 8 drug moieties are covalently attached to the antibody trastuzumab (US7097840, US2005 / 0276812, US2005 / 0166993). The average drug loading is approximately 3.5.

[0101] Trastuzumab can be produced by mammalian cell (Chinese hamster ovary, CHO) suspension culture. The HER2 (or c-erbB2) proto-oncogene encodes a 185 kDa transmembrane receptor protein structurally related to the epidermal growth factor receptor. Trastuzumab is an antibody with antigen-binding residues of or derived from the murine 4D5 antibody (ATCC CRL 10463, deposited under the Budapest Treaty with the American Type Culture Collection, 12301 Parklawn Drive, Rockville, Md. 20852, on May 24, 1990). 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 US Pat. No. 5,821,337.

[0102] Trastuzumab-MCC-DM1 may be prepared, for example, according to Example 1 of US Patent Application Publication No. 20110165155.

[0103] Anti-HER2-maytansinoid conjugate formulations Anti-HER2-maytansinoid conjugates, such as trastuzumab-MCC-DM1, can be formulated according to standard pharmaceutical practices for use in therapeutic combinations. Pharmaceutical compositions include trastuzumab-MCC-DM1 together with one or more pharmaceutically acceptable carriers, glidants, diluents, or excipients.

[0104] Suitable carriers, diluents, and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc. The particular carrier, diluent, or excipient used will be determined by the means and purpose for which the compounds of the present invention are to be applied. Solvents are selected based on solvents recognized by those skilled in the art as generally recognized as safe (GRAS) for mammalian administration. Generally, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), etc., and mixtures thereof. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, and other known additives to provide proper presentation of the drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (i.e., a medicament).

[0105] The formulations may be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., a compound of the invention or a stabilized form of the compound (e.g., a complex with a cyclodextrin derivative or other well-known complexing agent) is dissolved in a suitable solvent in the presence of one or more excipients described above. The compounds of the invention are typically formulated into pharmaceutical dosage forms to provide an easily controllable drug dose and to enable patient compliance with a prescribed regimen.

[0106] Pharmaceutical compositions (or formulations) for application may be packaged in a variety of ways depending on the method used to administer the drug. Generally, an article for distribution includes a container having disposed therein the pharmaceutical formulation in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, etc. 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.

[0107] Pharmaceutical formulations may be prepared in the form of lyophilized preparations, pulverized powders, or aqueous solutions with pharmaceutically acceptable diluents, carriers, excipients, or stabilizers (Remington's Pharmaceutical Sciences (1995) 18th edition, Mack Publishing Co., Easton, PA) for various routes and types of administration. Formulations may be made by mixing the compound at ambient temperature, at an appropriate pH, and to the desired degree of purity with a physiologically acceptable carrier, i.e., a carrier that is nontoxic to recipients at the dosage and concentration employed. The pH of the formulation is determined primarily by the specific application and the concentration of compound, but may range from about 3 to about 8.

[0108] 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.

[0109] Pharmaceutical formulations may typically be stored as solid compositions, lyophilized formulations, or as aqueous solutions.

[0110] The pharmaceutical formulations of the present invention will be formulated and administered in a manner consistent with good medical practicality, i.e., amounts, concentrations, schedules, courses, vehicles, and routes of administration. Factors to consider in this context include the particular disorder being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the scheduling of administration, and other factors known to medical practitioners.

[0111] Acceptable diluents, carriers, excipients, and stabilizers are nontoxic to recipients at the dosages and concentrations employed and include buffers such as phosphate, citrate, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl, ethanol, or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polyisoprene; 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 glycol (PEG) (including PEG400). The active pharmaceutical ingredient may also be incorporated into microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacylate) microcapsules, respectively, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences, 18th edition (1995), Mack Publishing Co., Easton, PA.Other examples of medicinal agents are found in Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, Vol 3, 2. nd Ed., New York, NY.

[0112] 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. The method includes 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.

[0113] Pharmaceutical preparations may be in the form of sterile injectable preparations, such as aqueous or oily sterile injectable suspensions. Such suspensions may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as described above. Sterile injectable preparations may also be solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol or prepared from lyophilized powders. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils are commonly used as solvents or suspending media. For this purpose, any bland fixed oil may be employed, including synthetic mono- or diglycerides. Additionally, fatty acids such as oleic acid may also be used in the preparation of injectables.

