Methods of treating her2-positive locally advanced or previously untreated metastatic breast cancer

Abstract

The present invention relates generally to methods of treating HER2-positive locally advanced or previously untreated metastatic breast cancer, and particularly provides methods of treating HER2-positive, locally advanced or previously untreated metastatic breast cancer with an anti-HER2-maytansine conjugate (e.g., trastuzumab-eimetanin) that has received prior treatment with a taxane, a method of treating a patient with locally advanced or previously untreated metastatic breast cancer.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202511623386.6 (22) Application Date 2016.05.27 (30) Priority Data 62 / 168,809 2015.05.30 US (62) Divisional Application Data 201680031816.8 2016.05.27 (71) Applicant Hofmeister Roche Ltd. Address Basel, Switzerland (72) Inventors A.E. Guardino M. Samanthain A. Strassac M. Schmidt M. Pat (74) Patent Agency Beijing Kunrui Law Firm 11494 Patent Attorney Cen Xiaodong (51) Int.Cl. A61K 47 / 68 (2017.01) A61K 31 / 537(2006.01) A61P 35 / 04(2006.01) A61P 15 / 14(2006.01) (54) Invention Title: Method for Treating HER2-Positive Locally Advanced or Previously Untreated Metastatic Breast Cancer (57) Abstract: This invention relates primarily to a method for treating HER2-positive locally advanced or previously untreated metastatic breast cancer, specifically providing a method for treating patients with HER2-positive, locally advanced or previously untreated metastatic breast cancer who have received prior treatment with taxanes using an anti-HER2-matenum alkaloid conjugate (e.g., trastuzumab-emestanesin). Claims 1 page, Description 22 pages, Sequence List (Electronic Publication), Drawings 9 pages, CN 121971642 A 2026.05.05 CN 1 21 97 16 42 A 1. A method for treating HER2-positive locally advanced or previously untreated metastatic breast cancer, the method comprising administering a therapeutically effective amount of an anti-HER2-maedentum alkaloid conjugate to a patient having said breast cancer, wherein the patient has received prior treatment with taxane. 2. The method of claim 1, wherein the administration occurs ≥6 months after the prior treatment with taxane. 3. The method of claim 1 or 2, wherein the patient has received prior treatment with taxane and at least one HER2-targeted therapy. 4. The method of claim 3, wherein the patient has received prior treatment with taxane and trastuzumab. 5. The method of claim 4, wherein the patient has received prior treatment with taxane, trastuzumab, and pertuzumab. 6. The method of any one of claims 1-5, wherein the prior treatment is administered in an auxiliary setting. 7. The method of any one of claims 1-5, wherein the prior treatment is administered in a new auxiliary setting. 8. The method of any one of the prior claims, wherein the taxane is palitaxetine. 9. The method of claim 8, wherein the palitaxetine is administered intravenously at 80 mg / m² once weekly.10. The method of claim 9, wherein the palitaxetine is administered for at least 18 weeks. Claims 1 / 1 page 2 CN 121971642 A Method for treating HER2-positive locally advanced or previously untreated metastatic breast cancer

[0001] This application is a divisional application of Chinese Patent Application No. 201680031816.8, filed on May 27, 2016, entitled “Method for treating HER2-positive locally advanced or previously untreated metastatic breast cancer”. Related Applications

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 168,809, filed on May 30, 2015, under 35 USC § 119, the disclosure of which is incorporated herein by reference in its entirety. Sequence List

[0003] This application contains a sequence list in ASCII format, which is incorporated herein by reference in its entirety. An ASCII text file was created on May 20, 2016, named GNE-0423R1-WO Sequence Listing.txt and is 30,476 bytes in size. Technical Field

[0004] This invention relates to a method of treating HER2-positive advanced or recurrent locally advanced or previously untreated metastatic breast cancer using anti-HER2-matenum alkaloid conjugates, such as trastuzumab-MCC-DM1, in a patient who has received prior treatment with taxanes. Background Art

[0005] Breast Cancer and HER2-Targeted Therapy

[0006] Breast cancer is a major cause of morbidity and mortality worldwide. More than 1.3 million cases of breast cancer are diagnosed globally each year, and more than 450,000 deaths are associated with the disease (Jemal A, Bray F, Center M, et al., Global cancer statistics. CA Cancer J Clin, 2011; 61(2):69-90).

[0007] 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 it is associated with aggressive growth and adverse clinical outcomes related to these tumors (Slamon et al. (1987) Science 235:177-182). HER2 protein overexpression can be determined using immunohistochemical assessment of fixed tumor masses (Press MF, et al. (1993) Cancer Res 53:4960-70).

[0008] Trastuzumab (CAS 180288-69-1, HERCEPTIN®)rhuMAb HER2 (Genentech) is a recombinant DNA-derived, IgG1κ monoclonal antibody, a humanized form of the mouse anti-HER2 antibody (4D5) that selectively binds to the extracellular domain of HER2 with high affinity (Kd = 5 nM) in a cell-based assay (US 5677171; US ​​5821337; US 6054297; US 6165464; US 6339142; US 6407213; US 6639055; US 6719971; US ​​6800738; US 7074404; Coussens et al (1985) Science 230:1132-9; Slamon et al (1989) Science 244:707-12; Slamon et al (2001) New Engl. J. Med. 344:783-792). Trastuzumab has been shown to inhibit the proliferation of human tumor cells overexpressing HER2 in both in vitro assays and in animals (Hudziak et al (1989) Mol Cell Biol 9:1165-72; Lewis et al (1993) Cancer Immunol Immunother; 37:255-63; Baselga et al (1998) Cancer Res. 58:2825-2831). Trastuzumab is a mediator of antibody-dependent cytotoxic ADCC (Lewis et al (1993) Cancer Immunol Immunother 37(4):255-263; Instructions 1 / 22 pages 3 CN 121971642 A 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, MacmillanMagazines, Ltd., Vol. 2:127‑137).

[0009] 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 more than 300,000 patients (Slamon DJ, et al., N Engl J Med 2001;344: 783-92; Vogel CL, et al., J Clin Oncol 2002;20:719-26; Marty M, et al., J Clin Oncol 2005;23:4265-74; Romond EH, et al., TN Engl J Med 2005;353:1673-84; Piccart-Gebhart MJ, et al., N Engl J Med). 2005;353:1659-72; Slamon D, et al. [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 containing doxorubicin, cyclophosphamide, and paclitaxel for adjuvant therapy in patients with HER2-positive nodular breast cancer.

[0010] One alternative 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 conjugated to highly potent cytotoxic agents. ADCs represent a novel approach to impart tumor selectivity to systemically administered antitumor therapeutic agents. ADCs are designed to focus the delivery of highly potent cytotoxic agents to tumor cells using tumor-specific and / or overexpressed surface antigens. The potential of this approach is to create a more favorable therapeutic window for such agents than that achievable by administering them as free drugs.

[0011] Maytansinoids, derivatives of the antimitotic drug maytansine, bind to microtubules in a manner similar to that of vinca alkaloids (Issell BF et al (1978) Cancer Treat. Rev. 5:199-207; Cabanillas F et al.).(1979) Cancer Treat Rep, 63:507-9). DM1 is a thiol-containing maytansine alkaloid derived from naturally occurring ester ester P3 (Remillard S, Rebhun LI, Howie GA, et al (1975) Science 189(4207):1002-1005.3; Cassady JM, Chan KK, Floss HG. (2004) Chem Pharm Bull 52(1):1-26.4). The related plant ester maytansine has been studied as a chemotherapeutic agent in approximately 800 patients, administered as a single dose every 3 weeks or for 3 consecutive days at a dose of 2.0 mg / m2 (Issell BF, Crooke ST. (1978) Maytansine. Cancer Treat Rev 5:199-207). Despite preclinical activity, clinical maytansine activity is moderate at doses that can be safely delivered. Dose-limiting toxicities (DLTs) are gastrointestinal, consisting of nausea, vomiting, and diarrhea (often followed by constipation). These toxicities are dose-dependent but not schedule-dependent. Peripheral neuropathy (primarily sensory) has been reported, and it is most pronounced in patients with pre-existing neuropathy. Subclinical transient increases in liver transaminases, alkaline phosphatase, and total bilirubin have been reported. Constitutional toxicities (including asthenia, somnolence, pathological dysphoria, and insomnia) are common. Less common toxicities include infusion site phlebitis and mild myelosuppression. Due to its narrow therapeutic window, further development of the drug was abandoned in the 1980s.

[0012] 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, consists of the cytotoxic agent DM1 (a thiol-containing maytansine alkaloid anti-microtubule agent) conjugated to trastuzumab at the lysine side chain via the MCC linker, with a mean drug load (drug to antibody ratio) of approximately 3.5. Upon binding to HER2 expressed on tumor cells, T-DM1 undergoes receptor-mediated internalization, leading to the intracellular release of DM1-containing cytotoxic degradation metabolites and subsequent cell death.

[0013] In the Phase I study of T-DM1 (TDM3569g), the maximum tolerated dose (MTD) of T-DM1 administered via IV infusion every 3 weeks (q3w) was 3.6 mg / kg. The DLT (dose-limiting toxicity) was 4.8 mg / kg.Transient thrombocytopenia was observed in patients treated with 3.6 mg / kg q3w. Treatment with 3.6 mg / kg q3w was completely tolerated and associated with significant clinical activity. (Krop (2010) J. Clin. Oncol. 28(16):2698-2704). That same study also showed that weekly dosing at 2.4 mg / kg was completely tolerated and had antitumor activity. (Beeram (2012) Cancer 118(23):5733-5740).

