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HK40012811A - Treatment of advanced her2 expressing cancer - Google Patents

Treatment of advanced her2 expressing cancer Download PDF

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Publication number
HK40012811A
HK40012811A HK62020002145.4A HK62020002145A HK40012811A HK 40012811 A HK40012811 A HK 40012811A HK 62020002145 A HK62020002145 A HK 62020002145A HK 40012811 A HK40012811 A HK 40012811A
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Hong Kong
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her2
cancer
pertuzumab
trastuzumab
advanced
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HK62020002145.4A
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Chinese (zh)
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Mary BEATTIE
Melissa BRAMMER
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豪夫迈•罗氏有限公司
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Description

Treatment of advanced HER2 expressing cancers
Sequence listing
This application contains a sequence listing, has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy created on 3/10/2017 was named GNE _0428_ PCT _ sl. txt and was 32,760 bytes in size.
Technical Field
The present invention relates to the treatment of patients with HER2 positive, HER2 amplified and/or HER2 mutated cancer, such as colorectal, biliary, urothelial, bladder, salivary gland, lung, pancreatic, ovarian, prostate, or skin (apocrine) cancer, by administering pertuzumab plus trastuzumab. In one aspect, the cancer is an advanced HER2 positive, HER2 amplified and/or HER2 mutated colorectal, biliary, urothelial, bladder, salivary gland, lung, pancreatic, ovarian, prostate, or skin (apocrine) cancer. In another aspect, the cancer is a HER2 positive, HER2 amplified and/or HER2 mutated colorectal, biliary, urothelial, bladder, salivary gland, lung, pancreatic, ovarian, prostate, or skin (apocrine) cancer that is refractory to one or more other treatment regimens.
Background
Members of the HER receptor tyrosine kinase family are important mediators of cell growth, differentiation and survival. The receptor family includes four distinct members, including epidermal growth factor receptor (EGFR, ErbB1, or HER1), HER2(ErbB2 or p 185)neu) HER3(ErbB3) and HER4(ErbB4 or tyro 2). Members of this receptor family have been implicated in various types of human malignancies.
Recombinant humanized versions of murine anti-HER 2 antibody 4D5 (huMAb4D5-8, rhuMAb HER2, trastuzumab orU.S. Pat. No.5,821,337) are clinically active in patients with metastatic breast cancer that overexpresses HER2, who have received an excessive number of prior anti-cancer therapies (Baselga et al, J.Clin. Oncol.14:737-744 (1996)).
Trastuzumab received marketing approval from the food and drug administration on day 9, 25 of 1998 for the treatment of metastatic breast cancer patients whose tumors overexpress HER2 protein. Trastuzumab is currently approved for use as a single agent or in combination with chemotherapy or hormone therapy in a metastatic setting, and as an adjuvant therapy as a single agent or in combination with chemotherapy for patients with early HER2 positive breast cancer. Trastuzumab-based therapy is now the recommended treatment for patients with HER2 positive early breast cancer, without their contraindications to use: (Prescription information; NCCN guidelines, version 2.2011). Trastuzumab plus docetaxel (or paclitaxel) is a registered standard of care in the context of first-line Metastatic Breast Cancer (MBC) treatment (Slamon et al, N Engl J Med.2001; 344(11): 783-.
Patients treated with HER2 antibody trastuzumab were selected for therapy based on HER2 expression. See, e.g., WO99/31140(Paton et al), US2003/0170234A1(Hellmann, S.) and US2003/0147884(Paton et al); and WO01/89566, US2002/0064785 and US2003/0134344(Mass et al). See also U.S. patent No.6,573,043, U.S. patent No.6,905,830 and US2003/0152987, Cohen et al, which relate to Immunohistochemistry (IHC) and Fluorescence In Situ Hybridization (FISH) for detection of HER2 overexpression and amplification. As such, optimal management of metastatic breast cancer now takes into account not only the general condition, medical history, and receptor status of the patient, but also HER2 status.
Pertuzumab (also known as recombinant humanized monoclonal antibody 2C4(rhuMAb 2C 4); Genentech, Inc, South San Francisco) represents the first of a new class of agents known as 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 HER 4. See, e.g., Harari and Yarden, Oncogene 19:6102-14 (2000); yarden and Sliwkowski, Nat Rev Mol Cell Biol 2:127-37 (2001); sliwkowski, Nat Struct Biol10:158-9 (2003); cho et al, Nature 421:756-60 (2003); and Malik et al, Pro Am Soc cancer Res44:176-7 (2003).