[0114] The amount of active ingredient that can be combined with carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. For example, a sustained-release formulation intended for oral administration to humans may contain from about 1 to 1000 mg of active ingredient combined with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 95% of the total composition (weight:weight). Pharmaceutical compositions can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 μg of active ingredient per milliliter of solution to allow infusion of a suitable volume at a rate of about 30 mL / hour.

[0115] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the solution isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile injectable solutions which may contain suspending agents and thickening agents.

[0116] 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, e.g., water, for injection immediately prior to use. 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 sub-dose, as herein above recited, of the active ingredient, or an appropriate fraction thereof.

[0117] As a general rule, the initial pharmaceutically effective amount of trastuzumab-MCC-DM1 administered per dose will be in the range of about 0.3 to 15 mg / kg / day of patient body weight.

[0118] The commercially available T-DM1 formulation (KADCYLA®, ado-trastuzumab emtansine) is a sterile, white to off-white, preservative-free, lyophilized powder in single-use vials. Each vial contains 100 mg or 160 mg of ado-trastuzumab emtansine. Following reconstitution, each single-use vial contains ado-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 contains 20 mg / mL of ado-trastuzumab emtansine and is administered by intravenous infusion after dilution.

[0119] Pertuzumab formulations The commercially available formulation of pertuzumab (PERJETA®) contains pertuzumab 420 mg / 14 mL (30 mg / mL) in the form of a preservative-free solution for IV infusion.

[0120] Administration of the Pharmaceutical Composition The pharmaceutical compositions described herein may be administered by any route appropriate to the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, inhalation, intradermal, intrathecal, epidural, and infusion techniques), transdermal, rectal, nasal, topical (including buccal and sublingual), intravaginal, intraperitoneal, intrapulmonary, and intranasal. Local administration can also involve the use of transdermal administration, such as transdermal patches or iontophoresis devices. For local immunosuppressive treatment, the compound may 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, depending on the condition of the recipient. When administered orally, the compound may be formulated as a pill, capsule, tablet, etc., along with a pharmaceutically acceptable carrier, glidant, or excipient. When administered parenterally, the compounds may be formulated in a unit dosage form for injection with a pharmaceutically acceptable parenteral vehicle or diluent, as detailed below.

[0121] product Articles of manufacture, or "kits," containing an anti-HER2-maytansinoid conjugate, such as trastuzumab-MCC-DM1, are provided that are useful in the therapeutic methods herein. In one embodiment, the kit includes a container containing trastuzumab-MCC-DM1. The kit may further include a label or package insert on or associated with the container. The term "package insert" is used to refer to instructions typically included in commercial packaging of therapeutic products, including information about the indications, usage, dosage, administration, contraindications, and / or warnings regarding the use of such therapeutic products. Suitable containers include, for example, bottles, vials, syringes, blister packs, and the like. The container may be formed from a variety of materials, such as glass or plastic. The container may hold an anti-HER2 maytansinoid conjugate, such as trastuzumab-MCC-DM1, or a formulation thereof effective for use in the therapeutic methods herein, and may have a sterile access port (e.g., the container may be an intravenous solution bag or a vial with a stopper pierceable by a hypodermic injection needle). The label or package insert indicates that the composition is used in the therapeutic methods described and claimed herein. The article of manufacture may further comprise a container containing a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0122] The kit may further include instructions for administering trastuzumab-MCC-DM1. For example, if the kit includes a first composition comprising trastuzumab-MCC-DM1 and a second pharmaceutical formulation, the kit may further include instructions for administering the first composition and the second pharmaceutical composition simultaneously, sequentially, or separately to a patient in need thereof. [Example]

[0123] To illustrate the invention, examples are included as provided in the figures, the brief description of the figures above, and the examples that follow, but it should be understood that these examples do not limit the invention and are merely representative of methods of practicing the invention.