[0014] A phase II study (TDM4374g) demonstrated that T-DM1 administered at 3.6 mg / kg q3w had single-agent antitumor activity in a heavily pretreated population of patients with HER2-positive metastatic breast cancer. (Krop (2012) 30(26):3234-3241). A phase III study (TDM4370g, “EMILIA”) demonstrated that in patients with HER2-positive advanced breast cancer (second- and third-line metastatic breast cancer) previously treated with trastuzumab and taxane, T-DM1 administered at 3.6 mg / kg q3w significantly prolonged progression-free survival and overall survival with less toxicity compared to treatment with lapatinib plus capecitabine. (Verma (2012) New England Journal of Medicine 367:1783-1791).

[0015] On February 22, 2013, the U.S. Food and Drug Administration approved ado-trastuzumab-emestane, marketed under the trademark KADCYLA®, for the treatment of patients with HER2-positive metastatic breast cancer who had previously received trastuzumab and taxane.

[0016] Pertuzumab (also known as recombinant humanized monoclonal antibody 2C4, rhuMAb 2C4, PERJETA®, Genentech, Inc, South San Francisco) represents the first in a new class of agents called HER dimerization inhibitors (HDIs) and functions to inhibit the ability of HER2 to form active heterodimers or homodimers with other HER receptors such as EGFR / HER1, HER2, HER3, and HER4. See, for example, 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); Choet al., Nature 421: 756-60 (2003); and Malik et al., Pro Am Soc Cancer Res 44:176-7 (2003).

[0017] Pertuzumab has been shown to block HER2-HER3 heterodimer formation in tumor cells by inhibiting cellular signaling pathways that are crucial for tumor proliferation and survival (Agus et al., Cancer Cell 2: 127-37 (2002)).

[0018] Pertuzumab has been clinically tested as a single agent in phase Ia trials in patients with advanced cancer and phase II trials in patients with ovarian and breast cancer, as well as lung and prostate cancer. In the phase I study, patients with refractory, locally advanced, recurrent, or metastatic solid tumors that had progressed during or after standard therapy were treated with pertuzumab administered intravenously every 3 weeks. Generally, pertuzumab was well tolerated. Tumor regression was achieved in 3 of the 20 evaluable patients. Partial response was confirmed in 2 patients. Stable disease lasting longer 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 2.0–15 mg / kg, the pharmacokinetics of pertuzumab were linear, with mean clearance ranging from 2.69 to 3.74 mL / day / kg and mean terminal elimination half-life ranging from 15.3 to 27.6 days. No antibody against pertuzumab was detected (Allison et al., Pro Am Soc Clin Oncol 22:197 (2003)).

[0019] US 2006 / 0034842 describes a method for treating ErbB-expressing cancers in combination with an anti-ErbB2 antibody. US 2008 / 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, page 3 / 22, CN 121971642, Part I, Col. 25, No. 18S (Supplement 20 June), 2007:1004, reported a combination therapy of trastuzumab and pertuzumab in patients with previously treated HER2-positive breast cancer that had progressed during trastuzumab treatment. Portera et al., J Clin Oncol, 2007 ASCO Annual MeetingProceedings Part I. Vol. 25, No. 18S (Supplement 20 June), 2007:1028 evaluated the efficacy and safety of trastuzumab plus pertuzumab combination therapy in patients with HER2-positive breast cancer who had progressive disease on trastuzumab-based therapy. The authors concluded that further evaluation of the efficacy of the combination therapy was needed to limit the overall risks and benefits of this treatment regimen.

[0020] Pertuzumab has been evaluated in combination with trastuzumab in a phase II study in patients with HER2-positive metastatic breast cancer who had previously received trastuzumab for metastatic disease. A study conducted by the National Cancer Institute (NCI) enrolled 11 patients with previously treated HER2-positive metastatic breast cancer. Two of the 11 patients showed partial response (PR) (Baselga et al., J Clin Oncol 2007 ASCO Annual Meeting Proceedings; 25:18 S (Supplement 20 June): 1004). Results of a phase II neoadjuvant study evaluating the effect of a novel combination regimen of pertuzumab and trastuzumab plus chemotherapy (docetaxel) in women with early HER2-positive breast cancer (presented at the CTRC-AACR San Antonio Breast Cancer Symposium (SABCS), December 8–12, 2010) showed that, compared with trastuzumab plus docetaxel (29.0% pCR), the combination of two HER2 antibodies plus docetaxel in the neoadjuvant setting prior to surgery significantly improved the rate of complete tumor disappearance in the breast (45.8% pathological complete response rate, pCR) by more than half, p=0.014.

[0021] Pertuzumab, marketed under the brand name PERJETA®, was approved in 2012 for the treatment of patients with advanced or advanced-stage (metastatic) HER2-positive breast cancer. HER2-positive breast cancer has increased levels of the HER2 protein, which promotes cancer cell growth and survival.

[0022] On September 30, 2013, the U.S. Food and Drug Administration granted accelerated approval to PERJETA® (pertuzumab) as part of a complete treatment regimen (neoadjuvant background) for patients with early-stage breast cancer (EBC) prior to surgery. PERJETA® was the first FDA-approved drug for neoadjuvant therapy in breast cancer.

[0023] Patent publications related 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; 6,800,738; 8,075,890; 5,648,237; 7,018,809; 6,267,958; 6,685,940; 6,821,515; 7,060,268; 7,682,609; 7,371,376; 6,127,526; 6,333,398; 6,797,814; 6,339,142; 6,417,335; 6,489,447; 7,074,404; 7,531,645; 7,846,441; 7,892,549; 8,075,892; 6,573,043; 6,905,830; 7,129,051; 7,344,840; 7,468,252; 7,674,589; 7,919,254; 6,949,245; 7,485,302; 7,498,030; 7,501,122; 7,537,931; 7,62004 / 0037823; US 2005 / 0002928; US 2007 / 0292419; US 2008 / 0187533; US 2011 / 0250194; US 2012 / 0034213; US 2003 / 0152987; US 2005 / 0100944; US 2006 / 0183150; US 2008 / 0050748; US Specification Page 4 / 22 6 CN 121971642 A 2009 / 0155803; US 2010 / 0120053; US 2005 / 0244417; US 2007 / 0026001; US 2008 / 0160026; US 2008 / 0241146; US 2005 / 0208043; US 2005 / 0238640; US 2006 / 0034842; US 2006 / 0073143; US 2006 / 0193854; US 2006 / 0198843; US 2011 / 0129464; US 2007 / 0184055; US 2007 / 0269429; US 2008 / 0050373; US 2006 / 0083739; US 2009 / 0087432; US 2006 / 0210561; US 2002 / 0035736; US 2002 / 0001587; US 2008 / 0226659; US 2002 / 0090662; US 2006 / 0046270; US 2008 / 0108096; US 2007 / 0166753; US 2008 / 0112958; US 2009 / 0239236; US 202010 / 0015157; US 2006 / 0121044; US 2008 / 0317753; US 2006 / 0165702; US 2009 / 0081223; US 2006 / 0188509; US 2009 / 0155259; US 2011 / 0165157; US 2006 / 0204505; US 2006 / 0212956; US 2006 / 0275305; US 2012 / 0003217; US 2007 / 0009976; US 2007 / 0020261; US 2007 / 0037228;US 2010 / 0112603;US 2006 / 0067930; US 2007 / 0224203; US 2011 / 0064736; US 2008 / 0038271; US ​​2008 / 0050385; US 2010 / 0285010; US 2011 / 0223159; US 2008 / 0102069; US 2010 / 0008975; US 2011 / 0245103; US 2011 / 0246399; US 2011 / 0027190; US 2010 / 0298156; US 2011 / 0151454; US 2011 / 0223619;US 2012 / 0107302;US US 2009 / 0098135; US 2009 / 0148435; US 2009 / 0202546; US 2009 / 0226455; US 2009 / 0317387; US 2011 / 0044977; US 2012 / 0121586. Summary of the Invention

[0024] This invention relates to a method of treating HER2-positive progressive or recurrent locally advanced or previously untreated metastatic breast cancer (first-line metastatic breast cancer) using anti-HER2-matenum alkaloid conjugates, such as trastuzumab-MCC-DM1, in patients who have previously been treated with taxanes. While treatment options exist in adjuvant, neoadjuvant, and metastatic settings for patients with HER2-positive cancer, additional options are needed, including those in the "first-line" metastatic setting, i.e., for patients with previously untreated metastatic breast cancer or patients with locally advanced breast cancer.

[0025] This invention is based in part on the observation that trastuzumab-MCC-DM1 was unexpectedly effective in treating patients with first-line metastatic HER2-positive breast cancer compared to patients who had not previously received taxane treatment.

[0026] In one aspect, the present invention provides a treatment for HER2-positive locally advanced or previously untreated metastatic breast cancer.A method comprising administering a therapeutically effective amount of the antiHER2-matenum alkaloid conjugate to a patient having said breast cancer, wherein the patient has received prior treatment with taxane.

[0027] In another aspect, the present invention provides the use of a therapeutically effective amount of the antiHER2-matenum alkaloid conjugate in the manufacture of a medicament for treating HER2-positive locally advanced or previously untreated metastatic breast cancer in a subject, wherein the subject has received prior treatment with taxane.