Blockade of HER2-HER3 heterodimer formation by pertuzumab has been shown to inhibit critical Cell signaling in tumor cells, which leads to reduced tumor proliferation and survival (Agus et al, Cancer Cell 2:127-37 (2002)).
Pertuzumab has been tested clinically as a single agent, phase Ia in patients with advanced cancer and phase II in patients with ovarian and breast cancer, as well as lung and prostate cancer. In the phase I study, patients with incurable, locally advanced, relapsed or metastatic solid tumors, who had progressed during or after standard therapy, were treated with pertuzumab administered intravenously every 3 weeks. Pertuzumab is generally well tolerated. Tumor regression was achieved in 3 of 20 patients with evaluable responses. Partial responses were confirmed for 2 patients. 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 2.0-15mg/kg, the pharmacokinetics of pertuzumab is linear with a mean clearance range of 2.69 to 3.74mL/d/kg and a mean terminal elimination half-life range of 15.3 to 27.6 days. No antibodies were detected against pertuzumab (Allison et al, Pro Am SocClin Oncol 22:197 (2003)).
US 2006/0034842 describes methods of treating ErbB expressing cancers with anti-ErbB 2 antibody combinations. US2008/0102069 describes the use of trastuzumab and pertuzumab in the treatment of HER2 positive metastatic cancer such as breast cancer. Basela et al, J Clin Oncol,2007ASCO Annual Meeting Proceedings Part I, Col.25, No.18S (June 20Supplement),2007:1004, reported treatment of patients with pre-treated HER2 positive breast cancer, who had progressed during treatment with trastuzumab, using a combination of trastuzumab and pertuzumab. Portera et al, J Clin Oncol,2007ASCO Annual Meeting procedures Part I.Vol.25, No.18S (June 20Supplement),2007:1028 evaluated the efficacy and safety of trastuzumab + pertuzumab combination therapy in HER2 positive breast cancer patients who had progressed on trastuzumab-based therapy. The authors conclude that further assessment of the efficacy of the combination treatment is needed to define the overall risk and benefit of the treatment regimen.
Pertuzumab has been evaluated in combination with trastuzumab in a phase II study in patients with HER2 positive metastatic breast cancer who previously received trastuzumab for metastatic disease. A study conducted by the National Cancer Institute (NCI) recruited 11 patients with previously treated HER2 positive metastatic breast cancer. 2 of 11 patients exhibited Partial Response (PR) (Baselga et al, J Clin Oncol 2007ASCO Annual meeting procedures; 25:18S (June 20Supplement): 1004.
Results of a phase II neoadjuvant study evaluating the effect of a new combination regimen of pertuzumab and trastuzumab plus chemotherapy (docetaxel) in women with early HER2 positive breast cancer (presented on CTRC-AACR san antonio breast cancer academic conference (SABCS) 12 months 8-12 days 2010) showed that the rate of complete tumor disappearance (pathology complete response rate, pCR, 45.8 percent) in the breast by the administration of two HER2 antibodies plus docetaxel in the preoperative neoadjuvant setting was significantly improved by more than half compared to trastuzumab plus docetaxel (pCR, 29.0 percent), p ═ 0.014.
Clinical evaluation of pertuzumab and trastuzumab (CLEOPATRA) phase II clinical studies evaluating the efficacy and safety of pertuzumab plus trastuzumab plus docetaxel as a first line treatment for patients with locally recurrent, unresectable, or metastatic HER2 positive breast cancer compared to placebo plus trastuzumab plus docetaxel. When used as first-line treatment for HER2 positive metastatic breast cancer, the combination of pertuzumab plus trastuzumab plus docetaxel significantly prolonged progression-free survival with no increase in cardiotoxic effects compared to placebo plus trastuzumab plus docetaxel (Baselga et al, NEng J Med 2012366: 2, 109-.