[0124] Example 1 Phase III clinical trial This study (clinicaltrials.gov identifier number NCT01120184; study number BO22589) was a randomized, three-arm, multicenter phase III trial evaluating the efficacy and safety of trastuzumab emtansine (T-DM1) in combination with pertuzumab, or trastuzumab emtansine (T-DM1) alone (i.e., in combination with pertuzumab placebo) versus trastuzumab (Herceptin) plus a taxane (docetaxel or paclitaxel) in patients with HER2-positive, advanced or recurrent, locally advanced, or previously untreated metastatic breast cancer (see Figure 6).

[0125] Stratification factors: region of operation, previous neoadjuvant therapy (if any: previous trastuzumab / lapatinib), visceral disease.

[0126] Primary endpoints: Progression-free survival (PFS), non-inferiority and superiority as assessed by an independent review facility (IRF).

[0127] Key secondary endpoints: Overall Survival (OS), Investigator-Performance Scale (PFS), Objective Response Rate (ORR), safety, and Patient-Reported Outcome.

[0128] The inclusion and exclusion criteria for this study are as follows:

[0129] standard Inclusion criteria were as follows: 1) adult patients aged 18 years or older; 2) HER2-positive breast cancer; 3) histologically or cytologically confirmed adenocarcinoma of the breast with locally recurrent or metastatic disease and chemotherapy candidates (patients with locally advanced disease must have recurrent or progressive disease and not undergo resection with curative intent); 4) patients must have measurable and / or nonmeasurable disease evaluable by RECIST 1.1; 5) ECOG performance status of 0 or 1; and 6) adequate organ function as determined by laboratory tests.

[0130] Exclusion criteria were: 1) history of previous (or any) chemotherapy for metastatic breast cancer or recurrent locally advanced disease; 2) less than 6 months between the last dose of vinca alkaloid or taxane cytotoxic chemotherapy and the time of metastatic diagnosis; 3) receipt of hormonal therapy less than 7 days prior to randomization; 4) receipt of trastuzumab therapy and / or lapatinib (neoadjuvant or adjuvant therapy) less than 21 days prior to randomization; 5) prior treatment with trastuzumab emtansine or pertuzumab therapy.

[0131] The outcome measures were as follows: The primary outcomes were assessed using the following measures: 1) progression-free survival (PFS) based on tumor assessment performed by an independent review facility (IRF); and 2) adverse event (AE) incidence.

[0132] Secondary outcomes were assessed using the following measures: 1) reduced overall survival (OS) at 2 years; 2) 1-year survival rate; 3) overall survival (OS) rate; 4) overall or objective response rate; 5) duration of response; 6) duration of treatment success as assessed by an independent review facility (IRF); and 7) clinical benefit rate.