[0028] In some embodiments, the administration occurs ≥6 months after the prior treatment with taxane. In some embodiments, the patient has received prior treatment with taxane and at least one HER2-targeted therapy. In one embodiment, the patient has received prior treatment with taxane and trastuzumab. In another embodiment, the patient has received prior treatment with taxane, trastuzumab, and pertuzumab. In some embodiments, the prior treatment is administered in an adjunct setting. (See page 5 / 22 of CN 121971642 A for the instructions). In other embodiments, the prior treatment is administered in a neoadjuvant setting.

[0029] In some other aspects, the present invention provides a method for treating HER2-positive locally advanced or previously untreated metastatic breast cancer, the method comprising (1) determining whether a patient has received prior treatment with taxane, and (2) if the patient has received prior treatment with taxane, administering a therapeutically effective amount of an anti-HER2-matenium alkaloid conjugate to the patient having said breast cancer. In some embodiments, the administration occurs ≥6 months after the prior treatment with taxane. In some embodiments, the patient has received prior treatment with taxane and at least one HER2-targeted therapy. In one embodiment, the patient has received prior treatment with taxane and trastuzumab. In another embodiment, the patient has received prior treatment with taxane, trastuzumab, and pertuzumab. In one embodiment, the prior treatment is administered in an adjuvant setting. In other embodiments, the prior treatment is administered in a neoadjuvant setting.

[0030] In some embodiments of the foregoing aspects, the taxane is palitaxel. In some embodiments, the palitaxel is administered intravenously at 80 mg / m² once weekly. In some embodiments, the palitaxel is administered for at least 18 weeks.

[0031] In other embodiments, the taxane is docetaxel. In some embodiments, the docetaxel is administered intravenously at 75 mg / m² or 100 mg / m² every 3 weeks. In some embodiments, the docetaxel is administered for at least 6 cycles.

[0032] In embodiments where the patient has received prior treatment with taxane and trastuzumab, and in one embodiment, the trastuzumab may be administered intravenously at 8 mg / kg per cycle 1, followed by 6 mg / kg per cycle every 3 weeks.The trastuzumab is administered at a dose of mg / kg. In another embodiment, the trastuzumab may be 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.

[0033] In embodiments where the patient has received prior treatment with taxane, trastuzumab, and pertuzumab, and in one embodiment, the pertuzumab may be administered intravenously at 840 mg on day 1 of cycle 1, followed by 420 mg intravenously every 3 weeks in subsequent cycles.

[0034] In all embodiments, the anti-HER2-matenum alkaloid conjugate may be a trastuzumab-matenum alkaloid conjugate. In some embodiments, the trastuzumab-matenum alkaloid conjugate is a trastuzumab-DM1 conjugate. In one embodiment, the trastuzumab-DM1 conjugate is trastuzumab-MCC-DM1. In some embodiments, the trastuzumab-MCC-DM1 is administered at 3.6 mg / kg every 3 weeks. In other embodiments, the trastuzumab-MCC-DM1 is administered at 2.4 mg / kg weekly.

[0035] In some embodiments of the invention, the breast cancer is previously untreated metastatic breast cancer. Brief Description of the Drawings

[0036] Figure 1 provides a schematic diagram of the structure of the HER2 protein and the amino acid sequences of domains I-IV of its extracellular domains (SEQ ID Nos. 1-4, respectively).

[0037] Figures 2A and 2B depict the amino acid sequences of the variable light (VL) (Figure 2A) and variable heavy (VH) (Figure 2B) domains of the mouse 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 common framework (hum id, light subgroup I; humIII, heavy subgroup III) (SEQ ID Nos. 9 and 10, respectively). An asterisk indicates a difference between the variable domains of pertuzumab and mouse monoclonal antibody 2C4 or between the variable domains of pertuzumab and the human frame. Complementarity-determining regions (CDRs) are enclosed in square brackets.

[0038] Figures 3A and 3B show the amino acid sequences of the light chain (Figure 3A; SEQ ID NO. 11) and heavy chain (Figure 3B; SEQ ID No. 12) of pertuzumab. CDRs are shown in bold. The calculated molecular weights of the light and heavy chains are 23,526.22 Da and 49,216.56 Da (cysteine ​​in reduced form). The carbohydrate module is attached to Asn 299 of the heavy chain.

[0039] Figures 4A and 4B show the light chain (Figure 4A; SEQ ID NO. 13) and heavy chain (Figure 4B; SEQ ID NO. 12) of trastuzumab, respectively.The amino acid sequence of NO. 14). The boundaries of the variable light and variable heavy domains are indicated by arrows.

[0040] Figures 5A and 5B depict the light chain sequence of the variant pertuzumab (Figure 5A; SEQ ID NO. 15) and the heavy chain sequence of the variant pertuzumab (Figure 5B; SEQ ID NO. 16), respectively.

[0041] Figure 6 depicts a schematic diagram of the MARIANNE clinical trial design described in Example 1. a. Locally progressive or recurrent resection that is not suitable for a cure; b. Pertuzumab placebo. LD, loading dose.

[0042] Figure 7 shows the results from the MARIANNE clinical trial described in Example 1. In summary, T-DM1 (KADCYLA®) demonstrated non-inferiority to progression-free survival (PFS) compared to standard care trastuzumab (HERCEPTIN®) + taxane (HT), but it was not superior to HT. However, the data (shaded box) suggests that KADCYLA® outperforms HT in patients who have previously received taxane therapy, indicating that such patients should be selected for KADCYLA® treatment of locally advanced and first-line metastatic Her2-positive breast cancer. Detailed Description

[0043] Certain embodiments of the invention will now be referenced in detail, examples of which are illustrated in the appended structures and formulas. While the invention is described in conjunction with the exemplified embodiments, it should be understood that they are not intended to limit the invention to those embodiments. Rather, the invention is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the invention as defined in the claims. Those skilled in the art will recognize many methods and materials similar to or equivalent to those described herein, which may be used in the practice of the invention. The invention is by no means limited to the methods and materials described.

[0044] All references cited throughout the disclosure are incorporated herein by reference in their entirety. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, usage of terminology, described techniques, etc.), this application shall prevail.

[0045] Definitions

[0046] The terms “comprising” and “including” are used in this specification and claims to prescribe the presence of a described feature, integer, component, or step, but do not exclude the presence or addition of one or more other features, integers, components, steps, or groups thereof.

[0047] The terms “treatment” and “treatment” refer to both therapeutic treatment and preventive or preventative measures, wherein the goal is to prevent or mitigate (alleviate) unwanted physiological changes or conditions, such as hyperproliferative conditions, such as the growth, formation, or spread of cancer. For the purposes of this invention, advantageous or desired clinical outcomes include, but are not limited to: symptom relief, reduction of the severity of the disease, and disease...A stable condition (i.e., no deterioration), delayed or slowed disease progression, improved or alleviated disease status, and remission (whether partial or complete), whether detectable or undetectable. "Treatment / treatment" may also refer to prolonged survival compared to expected survival without treatment. Subjects requiring treatment include those already suffering from the condition or disease, those predisposed to developing the condition or disease, or those seeking to prevent the condition or disease.

[0048] The terms "cancer" and "cancerous" refer to or describe a physiological condition in mammals typically characterized by unregulated cell growth. A "tumor" contains one or more cancerous cells. Examples of cancer include, but are not limited to, carcinomas, lymphomas, blastomas, sarcomas, and leukemias or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), lung cancer (including small cell lung cancer, non-small cell lung cancer (“NSCLC”), lung adenocarcinoma, and lung squamous cell carcinoma), peritoneal cancer, hepatocellular carcinoma, gastric cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer or uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, and head and neck cancer.

[0049] The tumor or cancer is referred to as “Stage 0”, “Stage I”, “Stage II”, “Stage III”, or “Stage IV” and the various sub-stages within this classification. The description page 7 / 22 9 CN 121971642 A indicates that the tumor or cancer is classified using the Overall Stage Grouping or Roman Numeral Staging methods known in the art. While the actual stage of cancer depends on the type of cancer, generally, stage 0 cancer is lesion in situ, stage I cancer is a small localized tumor, stage II and III cancer are locally advanced tumors exhibiting local lymph node involvement, and stage IV cancer represents metastatic cancer. The specific stage of each type of tumor is known to a skilled physician.

[0050] The term “metastatic breast cancer” means a state of breast cancer in which cancer cells spread from the initial site to one or more other sites in the body via blood vessels or lymphatic vessels to form one or more secondary tumors in one or more organs outside the breast.

[0051] The terms “first-line” metastatic breast cancer or “previously untreated” metastatic breast cancer refer to metastatic breast cancer that has not received treatment in a metastatic setting.

[0052] As used herein, the term “locally advanced” breast cancer refers to progressive or recurrent locally advanced breast cancer.

[0053] The term “previously treated” when referring to taxanes means treatment that occurred prior to a first-line metastatic or locally advanced setting. For example, “previously treated” could refer to neoadjuvant, adjuvant, or other settings prior to a first-line metastatic or locally advanced setting.Treatment in the context of cancer.

[0054] “Late-stage” cancer is cancer that has spread outside the site of origin or organ through local invasion or metastasis. Thus, the term “late-stage” cancer includes both locally advanced and metastatic disease.

[0055] “Refractory” cancer is cancer that progresses even when the cancer patient is given antitumor agents, such as chemotherapy. An example of refractory cancer is platinum-refractory cancer.

[0056] “Recurrent” cancer is cancer that has regrown at the initial site or at a distant site in response to initial therapy, such as surgery.