Phase II clinical study NeoSphere evaluated the efficacy and safety of neoadjuvant administration of pertuzumab and trastuzumab in untreated women with operable, locally advanced, and inflammatory breast cancer (patients who have not received any prior cancer therapy). Patients given pertuzumab and trastuzumab plus docetaxel showed significantly improved pathological complete response rates compared to patients given trastuzumab plus docetaxel without substantial differences in tolerability (Gianni et al, Lancet Oncol 201213 (1): 25-32). The results of the 5-year follow-up are reported (Gianni et al, Lancet Oncol 201617(6): 791-800).
Patent publications relating to HER2 antibodies include: U.S. Pat. Nos. 5,677,171; 5,720,937, respectively; 5,720,954, respectively; 5,725,856, respectively; 5,770,195, respectively; 5,772,997, respectively; 6,165,464, respectively; 6,387,371; 6,399,063, respectively; 6,015,567, respectively; 6,333,169, respectively; 4,968,603; 5,821,337; 6,054,297; 6,407,213, respectively; 6,639,055, respectively; 6,719,971, respectively; 6,800,738, respectively; 5,648,237; 7,018,809, respectively; 6,267,958; 6,695,940, respectively; 6,821,515, respectively; 7,060,268, respectively; 7,682,609, respectively; 7,371,376, respectively; 6,127,526; 6,333,398, respectively; 6,797,814, respectively; 6,339,142, respectively; 6,417,335, respectively; 6,489,447, respectively; 7,074,404, respectively; 7,531,645, respectively; 7,846,441, respectively; 7,892,549, respectively; 6,573,043, respectively; 6,905,830, respectively; 7,129,840, respectively; 7,344,840, respectively; 7,468,252, respectively; 7,674,589, respectively; 6,949,245; 7,485,302, respectively; 7,498,030, respectively; 7,501,122, respectively; 7,537,931, respectively; 7,618,631, respectively; 7,862,817, respectively; 7,041,292, respectively; 6,627,196, respectively; 7,371,379, respectively; 6,632,979, respectively; 7,097,840, respectively; 7,575,748, respectively; 6,984,494, respectively; 7,279,287, respectively; 7,811,773, respectively; 7,993,834, respectively; 7,435,797, respectively; 7,850,966, respectively; 7,485,704, respectively; 7,807,799, respectively; 7,560,111, respectively; 7,879,325, respectively; 7,449,184, respectively; 7,700,299, respectively; and US 2010/0016556; US 2005/0244929; US 2001/0014326; US 2003/0202972; US 2006/0099201; US 2010/0158899; US 2011/0236383; US 2011/0033460; US 2005/0063972; US 2006/018739; US 2009/0220492; US 2003/0147884; US 2004/0037823; US 2005/0002928; US 2007/0292419; US 2008/0187533; US 2003/0152987; US 2005/0100944; US 2006/0183150; US 2008/0050748; 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 007/0166753; US 2008/0112958; US 2009/0239236; US 2004/008204; US 2009/0187007; US 2004/0106161; US 2011/0117096; US 2004/048525; US 2004/0258685; US 2009/0148401; US 2011/0117097; US 2006/0034840; US 2011/0064737; US 2005/0276812; US 2008/0171040; US 2009/0202536; US 2006/0013819; US 2006/0018899; US 2009/0285837; US 2011/0117097; US 2006/0088523; US 2010/0015157; 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 2007/0009976; US 2007/0020261; US 2007/0037228; US 2010/0112603; US 2006/0067930; US 2007/0224203; US 2008/0038271; US 2008/0050385; 2010/0285010, respectively; US 2008/0102069; US 2010/0008975; US 2011/0027190; US 2010/0298156; US 2009/0098135; US 2009/0148435; US 2009/0202546; US 2009/0226455; US 2009/0317387; and US 2011/0044977.
Summary of The Invention
Despite significant advances over the past decade, patients with advanced or treatment refractory, HER2 positive, HER2 amplified, or HER2 mutated colorectal, biliary, urothelial, bladder, salivary gland, lung, pancreatic, ovarian, prostate, or skin (apocrine) cancers have few treatment options.
In one aspect, the invention concerns a method for treating advanced colorectal cancer comprising administering an effective amount of a combination of pertuzumab and trastuzumab to a human patient with HER2 positive, HER2 amplified, or HER2 mutant advanced colorectal cancer.