[0133] As shown in Figure 7, the data suggest a superior effect of T-DM1 (Kadcyla®) on patients with metastatic HER2-positive breast cancer in the first-line setting who have previously received taxane therapy. Sequence Listing SEQUENCE LISTING <110> GENENTECH, INC. <120> METHODS OF TREATING HER2-POSITIVE METASTATIC BREAST CANCER <130> GNE-0423R1-WO <140> <141> <150> 62 / 168,809 <151> 2015-05-30 <160> 16 <170> PatentIn version 3.5 <210> 1 <211> 195 <212> PRT <213> Homo sapiens <400> 1 Thr Gln Val Cys Thr Gly Thr Asp Met Lys Leu Arg Leu Pro Ala Ser 1 5 10 15 Pro Glu Thr His Leu Asp Met Leu Arg His Leu Tyr Gln Gly Cys Gln 20 25 30 Val Val Gln Gly Asn Leu Glu Leu Thr Tyr Leu Pro Thr Asn Ala Ser 35 40 45 Leu Ser Phe Leu Gln Asp Ile Gln Glu Val Gln Gly Tyr Val Leu Ile 50 55 60 Ala His Asn Gln Val Arg Gln Val Pro Leu Gln Arg Leu Arg Ile Val 65 70 75 80 Arg Gly Thr Gln Leu Phe Glu Asp Asn Tyr Ala Leu Ala Val Leu Asp 85 90 95 Asn Gly Asp Pro Leu Asn Asn Thr Thr Pro Val Thr Gly Ala Ser Pro 100 105 110 Gly Gly Leu Arg Glu Leu Gln Leu Arg Ser Leu Thr Glu Ile Leu Lys 115 120 125 Gly Gly Val Leu Ile Gln Arg Asn Pro Gln Leu Cys Tyr Gln Asp Thr 130 135 140 Ile Leu Trp Lys Asp Ile Phe His Lys Asn Asn Gln Leu Ala Leu Thr 145 150 155 160 Leu Ile Asp Thr Asn Arg Ser Arg Ala Cys His Pro Cys Ser Pro Met 165 170 175 Cys Lys Gly Ser Arg Cys Trp Gly Glu Ser Ser Glu Asp Cys Gln Ser 180 185 190 Leu Thr Arg 195 <210> 2 <211> 124 <212> PRT <213> Homo sapiens <400> 2 Thr Val Cys Ala Gly Gly Cys Ala Arg Cys Lys Gly Pro Leu Pro Thr 1 5 10 15 Asp Cys Cys His Glu Gln Cys Ala Ala Gly Cys Thr Gly Pro Lys His 20 25 30 Ser Asp Cys Leu Ala Cys Leu His Phe Asn His Ser Gly Ile Cys Glu 35 40 45 Leu His Cys Pro Ala Leu Val Thr Tyr Asn Thr Asp Thr Phe Glu Ser 50 55 60 Met Pro Asn Pro Glu Gly Arg Tyr Thr Phe Gly Ala Ser Cys Val Thr 65 70 75 80 Ala Cys Pro Tyr Asn Tyr Leu Ser Thr Asp Val Gly Ser Cys Thr Leu 85 90 95 Val Cys Pro Leu His Asn Gln Glu Val Thr Ala Glu Asp Gly Thr Gln 100 105 110 Arg Cys Glu Lys Cys Ser Lys Pro Cys Ala Arg Val 115 120 <210> 3 <211> 169 <212> PRT <213> Homo sapiens <400> 3 Cys Tyr Gly Leu Gly Met Glu His Leu Arg Glu Val Arg Ala Val Thr 1 5 10 15 Ser Ala Asn Ile Gln Glu Phe Ala Gly Cys Lys Lys Ile Phe Gly Ser 20 25 30 Leu Ala Phe Leu Pro Glu Ser Phe Asp Gly Asp Pro Ala Ser Asn Thr 35 40 45 Ala Pro Leu Gln Pro Glu Gln Leu Gln Val Phe Glu Thr Leu Glu Glu 50 55 60 Ile Thr Gly Tyr Leu Tyr Ile Ser Ala Trp Pro Asp Ser Leu Pro Asp 65 70 75 80 Leu Ser Val Phe Gln Asn Leu Gln Val Ile Arg Gly Arg Ile Leu His 85 90 95 Asn Gly Ala Tyr Ser Leu Thr Leu Gln Gly Leu Gly Ile Ser Trp Leu 100 105 110 Gly Leu Arg Ser Leu Arg Glu Leu Gly Ser Gly Leu Ala Leu Ile His 115 120 125 His Asn Thr His Leu Cys Phe Val His Thr Val Pro Trp Asp Gln Leu 130 135 140 Phe Arg Asn Pro His Gln Ala Leu Leu His Thr Ala Asn Arg Pro Glu 145 150 155 160 Asp Glu Cys Val Gly Glu Gly Leu Ala 165 <210> 4 <211> 142 <212> PRT <213> Homo sapiens <400> 4 Cys His Gln Leu Cys Ala Arg Gly His Cys Trp Gly Pro Gly Pro Thr 1 5 10 15 Gln Cys Val Asn Cys Ser Gln Phe Leu Arg Gly Gln Glu Cys Val Glu 20 25 30 Glu Cys Arg Val Leu Gln Gly Leu Pro Arg Glu Tyr Val Asn Ala Arg 35 40 45 His Cys Leu Pro Cys His Pro Glu Cys Gln Pro Gln Asn Gly Ser Val 50 55 60 Thr Cys Phe Gly Pro Glu Ala Asp Gln Cys Val Ala Cys Ala His Tyr 65 70 75 80 Lys Asp Pro Pro Phe Cys Val Ala Arg Cys Pro Ser Gly Val Lys Pro 85 90 95 Asp Leu Ser Tyr Met Pro Ile Trp Lys Phe Pro Asp Glu Glu Gly Ala 100 105 110 Cys Gln Pro Cys Pro Ile Asn Cys Thr His Ser Cys Val Asp Leu Asp 115 120 125 Asp Lys Gly Cys Pro Ala Glu Gln Arg Ala Ser Pro Leu Thr 130 135 140 <210> 5 <211> 107 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic polypeptide" <400> 5 Asp Thr Val Met Thr Gln Ser His Lys Ile Met Ser Thr Ser Val Gly 1 5 10 15 Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Ile Gly 20 25 30 Val Ala Trp Tyr Gln Gln Arg Pro Gly Gln Ser Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala 65 70 75 80 Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln Tyr Tyr Ile Tyr Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 6 <211> 119 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic polypeptide" <400> 6 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Thr 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Phe Thr Phe Thr Asp Tyr 20 25 30 Thr Met Asp Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile 35 40 45 Gly Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe 50 55 60 Lys Gly Lys Ala Ser Leu Thr Val Asp Arg Ser Ser Arg Ile Val Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Phe Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Leu Thr Val Ser Ser 115 <210> 7 <211> 107 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic polypeptide" <400> 7 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Ile Gly 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ile Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 8 <211> 119 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic polypeptide" <400> 8 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr 20 25 30 Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe 50 55 60 Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 9 <211> 107 <212> PRT <213> Homo sapiens <400> 9 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Leu Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 10 <211> 119 <212> PRT <213> Homo sapiens <400> 10 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Gly Asp Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Arg Val Gly Tyr Ser Leu Tyr Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 11 <211> 214 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic polypeptide" <400> 11 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Ile Gly 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ile Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 12 <211> 448 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic polypeptide" <400> 12 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr 20 25 30 Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe 50 55 60 Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 <210> 13 <211> 214 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic polypeptide" <400> 13 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 14 <211> 449 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic polypeptide" <400> 14 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly <210> 15 <211> 217 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic polypeptide" <400> 15 Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala 1 5 10 15 Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val 20 25 30 Ser Ile Gly Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys 35 40 45 Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg 50 55 60 Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser 65 70 75 80 Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ile 85 90 95 Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr 100 105 110 Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu 115 120 125 Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro 130 135 140 Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly 145 150 155 160 Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr 165 170 175 Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His 180 185 190 Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val 195 200 205 Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 16 <211> 449 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note="Description of Artificial Sequence: Synthetic polypeptide" <400> 16 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr 20 25 30 Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe 50 55 60 Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys

Claims

1. 1. A method for treating HER2-positive locally advanced or untreated metastatic breast cancer, comprising administering a therapeutically effective amount of an anti-HER2-maytansinoid conjugate to a patient having said breast cancer, wherein said patient has received prior treatment with a taxane.

2. 10. The method of claim 1, wherein said administration occurs six months or more after prior treatment with said taxane.

3. 3. The method of claim 1 or 2, wherein the patient has received prior treatment with a taxane and at least one HER2-targeted therapy.

4. 4. The method of claim 3, wherein the patient has been pretreated with a taxane and trastuzumab.

5. 5. The method of claim 4, wherein the patient has been pretreated with a taxane, trastuzumab, and pertuzumab.

6. The method of any one of claims 1 to 5, wherein the pretreatment is administered in an adjuvant setting.

7. The method of any one of claims 1 to 5, wherein the prior treatment is administered non-adjuvant.

8. 10. The method of any one of the preceding claims, wherein the taxane is paclitaxel.

9. 9. The method of claim 8, wherein the paclitaxel was administered intravenously weekly at 80 mg / m2.

10. 10. The method of claim 9, wherein the paclitaxel has been administered for a minimum of 18 weeks.

11. The method of any one of claims 1 to 7, wherein the taxane is docetaxel.

12. 12. The method of claim 11, wherein the docetaxel was administered intravenously at 75 mg / m2 or 100 mg / m2 every three weeks.

13. 13. The method of claim 12, wherein the docetaxel has been administered for a minimum of 6 cycles.

14. 14. The method of any one of claims 4 to 13, wherein the trastuzumab was administered intravenously every three weeks at 8 mg / kg in cycle 1, followed by 6 mg / kg in subsequent cycles.