[0057] “Locally recurrent” cancer is cancer that has recurred in the same location as the previously treated cancer after treatment.

[0058] “Operationally resectable” or “resectable” cancer is cancer that is confined to the primary organ and is suitable for surgery (resection).

[0059] “Non-resectable” or “unresectable” cancer cannot be removed (resected) by surgery.

[0060] “HER2-positive” cancer contains cancer cells with higher than normal HER2 levels. Examples of HER2-positive cancers include HER2-positive breast cancer and HER2-positive gastric cancer. Optionally, HER2-positive cancers have an immunohistochemical (IHC) score of 2+ or 3+ and / or an in situ hybridization (ISH) amplification ratio of ≥2.0.

[0061] In this document, “patient” or “subject” refers to a human patient. A patient can be a “cancer patient,” i.e., a patient who has or is at risk of having one or more symptoms of cancer, particularly gastric or breast cancer.

[0062] A “patient population” refers to a group of cancer patients. Such populations can be used to demonstrate statistically significant efficacy and / or safety of drugs, such as pertuzumab.

[0063] A “relapsed” patient is a patient who has signs or symptoms of cancer after regression. Optionally, a patient has relapsed after adjuvant or neoadjuvant therapy.

[0064] A cancer or biological sample that “exhibits HER expression, amplification, or activation” is a sample that expresses (including overexpresses) the HER receptor in a diagnostic test, has an amplified HER gene, and / or otherwise indicates activation or phosphorylation of the HER receptor.

[0065] “Neoadjuvant therapy” or “preoperative therapy” herein refers to therapy administered before surgery. The purpose of neoadjuvant therapy is to provide immediate systemic treatment that can potentially eradicate micrometastases that would otherwise proliferate in a standard sequence following surgery, followed by systemic therapy. Neoadjuvant therapy can also help shrink tumor size, thereby allowing for complete resection of tumors that were initially unresectable or partial preservation of organs and their functions. Furthermore, neoadjuvant therapy allows for in vivo assessment of efficacy, which can guide the selection of subsequent treatments.

[0066] “Adjuvant therapy” herein refers to therapy administered after definitive surgery (in which no evidence of residual disease can be detected).Therapies that reduce the risk of disease recurrence. The goal of adjuvant therapy is to prevent cancer recurrence and thus reduce the chance of cancer-related death. Adjuvant therapy explicitly excludes neoadjuvant therapy in this document.

[0067] “Survival” means that a patient remains alive, including disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS). Survival can be assessed by the Kaplan-Meier method, and any differences in survival can be calculated using stratified time-series tests.

[0068] “Progression-free survival” (PFS) is the time from the first day of treatment to proven disease progression (including isolated CNS progression) or death from any cause of study (whichever occurs first).

[0069] “Disease-free survival (DFS)” means that a patient remains alive for a defined period of time without cancer recurrence since the start of treatment or since the initial diagnosis, such as about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 10 years, etc. In one aspect of the invention, DFS is analyzed according to the principle of treatment intent, i.e., the patient is evaluated based on their assigned therapy. Events used in DFS analysis may include local, regional, and distant cancer recurrence, secondary cancer occurrence, and death from any cause in patients without a prior event (e.g., breast cancer recurrence or a second primary cancer).

[0070] "Overall survival" refers to a patient remaining alive for a defined period of time from treatment initiation or initial diagnosis, such as about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 10 years, etc. In the study on which this invention is based, the event used for survival analysis is death from any cause.

[0071] "Prolonged survival" means DFS and / or OS in patients who are untreated or who receive additional treatment compared to a control treatment regimen. 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 treatment initiation or initial diagnosis.

[0072] The "hazard ratio" in survival analysis is the sum of the differences between two survival curves, representing a reduction in the risk of death with treatment compared to a control during the follow-up period. The hazard ratio is a statistical definition of the event ratio. For the purposes of this invention, the hazard ratio is defined as the probability of an event in the experimental segment at any given time point divided by the probability of an event in the control segment.

[0073] “Monotherapy” means a treatment regimen that includes only a single therapeutic agent to treat cancer or tumor during the course of treatment.

[0074] “Maintenance therapy” means a treatment regimen given to reduce the likelihood of disease recurrence or progression. Maintenance therapy may be provided for any length of time, including extended periods up to the subject’s lifetime. Maintenance therapy may be provided after initial therapy or in combination with initial or other therapies. The dosage used for maintenance therapy may vary and may include a reduced dosage compared to that used for other types of therapy.

[0075] “Definitive surgery” is used as the term is used in the medical community. Definitive surgery includes, for example, procedures, surgeries, or other procedures that result in the removal or excision of a tumor, including those that result in the removal or excision of all visibly visible tumors. Definitive surgery includes, for example, complete or curative excision or total removal of a tumor. Definitive surgery includes procedures performed in one or more stages, and includes, for example, multi-stage surgical procedures in which one or more surgeries or other procedures are performed prior to tumor excision. Definitive surgery includes procedures that remove or excise a tumor, including involved organs, parts of organs and tissues, and surrounding organs, such as lymph nodes, parts of organs, or tissues.

[0076] As defined herein, the terms “trastuzumab,” “HERCEPTIN®,” and “huMAb4D5-8” are used interchangeably. Preferably, such antibodies comprise the light chain and heavy chain amino acid sequences shown in Figure 4A (SEQ ID NO: 13) and Figure 4B (SEQ ID NO. 14), respectively.

[0077] “Epitope 4D5” or “4D5 epitope” or “4D5” refers to the region of the extracellular domain of HER2 that binds to antibody 4D5 (ATCC CRL 10463) and trastuzumab. This epitope is close to the transmembrane domain of HER2 and is within domain IV of HER2. To screen for antibodies that bind to the 4D5 epitope on page 9 / 22 of the specification, conventional cross-blocking assays can be performed, such as those described in Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory, Ed Harlow and David Lane, 1988. Alternatively, epitope mapping can be performed to assess whether the antibody binds to the 4D5 epitope of HER2 (e.g., any one or more residues in the region of HER2 from approximately residue 529 to approximately residue 625 (including the two endpoints).

[0078] “Epitope 2C4” or “2C4 epitope” refers to the region of the extracellular domain of HER2 that binds to antibody 2C4. To screen for antibodies that bind to the 2C4 epitope, conventional cross-blocking assays can be performed, such as those described in *Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory, Ed Harlow and David Lane* (1988). Alternatively, epitope mapping can be performed to assess whether an antibody binds to the HER2 2C4 epitope. Epitope 2C4 contains residues from domain II of the HER2 extracellular domain. 2C4 antibodies and pertuzumab bind to the HER2 extracellular domain at the junction of domains I, II, and III (Franklin et al., *Cancer Cell*).5:317-328 (2004)).

[0079] For the purposes of this document, “pertuzumab”, “PERJETA®” and “rhuMAb 2C4” are used interchangeably. Preferably, such antibodies comprise the light chain and heavy chain amino acid sequences in SEQ ID NO: 7 and 8, respectively. In the case where the pertuzumab is a complete antibody, it preferably comprises an IgG1 antibody; in one embodiment, it comprises the light chain amino acid sequence in SEQ ID NO: 11 or 15 and the heavy chain amino acid sequence in SEQ ID NO: 12 or 16. Optionally, the antibody is generated by recombinant Chinese hamster ovary (CHO) cells.

[0080] As defined herein, the terms “T-DM1,” “trastuzumab-MCC-DM1,” “ado-trastuzumab-emestane,” “trastuzumab-emestane,” and “KADCYLA®” are used interchangeably and refer to trastuzumab linked to the maytenum alkaloid drug module DM1 via the adapter module MCC, including all mixtures of various loaded and attached antibody-drug conjugates, wherein drug modules 1, 2, 3, 4, 5, 6, 7, and 8 are covalently attached to the antibody trastuzumab (US 7097840; US 2005 / 0276812; US 2005 / 0166993).

[0081] In this document, “antitumor agent” means a drug used to treat cancer. Non-limiting examples of antitumor agents in this article include chemotherapeutic agents, HER dimerization inhibitors, HER antibodies, antibodies against tumor-associated antigens, anti-hormonal compounds, cytokines, EGFR-targeting drugs, anti-angiogenic agents, tyrosine kinase inhibitors, growth inhibitors and growth-inhibiting antibodies, cytotoxic agents, apoptosis-inducing antibodies, COX inhibitors, farnesyltransferase inhibitors, antibodies binding to carcinoembryonic protein CA125, HER2 vaccines, Raf or ras inhibitors, doxorubicin liposomes, topotecan, taxanes, dual tyrosine kinase inhibitors, TLK286, EMD-7200, pertuzumab, trastuzumab, erlotinib, and bevacizumab.

[0082] "Chemotherapy" is the use of chemotherapeutic agents that can be used to treat cancer.