In a second aspect, the invention concerns a method for treating advanced biliary cancer comprising administering an effective amount of a combination of pertuzumab and trastuzumab to a human patient with advanced biliary cancer that is HER2 positive, HER2 amplified, or HER2 mutant.
In a third aspect, the present invention concerns a method for treating advanced urothelial cancer comprising administering an effective amount of a combination of pertuzumab and trastuzumab to a human patient with HER2 positive, HER2 amplified, or HER2 mutant advanced urothelial cancer.
In a fourth aspect, the invention concerns a method for treating advanced bladder cancer comprising administering an effective amount of a combination of pertuzumab and trastuzumab to a human patient with HER2 positive, HER2 amplified, or HER2 mutant advanced bladder cancer. In one embodiment, the bladder cancer is urothelial bladder cancer.
In a fifth aspect, the present invention concerns a method for treating advanced salivary gland cancer comprising administering an effective amount of a combination of pertuzumab and trastuzumab to a human patient with advanced salivary gland cancer that is HER2 positive, HER2 amplified, or HER2 mutant.
In a sixth aspect, the invention concerns a method for treating advanced lung cancer comprising administering an effective amount of a combination of pertuzumab and trastuzumab to a human patient with HER2 positive, HER2 amplified, or HER2 mutant lung cancer.
In a seventh aspect, the invention concerns a method for treating advanced pancreatic cancer comprising administering an effective amount of a combination of pertuzumab and trastuzumab to a human patient with HER2 positive, HER2 amplified, or HER2 mutant lung cancer.
In an eighth aspect, the invention concerns a method for treating advanced ovarian cancer comprising administering an effective amount of a combination of pertuzumab and trastuzumab to a human patient with HER 2-positive, HER 2-amplified, or HER 2-mutated lung cancer.
In a ninth aspect, the invention concerns a method for treating advanced prostate cancer comprising administering an effective amount of a combination of pertuzumab and trastuzumab to a human patient with HER2 positive, HER2 amplified, or HER2 mutant lung cancer.
In a tenth aspect, the invention concerns a method for treating advanced skin cancer comprising administering an effective amount of a combination of pertuzumab and trastuzumab to a human patient with HER2 positive, HER2 amplified, or HER2 mutant lung cancer.
In all aspects, if the cancer is HER2 positive, then HER2 expression level may be, for example, IHC2+ or 3 +.
In all aspects, if the cancer is HER2 amplified, then HER2 amplification may be determined, for example, by Fluorescence In Situ Hybridization (FISH).
In all aspects, if the cancer is HER2 mutant, the mutation can be detected, for example, by Next Generation Sequencing (NGS) or real-time polymerase chain reaction (RT-PCR).
In certain embodiments, the HER2 mutation is selected from the group consisting of an insertion within exon 20 of HER2, a deletion around amino acid residues 755-759 of HER2, G309A, G309E, S310F, D769H, D769Y, V777L, P780-Y781insGSP, V8421I, R896C and other putative activating mutations found in two or more unique specimens.
The advanced cancer may be locally advanced or metastatic.
In other embodiments, the cancer is refractory to another treatment regimen. As such, the cancer may be chemotherapy-resistant, including platinum-resistant.
In other embodiments, the patient treated with pertuzumab plus trastuzumab received 1 to 5 rounds of prior treatment for treating the cancer.
In various embodiments, the prior treatment may comprise chemotherapy, and/or HER 2-directed therapy.
In other embodiments, at least one of such prior treatments is administered in an advanced stage.
The prior treatment may include neoadjuvant and/or adjuvant treatment.
In certain embodiments, the patient's cancer is resistant to at least one of the prior treatments.
In yet another embodiment, the combination of pertuzumab and trastuzumab is administered in the absence of other anti-cancer drugs.
In yet another embodiment, the combination of pertuzumab and trastuzumab is administered in the absence of chemotherapy.
In a different embodiment, the combination of pertuzumab and trastuzumab is administered in the absence of another HER 2-directed therapy.
In yet another embodiment, the treatment consists essentially of combined administration of pertuzumab and trastuzumab in combination.
The treatment methods of the invention may result in an improved Overall Response Rate (ORR) relative to the administration of pertuzumab or trastuzumab as the single agent and/or an improved Partial Response (PR) relative to the administration of pertuzumab or trastuzumab as the single agent and/or an improved Complete Response (CR) relative to the administration of pertuzumab or trastuzumab as the single agent.