15. 14. The method of any one of claims 4 to 13, wherein the trastuzumab was administered intravenously at 4 mg / kg on day 1 of cycle 1, followed by 2 mg / kg weekly from day 8 of cycle 1.

16. 16. The method of any one of claims 5 to 15, wherein the trastuzumab was administered intravenously at 840 mg on day 1 of cycle 1, followed by 420 mg every 3 weeks in subsequent cycles.

17. 10. The method of any one of the preceding claims, wherein the anti-HER2-maytansinoid conjugate is a trastuzumab-maytansinoid conjugate.

18. 18. The method of claim 17, wherein the trastuzumab-maytansinoid conjugate is a trastuzumab-DM1 conjugate.

19. 19. The method of claim 18, wherein the trastuzumab-DM1 conjugate is trastuzumab-MCC-DM1.

20. 20. The method of claim 19, wherein the trastuzumab-MCC-DM1 is administered at 3.6 mg / kg every three weeks.

21. 20. The method of claim 19, wherein the trastuzumab-MCC-DM1 is administered at 2.4 mg / kg weekly.

22. 10. The method of any one of the preceding claims, wherein the breast cancer is untreated metastatic breast cancer.

23. A method for treating HER2-positive locally advanced or untreated metastatic breast cancer, comprising: (1) determining whether the patient has received prior taxane treatment; and (2) administering a therapeutically effective amount of an anti-HER2-maytansinoid conjugate to the patient if the patient has received prior taxane treatment.

24. 24. The method of claim 23, wherein said administration occurs six months or more after prior treatment with said taxane.

25. 25. The method of claim 23 or 24, wherein the patient has received prior treatment with a taxane and at least one HER2-targeted therapy.

26. 26. The method of claim 25, wherein the patient has been pretreated with a taxane and trastuzumab.

27. 27. The method of claim 26, wherein the patient has been previously treated with a taxane, trastuzumab, and pertuzumab.

28. The method of any one of claims 23 to 27, wherein the pretreatment is administered in an adjuvant setting.

29. The method of any of claims 23 to 27, wherein the prior treatment is administered non-adjuvant.

30. 30. The method of any one of claims 23 to 29, wherein the taxane is paclitaxel.

31. 31. The method of claim 30, wherein the paclitaxel was administered intravenously weekly at 80 mg / m2.

32. 32. The method of claim 31, wherein the paclitaxel has been administered for a minimum of 18 weeks.

33. The method of any one of claims 23 to 30, wherein the taxane is docetaxel.

34. 34. The method of claim 33, wherein the docetaxel was administered intravenously at 75 mg / m2 or 100 mg / m2 every three weeks.

35. 35. The method of claim 34, wherein the docetaxel has been administered for a minimum of 6 cycles.

36. 36. The method of any one of claims 26 to 35, wherein the trastuzumab was administered intravenously every three weeks at 8 mg / kg in cycle 1, followed by 6 mg / kg in subsequent cycles.

37. 36. The method of any one of claims 26-35, wherein the trastuzumab was administered intravenously at 4 mg / kg on day 1 of cycle 1, followed by 2 mg / kg weekly from day 8 of cycle 1.

38. 38. The method of any one of claims 27-37, wherein the trastuzumab was administered intravenously at 840 mg on day 1 of cycle 1, followed by 420 mg every 3 weeks in subsequent cycles.

39. 39. The method of any one of claims 23 to 38, wherein the anti-HER2-maytansinoid conjugate is a trastuzumab-maytansinoid conjugate.

40. 40. The method of claim 39, wherein the trastuzumab-maytansinoid conjugate is a trastuzumab-DM1 conjugate.

41. 41. The method of claim 40, wherein the trastuzumab-DM1 conjugate is trastuzumab-MCC-DM1.

42. 42. The method of claim 41, wherein the trastuzumab-MCC-DM1 is administered at 3.6 mg / kg every three weeks.

43. 42. The method of claim 41, wherein the trastuzumab-MCC-DM1 is administered at 2.4 mg / kg weekly.

44. The method of any one of claims 23 to 43, wherein the breast cancer is untreated metastatic breast cancer.

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