[0083] "Chemotherapy agent" refers to a chemical compound that can be used to treat cancer, regardless of its mechanism of action. Chemotherapy agents include, but are not limited to: alkylating agents, antimetabolites, spindle poison plant alkaloids, and cytotoxic / antitumor antibiotics.Antibiotics, topoisomerase inhibitors, antibodies, photosensitizers, and kinase inhibitors. Examples of chemotherapy agents include: erlotinib (TARCEVA®, Genentech / OSI Pharm.), docetaxel (TAXOTERE®, Sanofi-Aventis), 5-FU (fluorouracil, CAS No. 51-21-8), gemcitabine (GEMZAR®, Lilly), PD-0325901 (CAS No. 391210-10-9, Pfizer), cisplatin (cis-diamine, dichloroplatin(II), CAS No. 15663-27-1), carboplatin (CAS No. 41575-94-4), and paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton). NJ), temozolomide (4-methyl-5-oxo-2,3,4,6,8-pentazonobicyclo[4.3.0] Specification 10 / 22 pages 12 CN 121971642 A 9-2,7,9-triene-9-carboxamide, CAS No. 85622-93-1, TEMODAR®, TEMODAL®, Schering Plough), tamoxifen ((Z)-2-[4-(1,2-diphenylbut-1-enyl)phenoxy]-N,N-dimethyl-ethylamine, NOLVADEX®, ISTUBAL®, VALODEX®), and doxorubicin (ADRIAMYCIN®), Akti-1 / 2, HPPD, and rapamycin.

[0084] Further examples of chemotherapy agents include: oxaliplatin (ELOXATIN®, Sanofi), bortezomib (VELCADE®, Millennium Pharm.), sutent (SUNITINIB®, SU11248, Pfizer), letrozole (FEMARA®, Novartis), and imatinib mesylate.mesylate (GLEEVEC®, Novartis), XL-518 (MEK inhibitor, Exelixis, WO 2007 / 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 (Glaxo Smith Kline), 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-modified nanoparticle formulation pallitaxel (American Pharmaceutical Partners, Schaumberg, IL), vandetanib (rINN, ZD6474, ZACTIMA®, AstraZeneca). chloranmbucil, AG1478, AG1571 (SU 5271; Sugen), temsirolimus (TORISEL®, Wyeth), pazopanib (GlaxoSmithKline), canfosfamide (TELCYTA®, Telik), thiotepa, and cyclophosphamideCyclophosphamide (CYTOXAN®, NEOSAR®); alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines, including altretamine, triethylenemelamine, and triethylenephosphoramide. Triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bulbatacin and bulbatacinone); camptothecin (including the synthetic analogue topotecan); bryostatin; Callystatin; CC-1065 (including its synthetic analogs adozelesin, carzelesin, and bizelesin); cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards, such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, mechlorfatine, and methylphenidate.Melphalan, novelbichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas (see page 11 / 22, CN 121971642 A), such as carmustine, chlorozotocin, formustine, lomustine, nimustine, and ranimnustine; antibiotics, such as enediyne antibiotics (e.g., calicheamicin, calicheamicin γ1I, calicheamicin ωI1 (Angew Chem. Intl. Ed. Engl., (1994)). 33:183-186); anthracycline antibiotics (dynemicin), dynemicin A; bisphosphonates, such as clodronate; esperamicin; and neocarzinostatin chromophores and related chromogenic proteins (ene diyne antibiotic chromophores), aclacinomysin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, actinomycin D (dactinomycin), daunorubicin, detorubicin, 6-diazol-5-oxo-L-leucine, morpholinodoxorubicin, cyanomorpholinodoxorubicin, 2-pyrroledoxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acidDrugs containing citric acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as denopterin, methotrexate, pteropterin, and trimetrexate; and purine analogs, such as fludarabine. Arabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, fluxuridine; and androgens, such as calusterone and dromostanolone. Propionate, epitiostanol, mepitiostane, testolactone; anti-adrenergics, such as aminoglutethimide, mitotane, trilostane; folic acid supplements, such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; acridine(amsacrine); bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate); epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids, such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); Razo product information, page 12 / 22, 14 CN 121971642 A razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes (T-2 toxin, verracurin A, roridin) A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactalol; piperobroman; gacytosine; ara binoside (Ara-C); cyclophosphamideCyclophosphamide; Thiotepa; Thioguanine; Mercaptopurine; Methotrexate; Platinum analogs, such as cisplatin and carboplatin; Vinblastine; Etoposide (VP-16); Ifosfamide; Mitoxantrone; Vincristine; Vinorelbine (NAVELBINE®); Novantrone; Teniposide; Edatraxate; Daunomycin; Aminopterin; Capecitabine (XELODA®) Roche); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; and pharmaceutically acceptable salts, acids, and derivatives of any of the above substances.

[0085] The term “effective amount” refers to the amount of drug that is effective in treating cancer in a patient. An effective amount of drug can reduce the number of cancer cells; shrink the size of the tumor; inhibit (i.e., to some extent slow down and preferably prevent) the infiltration of cancer cells into surrounding organs; inhibit (i.e., to some extent slow down and preferably prevent) tumor metastasis; inhibit tumor growth to some extent; and / or alleviate one or more cancer-related symptoms to some extent. Depending on the extent to which the drug can prevent the growth of existing cancer cells and / or kill existing cancer cells, it can be cytoseptic and / or cytotoxic. Effective doses can prolong progression-free survival (e.g., according to the Response Evaluation Criteria for Solid Tumors (RECIST) or a measure of CA-125 change), result in an objective response (including partial response, PR, or complete response, CR), increase overall survival, and / or improve one or more symptoms of cancer (e.g., according to FOSI assessment). The term “effective dose” explicitly includes a dose suitable for achieving any primary or secondary endpoint of the clinical trial described in Example 1.

[0086] “Taxol” is a chemotherapy that inhibits mitosis and interferes with microtubules. Examples of taxanes include palitaxy (TAXOL®; Bristol-Myers Squibb Oncology,Princeton, NJ); cremophor-free, albumin-engineered nanoparticle formulations of palitaxine or nab-palitaxine (ABRAXANE™; American Pharmaceutical Partners, Schaumberg, Illinois); and docetaxel (TAXOTERE®; Rhône-Poulenc Rorer, Antony, France).

[0087] "Anthracycline antibiotics" are a class of antibiotics derived from the fungus *Streptococcus peucetius*, examples of which include: daunorubicin, doxorubicin, and epirubicin, etc.

[0088] "Anthracycline-based chemotherapy" refers to a chemotherapy regimen consisting of or containing one or more anthracycline antibiotics. Examples include 5-FU, epirubicin, and cyclophosphamide (FEC); 5-FU, doxorubicin, and cyclophosphamide (FAC); doxorubicin and cyclophosphamide (AC); epirubicin and cyclophosphamide (EC); etc.

[0089] For the purposes of this document, “carboplatin-based chemotherapy” means a chemotherapy regimen consisting of or containing one or more carboplatins. An example is TCH (docetaxel / TAXOL®, carboplatin, and trastuzumab / HERCEPTIN®).

[0090] “Aromatase inhibitors” inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands. Aromatase inhibitors are described in the specification 13 / 22 pages 15 CN 121971642 A. Examples 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.

[0091] "Antimetabolite chemotherapy" refers to the use of agents that are structurally similar to metabolites but cannot be utilized by the body in a productive manner. 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, and pemetrexed.Raltitrexed, arabinosylcytosine (ARA-C cytarabine) (CYTOSAR-U®), dacarbazine (DTIC-DOME®), azocytosine, deoxycytosine, pyridmidene, fludarabine (FLUDARA®), cladrabine, 2-deoxy-D-glucose, etc.

[0092] “Chemotherapy-resistant” cancer means that a cancer patient has progressed despite receiving a chemotherapy regimen (i.e., the patient is “chemotherapy-refractory”), or that the patient has progressed within 12 months (e.g., within 6 months) after completing a chemotherapy regimen.

[0093] The term “platinum” is used herein to refer to platinum-based chemotherapy, including but not limited to cisplatin, carboplatin, and oxaliplatin.

[0094] The term “fluoropyrimidine” is used herein to refer to antimetabolite chemotherapy, including but not limited to capecitabine, fluorouridine, and fluorouracil (5-FU).

[0095] A “fixed” or “flat” dose of a therapeutic agent refers herein to a dose administered to a human patient regardless of the patient’s weight (WT) and body surface area (BSA). Therefore, a fixed or flat dose is not provided as a mg / kg dose or mg / m2 dose, but as an absolute amount of the therapeutic agent.

[0096] A “load” dose or “LD” generally includes herein an initial dose of the therapeutic agent administered to a patient, followed by one or more maintenance doses thereof. Generally, a single load dose is administered, but multiple load doses are also contemplated herein. Typically, the amount of the load dose administered exceeds the amount of the maintenance dose administered, and / or the load dose is administered more frequently than the maintenance dose, thereby reaching the desired steady-state concentration of the therapeutic agent earlier than with the maintenance dose.

[0097] A “maintenance” dose herein refers to one or more doses of a therapeutic agent administered to a patient during the treatment period. Typically, a maintenance dose is administered at therapeutic intervals, such as approximately weekly, approximately every two weeks, approximately every three weeks, or approximately every four weeks, preferably every three weeks.

[0098] “Infusion” refers to the introduction of a solution containing a drug into the body via a vein for therapeutic purposes. Generally, this is achieved via an intravenous (IV) bag.

[0099] An “intravenous bag” or “IV bag” is a bag that can hold a solution that can be administered via a patient’s vein. In one embodiment, the solution is a saline solution (e.g., about 0.9% or about 0.45% NaCl). Optionally, the IV bag is formed of polyolefin or polyvinyl chloride.

[0100] “Co-administration” means the intravenous administration of two (or more) drugs during the same administration period, rather than sequential infusion.Note two or more drugs. Generally, this involves combining two (or more) drugs into the same IV bag before their co-administration.

[0101] Drugs administered "in parallel" with one or more other drugs during the same treatment cycle, on the same treatment day, and optionally at the same time as one or more other drugs. For example, for cancer therapy given every 3 weeks, on page 14 / 22 of the instructions for use, 16 CN 121971642 A, each drug administered in parallel is given on day -1 of the 3-week cycle.

[0102] "Cardiotoxicity" refers to any toxic side effect that affects the heart and is derived from the administration of the drug or combination of drugs. Cardiotoxicity is assessed based on 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 ejection fraction (LVEF).

[0103] The phrase “in cases where there is no increase in cardiotoxicity of a combination of drugs containing pertuzumab” refers to the occurrence of cardiotoxicity equal to or less than that observed in patients treated with a drug in the combination of drugs different from pertuzumab (e.g., equal to or less than cardiotoxicity derived from administration of trastuzumab and chemotherapy, such as docetaxel).

[0104] “Tube bottle” is a container suitable for containing liquid or lyophilized formulations. In one embodiment, the tube bottle is a disposable tube bottle, such as a 20-cc disposable tube bottle with a stopper.

[0105] The term “packaging insert” is used to refer to instructions for use typically included in the commercial packaging of a therapeutic product, which contains information regarding the indications, usage, dosage, administration, contraindications, and / or warnings relating to the use of such therapeutic products.

[0106] An “adverse event” is any adverse and unwanted sign, symptom, or illness that is transiently associated with the use of an intervention (regardless of its nature) imposed by an investigation (medical) product or other protocol; and includes: an AE that occurred during the protocol-defined AE reporting period that was not previously observed in the patient, including signs or symptoms related to breast cancer that were not present before the AE reporting period; complications arising from a protocol-mandated intervention (e.g., invasive procedures such as biopsy); AEs that occurred prior to the allocation of study treatment related to drug clearance, no-treatment operation, or other protocol-mandated interventions, if applicable; and pre-existing medical conditions (other than study conditions) that the investigator judges to have worsened in severity or frequency or changed in characteristics during the protocol-defined AE reporting period.

[0107] An adverse event is classified as a “serious adverse event” (SAE) if it meets the following criteria: resulting in death (i.e., the AE actually causes or results in death); life-threatening (i.e., the AE, in the investigator’s opinion, puts the patient at immediate risk of death, but does not include AEs that could have caused death if they occurred in a more serious form); requiring or prolonging the patient’s hospitalization.Severity AEs are defined as: hospitalization; resulting in lasting or significant disability / incapacity (i.e., AEs that substantially impair a patient's ability to perform normal daily activities); resulting in congenital malformations / birth defects in newborns / infants born to mothers exposed to the investigated product; or medical events deemed significant by the investigated person based on medical judgment (e.g., events that could endanger the patient or require medical / surgical intervention to prevent one of the consequences listed above). All AEs deemed not to meet any severity criteria are considered non-severe AEs. The terms "severe" and "serious" are not synonymous. Severity (or intensity) refers to the grade of a particular AE, such as mild (Grade 1), moderate (Grade 2), or severe (Grade 3) myocardial infarction (see Section 5.2.2). "Severe" is a management definition (see previous definition) and is a behavioral standard based on the patient or event consequences or generally related to an event that threatens the patient's life or functioning. Severity (not severity) serves as a guideline for defining management reporting obligations from the initiator to the applicable management authority. Severity and severity should be independently assessed when AEs and SAEs are documented on the eCRF.

[0108] Detailed Description

[0109] This invention is based in part on the observation that trastuzumab-MCC-DM1 is unexpectedly effective in treating patients with first-line metastatic HER2-positive breast cancer compared to patients who have not previously received taxane treatment. This invention provides a method for treating HER2-positive progressive or recurrent locally advanced or previously untreated metastatic breast cancer (first-line metastatic breast cancer) using an anti-HER2-matenum alkaloid conjugate, such as trastuzumab-MCC-DM1, in patients who have previously been treated with taxane. While treatment options exist in adjuvant, neoadjuvant, and metastatic settings for patients with HER2-positive cancer, additional options are needed, including in the “first-line” metastatic setting, i.e., for patients with previously untreated metastatic breast cancer or patients with locally advanced breast cancer. In summary, T-DM1 demonstrated non-inferiority in progression-free survival (PFS) compared to standard care HERCEPTIN + taxane (HT), but according to the product information page 15 / 22, 17 CN 121971642 A, it was not superior to HT. However, data suggest that T-DM1 outperforms HT in patients who have previously received taxane therapy, indicating that such patients should be selected for treatment with anti-HER2-matenum alkaloid conjugates, such as trastuzumab-MCC-DM1, for locally advanced and first-line metastatic HER2-positive breast cancer.

[0110] Trastuzumab-MCC-DM1 (T-DM1)

[0111] The present invention includes trastuzumab-MCC-DM1 (T-DM1), an antibody-drug conjugate (CAS Reg. No.).Therapeutic treatment of trastuzumab-MCC-DM1 (T-DM1) has the following structure:

[0112]

[0113] where Tr is trastuzumab, which is linked to the maytenum alkaloid drug module DM1 via the adapter module MCC (US 5208020; US 6441163). 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 an integer value of about 8. Trastuzumab-MCC-DM1 comprises all mixtures of various loaded and attached antibody-drug conjugates, wherein 1, 2, 3, 4, 5, 6, 7, and 8 drug modules are covalently attached to the antibody trastuzumab (US 7097840; US 2005 / 0276812; US 2005 / 0166993). The average drug loading is about 3.5.

[0114] Trastuzumab can be generated from mammalian cell (Chinese hamster ovary, CHO) suspension cultures. The HER2 (or c-erbB2) proto-oncogene encodes a 185 kDa transmembrane receptor protein that is structurally associated with the epidermal growth factor receptor. Trastuzumab is an antibody containing or derived from mouse 4D5 antibody antigen-binding residues. (ATCC CRL 10463, deposited on May 24, 1990, at the American Center for Type Culture Collection, 12301 Parklawn Drive, Rockville, Md. 20852, pursuant to the Budapest Treaty.) Exemplary humanized 4D5 antibodies include huMAb4D5-1, huMAb4D5-2, huMAb4D5-3, huMAb4D5-4, huMAb4D5-5, huMAb4D5-6, huMAb4D5-7, and huMAb4D5-8 (HERCEPTIN®), as in US 5821337.

[0115] For example, trastuzumab-MCC-DM1 can be prepared according to Example 1 of U.S. Application Publication No. 20110165155.

[0116] Formulation of anti-HER2-maytenoid conjugates

[0117] Anti-HER2-maytenoid conjugates, such as trastuzumab-MCC-DM1, can be formulated according to standard pharmaceutical practices used in treatment combinations. The pharmaceutical composition comprises trastuzumab-MCC-DM1 conjugated with one or more pharmaceutically acceptable carriers, gliding agents, diluents, or excipients.

[0118] Suitable carriers, diluents, and excipients are well known to those skilled in the art and include substances such as carbohydrates, waxes, water-soluble and / or expandable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water, etc. The specific carrier, diluent, or excipient used will depend on the means and purpose of applying the compounds of the present invention. GenerallySolvents are selected based on those generally recognized by those skilled in the art as being safe for mammalian administration (GRAS). Generally, the solvents described in Safety Data Sheet 16 / 22, page 18, CN 121971642 A, are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG 400, PEG 300), and mixtures thereof. Formulations may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow aids, handling aids, colorants, sweeteners, flavoring agents, tasters, and other known additives to provide a refined appearance for the pharmaceutical product (i.e., the compound of the present invention or a pharmaceutical composition thereof) or to aid in the manufacture of the pharmaceutical product (i.e., the drug).

[0119] Formulations can be prepared using conventional dissolution and mixing procedures. For example, a bulk pharmaceutical substance (i.e., a compound of the present invention or a stabilized form of the compound (e.g., in combination with a cyclodextrin derivative or other known complexing agent)) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. The compounds of the present invention are typically formulated in pharmaceutical dosage forms to provide a drug with easily controllable dosage and to ensure patient compliance with the prescription regimen.

[0120] Pharmaceutical compositions (or formulations) for supply can be packaged in a variety of ways, depending on the method of administration. Generally, the dispensing articles include containers in which the pharmaceutical formulation is placed in a suitable form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), capsules, ampoules, plastic bags, metal tubes, etc. Containers may also include anti-interference devices to prevent accidental access to the contents of the package. Additionally, a label describing the contents of the container is placed on the container. The label may also include appropriate warnings.

[0121] Pharmaceutical formulations can be formulated in the form of lyophilized formulations, crushed powders, or aqueous solutions using pharmaceutically acceptable diluents, carriers, excipients, or stabilizers (Remington's Pharmaceutical Sciences (1995) 18th edition, Mack Publ. Co., Easton, PA) for administration via various routes and types. Formulation can be performed by mixing with a physiologically acceptable carrier (i.e., a carrier that is non-toxic to the recipient at the dose and concentration used) at ambient temperature and a suitable pH, and to the desired purity. The pH of the formulation depends primarily on the specific application and the concentration of the compound, but can range from about 3 to about 8.

[0122] Pharmaceutical formulations are preferably sterile. Specifically, formulations intended for in vivo administration must be sterile. This sterility is readily achieved through filtration via a sterile filter membrane.

[0123] Pharmaceutical formulations can generally be stored as solid compositions, lyophilized formulations, or as aqueous solutions.

[0124] The pharmaceutical formulations of this invention will be administered and dosed in accordance with good medical practice, namely, in terms of dosage, concentration, schedule, course of treatment, medium, and route of administration. Factors to be considered in this context include the specific condition being treated, the individual patient's clinical condition, the cause of the condition, the site of drug delivery, the method of administration, the schedule of administration, and other factors known to a medical practitioner.

[0125] Acceptable diluents, carriers, excipients, and stabilizers are non-toxic to the recipient at the doses and concentrations used, and include: buffers such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; chlorohexammonium; benzalkonium chloride, benzyl chloride; phenol, butanol, ethanol, or benzyl alcohol; p-hydroxybenzoic acid hydrocarbon esters, such as methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) peptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, etc. 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 nonionic surfactants, such as TWEEN™ (including Tween 80), PLURONICS™, or polyethylene glycol (PEG) (including PEG400). The active pharmaceutical ingredient may also be encapsulated, for example, in microcapsules prepared by coagulation techniques or by interfacial polymerization (e.g., hydroxymethyl cellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively), in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or in coarse-drop emulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences, 18th edition, (1995) Mack Publ. Co., Easton, PA. Other examples of pharmaceutical formulations can be found in Liberman, H. A. and Lachman, L. (eds.), Pharmaceutical Dosage Forms, Marcel Decker, Vol. 3, 2nd Ed., New York, NY.

[0126] Pharmaceutical formulations include those suitable for the routes of administration detailed herein. Formulations may be readily available in unit dose form and may be prepared by any method known in the pharmaceutical field. Techniques and formulations are generally found inRemington's Pharmaceutical Sciences, 18th Edition (1995), Mack Publishing Co., Easton, PA. Such methods involve the step of combining an active ingredient with a carrier constituting one or more auxiliary components. Generally, formulations are prepared by uniformly and tightly combining the active ingredient with a liquid carrier or a pulverized solid carrier, or both, and then, if necessary, shaping the product.

[0127] The pharmaceutical composition may be in the form of a sterile injectable formulation, such as a sterile injectable aqueous or oily suspension. Such suspensions may be formulated using suitable dispersants or wetting agents and suspending agents described above, in accordance with known techniques. Sterile injectable formulations may be solutions or suspensions in non-toxic parenteral acceptable diluents or solvents, such as in 1,3-butanediol or solutions prepared from lyophilized powders. Water, Ringer's solution, and isotonic sodium chloride solution are among the acceptable media and solvents that may be used. Additionally, sterile non-volatile oils may be conveniently used as solvents or suspension media. For this purpose, any mild, non-volatile oil, including synthetic monoglycerides or diesters, can be used. Additionally, fatty acids such as oleic acid can also be used to prepare injectable formulations.

[0128] The amount of active ingredient that can be combined with a carrier material to produce a single dose varies depending on the host being treated and the specific mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of the active material combined with an appropriate and convenient amount of carrier material, which may vary from approximately 5% to approximately 95% (by weight) of the total composition. Pharmaceutical compositions can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain approximately 3 to 500 μg of the active ingredient per milliliter of solution to allow for the infusion of a suitable volume at a rate of approximately 30 mL / hour.

[0129] Suitable formulations for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may include suspending agents and thickeners.

[0130] Formulations may be packaged in unit-dose or multi-dose containers, such as sealed ampoules and tubular vials, and may be stored under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile liquid carrier, such as water, for immediate injection before use. Solutions and suspensions for temporary injection are prepared from sterile powders, granules, and tablets of the types described above. Preferred unit-dose formulations are those containing the active component as described above at a daily dose or a unit daily sub-dose or a suitable portion thereof.

[0131] As a general recommendation, the initial pharmaceutically effective amount of trastuzumab-MCC-DM1 per dose is approximately 0.3 to 15.The range of mg / kg / day for patients is within the range of body weight.

[0132] The commercial T-DM1 formulation (KADCYLA®, ado-trastuzumab-metasin) is a sterile, white to off-white, preservative-free lyophilized powder in single-use tubular vials. Each tubular vial contains 100 mg or 160 mg of ado-trastuzumab-metasin. After reconstitution, each single-use tubular vial contains ado-trastuzumab-metasin (20 mg / mL), Polysorbate 20 [0.02% (w / v)], sodium succinate (10 mM), and sucrose [6% (w / v)], with a pH of 5.0 and a density of 1.026 g / mL. The resulting solution containing 20 mg / mL ado-trastuzumab-metasin is administered by intravenous infusion after dilution. Instructions for Use, Pages 18 / 22, 20 CN 121971642 A

[0133] Formulations of Pertuzumab

[0134] The commercial formulation of pertuzumab (PERJETA®) contains 420 mg / 14 mL (30 mg / mL) of pertuzumab in a preservative-free solution for IV infusion.

[0135] Administration of the Pharmaceutical Composition

[0136] The pharmaceutical composition described herein may be administered via any route suitable for the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intra-arterial, inhalation, intradermal, intrathecal, epidural, and infusion techniques), transdermal, rectal, nasal, surface (including oral and sublingual), vaginal, intraperitoneal, intrapulmonary, and intranasal administration. Surface administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. For local immunosuppressive therapy, the compound may be administered via intralesional administration, including perfusion or otherwise exposing the graft to the inhibitor prior to transplantation. It should be understood that the preferred route can vary depending on, for example, the recipient's condition. If the compound is administered orally, it can be formulated into pills, capsules, tablets, etc., together with a pharmaceutically acceptable carrier, gliding agent, or excipient. If the compound is administered parenterally, it can be formulated in a unit-dose injectable form together with a pharmaceutically acceptable parenteral medium or diluent, as detailed below.

[0137] Products

[0138] Products containing anti-HER2-maedentem alkaloid conjugates, such as trastuzumab-MCC-DM1, which can be used in the treatments described herein, or "kits" are provided. In one embodiment, the kit comprises a container containing trastuzumab-MCC-DM1. The kit may further comprise a label or packaging insert, which is on or associated with the container. The term "packaging insert" is used to refer to instructions for use typically included in the commercial packaging of therapeutic products, which contain information about indications, usage, dosage, administration, contraindications, and / or warnings relating to the use of such therapeutic products. Suitable container packagingContainers, including, for example, bottles, tubular vials, syringes, blister packs, etc., can be formed from various materials, such as glass or plastic. Containers may contain an anti-HER2-maedentem alkaloid conjugate, such as trastuzumab-MCC-DM1 or a formulation thereof, which is effective for use in the treatments described herein, and may have a sterile access port (e.g., the container may be an intravenous solution bag or tubular vial with a stopper pierced by a subcutaneous needle). Labels or packaging inserts indicate the composition for use in the treatment of the disease, as described and claimed herein. The product may also contain other containers containing pharmaceutically acceptable buffers, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextran solution. It may further include other materials desired from a commercial and user perspective, including other buffers, diluents, filters, needles, and syringes.

[0139] The kit may further include instructions regarding the administration of trastuzumab-MCC-DM1. For example, if the kit includes a first composition comprising trastuzumab-MCC-DM1 and a second drug formulation, then the kit may further include instructions on administering the first and second drug compositions simultaneously, sequentially, or separately to patients in need.

[0140] Examples

[0141] For the purpose of illustrating the invention, the accompanying drawings, the foregoing summary of the drawings, and the examples provided in the following examples are included. However, it is to be understood that these examples are not intended to limit the invention and are merely intended to illustrate methods of carrying out the invention.

[0142] Example 1

[0143] Phase III Clinical Study

[0144] This study (clinicaltrials.gov identifier # NCT01120184; study number BO22589) was a randomized, 3-branch, multicenter, phase III study evaluating the efficacy and safety of trastuzumab-metasin (T-DM1) with pertuzumab, or trastuzumab-metasin alone (T-DM1) (i.e., pertuzumab-placebo) compared to a combination of trastuzumab (Herceptin) plus taxane (docetaxel or palitaxel) in patients with HER2-positive progressive or recurrent locally advanced or previously untreated metastatic breast cancer (see Figure 6).

[0145] Stratification factors: World region, prior neoadjuvant therapy (if: prior trastuzumab / lapatinib), visceral package insert 19 / 22 pages 21 CN 121971642 A disease.

[0146] Primary endpoint: Progression-free survival (PFS) assessed by an independent review body (IRF), and assessment of non-inferiority and superiority.

[0147] Key secondary endpoints: Overall survival (OS), PFS (investigator-assessed), objective response rate (ORR), safety, and patient-reported outcomes.

[0148] The inclusion and exclusion criteria for this study are as follows:

[0149] Criteria

[0150] The inclusion criteria are as follows: 1) Adult patients > / = 18 years of age; 2) HER2-positive breast cancer; 3) Histologically or cytologically confirmed breast adenocarcinoma with locally recurrent or metastatic disease, and a candidate for chemotherapy. Patients with locally advanced disease must have recurrent or progressive disease and must not be suitable for curative resection; 4) Patients must have measurable and / or non-measurable disease that is evaluable according to RECIST 1.1; 5) ECOG performance status 0 or 1; 6) Organ function is determined to be adequate based on laboratory results.

[0151] Exclusion criteria were as follows: 1) a history of prior (or any) chemotherapy for metastatic breast cancer or recurrent locally advanced disease; 2) an interval of <6 months from the last dose of vinca alkaloid or taxane cytotoxic chemotherapy to the time of metastatic diagnosis; 3) hormone therapy <7 days prior to randomization; 4) trastuzumab therapy and / or lapatinib (new or adjuvant setting) <21 days prior to randomization; 5) prior trastuzumab-emestane or pertuzumab therapy.

[0152] Outcome measures were as follows:

[0153] The primary outcome was assessed using the following measures: 1) progression-free survival (PFS) based on tumor assessment performed by an independent review body (IRF); and 2) incidence of adverse events (AEs).

[0154] Secondary outcomes were assessed using the following measures: 1) overall survival (OS) cutoff at 2 years; 2) 1-year survival rate; 3) overall survival (OS) rate; 4) overall or objective response rate; 5) duration of response; 6) time to treatment failure as assessed by an independent review body (IRF); and 7) clinical benefit rate.

[0155] As shown in Figure 7, the data suggest a favorable effect of T-DM1 (Kadcyla®) for patients with first-line metastatic HER2-positive breast cancer who have previously received taxane therapy.

[0156] This disclosure relates to the following embodiments.

[0157] 1. A method of treating HER2-positive locally advanced or previously untreated metastatic breast cancer, the method comprising administering a therapeutically effective amount of an anti-HER2-maytenoid alkaloid conjugate to a patient having said breast cancer, wherein the patient has received prior treatment with taxane.

[0158] 2. The method of embodiment 1, wherein the administration of the taxane occurs ≥6 months after prior treatment.

[0159] 3. The method of embodiment 1 or 2, wherein the patient has received prior treatment with taxane and at least one HER2-targeted therapy.

[0160] 4. The method of embodiment 3, wherein the patient has received prior treatment with taxane and trastuzumab.

[0161] 5. The method of embodiment 4, wherein the patient has received prior treatment with taxane, trastuzumab, and pertuzumab.

[0162] 6. The method of any one of embodiments 1-5, wherein the prior treatment is administered in an auxiliary setting.

[0163] 7. The method of any one of embodiments 1-5, wherein the prior treatment is administered in a new auxiliary setting.

[0164] 8. The method of any one of the prior embodiments, wherein the taxane is palitaxetine.

[0165] 9. The method of embodiment 8, wherein the palitaxetine is administered intravenously at 80 mg / m2 once weekly.

[0166] 10. The method of embodiment 9, wherein the palitaxetine is administered for at least 18 weeks.

[0167] 11. The method of any one of embodiments 1-7, wherein the taxane is docetaxel.

[0168] 12. The method of embodiment 11, wherein the docetaxel is administered intravenously at 75 mg / m2 or 100 mg / m2 every 3 weeks.

[0169] 13. The method of embodiment 12, wherein the docetaxel is administered for at least 6 cycles.

[0170] 14. The method of any one of embodiments 4-13, wherein the trastuzumab is administered intravenously at 8 mg / kg in cycle 1, followed by 6 mg / kg every 3 weeks in subsequent cycles.

[0171] 15. The method of any one of embodiments 4-13, wherein the trastuzumab is administered intravenously at 4 mg / kg on day 1 of cycle 1, followed by 2 mg / kg weekly starting from day 8 of cycle 1.

[0172] 16. The method of any one of embodiments 5-15, wherein the pertuzumab is administered intravenously at 840 mg on day 1 of cycle 1, followed by 420 mg intravenously every 3 weeks in subsequent cycles.

[0173] 17. The method of any one of the prior embodiments, wherein the anti-HER2-matenum alkaloid conjugate is a trastuzumab-matenum alkaloid conjugate.

[0174] 18. The method of embodiment 17, wherein the trastuzumab-matenum alkaloid conjugate is a trastuzumab-DM1 conjugate.

[0175] 19. The method of embodiment 18, wherein the trastuzumab-DM1 conjugate is trastuzumab-MCC-DM1.

[0176] 20. The method of embodiment 19, wherein the trastuzumab-MCC-DM1 is administered at 3.6 mg / kg every 3 weeks.

[0177] 21. The method of embodiment 19, wherein the trastuzumab-MCC-DM1 is administered at 2.4 mg / kg weekly.

[0178] 22. The method of any of the preceding embodiments, wherein the breast cancer is previously untreated metastatic breast cancer.

[0179] 23. A method for treating HER2-positive locally advanced or previously untreated metastatic breast cancer, the method comprising (1) determining whether the patient has received prior treatment with taxane, and (2) if the patient has received prior treatment with taxane...In the prior treatment, a therapeutically effective amount of the anti-HER2-matenium alkaloid conjugate is administered to the patient with said breast cancer.

[0180] 24. The method of embodiment 23, wherein the administration occurs ≥6 months after the prior treatment with the taxane.

[0181] 25. The method of embodiment 23 or 24, wherein the patient has received prior treatment with taxane and at least one HER2-targeted therapy.

[0182] 26. The method of embodiment 25, wherein the patient has received prior treatment with taxane and trastuzumab.

[0183] 27. The method of embodiment 26, wherein the patient has received prior treatment with taxane, trastuzumab, and pertuzumab.

[0184] 28. The method of any one of embodiments 23-27, wherein the prior treatment is administered in an adjuvant setting.

[0185] 29. The method of any one of embodiments 23-27, wherein the prior treatment is administered in a neoadjuvant setting.

[0186] 30. The method of any one of embodiments 23-29, wherein the taxane is palitaxel.

[0187] 31. The method of embodiment 30, wherein the palitaxel is administered intravenously at 80 mg / m² once weekly.

[0188] 32. The method of embodiment 31, wherein the palitaxel is administered for at least 18 weeks.

[0189] 33. The method of any one of embodiments 23-30, wherein the taxane is docetaxel.

[0190] 34. The method of embodiment 33, wherein the docetaxel is administered intravenously at 75 mg / m² or 100 mg / m² every 3 weeks.

[0191] 35. The method of embodiment 34, wherein the docetaxel is administered for at least 6 cycles.

[0192] 36. The method of any one of embodiments 26-35, wherein the trastuzumab is administered intravenously at 8 mg / kg in cycle 1, followed by 6 mg / kg every 3 weeks in subsequent cycles.

[0193] 37. The method of any one of embodiments 26-35, wherein the trastuzumab is administered intravenously at 4 mg / kg on day 1 of cycle 1, followed by 2 mg / kg once weekly starting on day 8 of cycle 1.

[0194] 38. The method of any one of embodiments 27-37, wherein the pertuzumab is administered intravenously at 840 mg on day 1 of cycle 1, followed by 420 mg intravenously every 3 weeks in subsequent cycles.

[0195] 39. The method of any one of embodiments 23-38, wherein the anti-HER2-matenum alkaloid conjugate is a trastuzumab-matenum alkaloid conjugate.

[0196] 40. The method of embodiment 39, wherein the trastuzumab-matenum alkaloid conjugate is a trastuzumab-DM1 conjugate.

[0197] 41. The method of embodiment 40, wherein the trastuzumab-DM1 conjugate is trastuzumab-MCC-DM1.

[0198] 42. The method of embodiment 41, wherein the trastuzumab-MCC-DM1 is administered at 3.6 mg / kg every 3 weeks.

[0199] 43. The method of embodiment 41, wherein the trastuzumab-MCC-DM1 is administered at 2.4 mg / kg weekly.

[0200] 44. The method of any one of embodiments 23-43, wherein the breast cancer is previously untreated metastatic breast cancer. Instruction manual 22 / 22 pages 24 CN 121971642 A Figure 1 Instruction manual Figure 1 / 9 pages 25 CN 121971642 A Figure 2A Figure 2B Instruction manual Figure 2 / 9 pages 26 CN 121971642 A Figure 3A Figure 3B Instruction manual Figure 3 / 9 pages 27 CN 121971642 A Figure 4A Instruction manual Figure 4 / 9 pages 28 CN 121971642 A Figure 4B Instruction manual Figure 5 / 9 pages 29 CN 121971642 A Figure 5A Instruction manual Figure 6 / 9 pages 30 CN 121971642 A Figure 5B Instruction manual Figure 7 / 9 pages 31 CN 121971642 A Figure 6 Instruction manual Figure 8 / 9 pages 32 CN 121971642 A Figure 7 Instruction manual Figure 9 / 9 pages 33 CN 121971642 A Abstract Abdominal ultrasound examination method, system and device METHODS OF TREATING HER2-POSITIVE LOCALLY ADVANCED OR PREVIOUSLY UNTREATED METASTATIC BREAST CANCER The present invention mainly relates to methods for treating HER2-positive, locally advanced or previously untreated metastatic breast cancer. Specifically, methods of treating patients having HER2-positive, locally advanced or previously untreated metastatic breast cancer.metastatic breast cancer having received prior treatment with a taxane using an anti-HER2-maytansinoid conjugate (for example trastuzumab emtansine) are provided.

Claims

1. A method for treating HER2-positive locally advanced or previously untreated metastatic breast cancer, the method comprising administering a therapeutically effective amount of an antiHER2-matenium alkaloid conjugate to a patient having said breast cancer, wherein the patient has received prior treatment with taxane.

2. The method of claim 1, wherein the administration of the taxane occurs ≥6 months after prior treatment with the taxane.

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

4. The method of claim 3, wherein the patient has received prior treatment with taxane and trastuzumab.

5. The method of claim 4, wherein the patient has received prior treatment with taxane, trastuzumab, and pertuzumab.

6. The method of any one of claims 1-5, wherein the prior treatment is applied in an auxiliary setting.

7. The method of any one of claims 1-5, wherein the prior treatment is applied in the new auxiliary setting.

8. The method of any of the prior claims, wherein the taxane is palitaxetine.

9. The method of claim 8, wherein the palitaxetine is administered intravenously at a dose of 80 mg / m2 once weekly.

10. The method of claim 9, wherein the palitaxol is administered for at least 18 weeks.

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