In other embodiments, the combined administration of pertuzumab and trastuzumab prolongs the survival of the patient relative to the administration of pertuzumab or trastuzumab as the single agent.
In still other embodiments, the combined administration of pertuzumab and trastuzumab prolongs the Progression Free Survival (PFS) of the patient.
In still further embodiments, the combined administration of pertuzumab and trastuzumab extends the Overall Survival (OS) of the patient.
In another embodiment, the combined administration of pertuzumab and trastuzumab results in a synergistic effect.
In yet another embodiment, the combined administration of pertuzumab and trastuzumab does not result in an increase in side effects relative to monotherapy with pertuzumab or trastuzumab.
In yet another embodiment, the combined administration of pertuzumab and trastuzumab does not result in an increase in cardiac side effects relative to monotherapy with pertuzumab or trastuzumab.
In another aspect, the invention concerns an article of manufacture comprising a vial containing pertuzumab and a package insert, wherein the package insert provides instructions for administering the pertuzumab as described above.
In yet another aspect, the invention concerns a composition of pertuzumab for use in combination with trastuzumab in the treatment of a human patient with HER2 positive, HER2 amplified, or HER2 mutated advanced colorectal cancer.
In a second aspect, the invention concerns a composition of pertuzumab for use in combination with trastuzumab in the treatment of a human patient with HER2 positive, HER2 amplified, or HER2 mutated advanced bile duct cancer.
In a third aspect, the invention concerns a composition of pertuzumab for use in combination with trastuzumab in the treatment of a human patient with HER2 positive, HER2 amplified, or HER2 mutated advanced urothelial cancer.
In a fourth aspect, the invention concerns a composition of pertuzumab for use in combination with trastuzumab in the treatment of a human patient with HER2 positive, HER2 amplified, or HER2 mutated advanced bladder cancer. In one embodiment, the bladder cancer is urothelial bladder cancer.
In a fifth aspect, the invention concerns a composition of pertuzumab for use in combination with trastuzumab in the treatment of a human patient with HER2 positive, HER2 amplified, or HER2 mutated advanced salivary gland cancer.
In a sixth aspect, the invention concerns a composition of pertuzumab for use in combination with trastuzumab in the treatment of a human patient with HER2 positive, HER2 amplified, or HER2 mutated lung cancer.
In a seventh aspect, the invention concerns a composition of pertuzumab for use in combination with trastuzumab in the treatment of HER2 positive, HER2 amplified, or HER2 mutated pancreatic cancer.
In an eighth aspect, the invention concerns a composition of pertuzumab for use in combination with trastuzumab in the treatment of HER2 positive, HER2 amplified, or HER2 mutated ovarian cancer.
In a ninth aspect, the invention concerns a composition of pertuzumab for use in combination with trastuzumab in the treatment of HER2 positive, HER2 amplified, or HER2 mutated prostate cancer.
In a tenth aspect, the invention concerns a composition of pertuzumab for use in combination with trastuzumab in the treatment of HER2 positive, HER2 amplified, or HER2 mutated skin (apocrine) cancer.
In another aspect, the invention concerns the use of pertuzumab for the preparation of a medicament for the treatment of a human patient with HER2 positive, HER2 amplified, or HER2 mutated advanced colorectal cancer in combination with trastuzumab.
In a second aspect, the invention concerns the use of the pertuzumab in the manufacture of a medicament for the treatment in combination with trastuzumab of a human patient with HER2 positive, HER2 amplified, or HER2 mutated advanced bile duct cancer.
In a third aspect, the invention concerns the use of the pertuzumab in the manufacture of a medicament for the treatment in combination with trastuzumab of a human patient with HER2 positive, HER2 amplified, or HER2 mutated advanced urothelial cancer.
In a fourth aspect, the invention concerns the use of the pertuzumab in the manufacture of a medicament for the treatment in combination with trastuzumab of a human patient with HER2 positive, HER2 amplified, or HER2 mutated advanced bladder cancer. In one embodiment, the bladder cancer is urothelial bladder cancer.
In a fifth aspect, the invention concerns the use of the pertuzumab in the manufacture of a medicament for the treatment of a human patient with HER2 positive, HER2 amplified, or HER2 mutated advanced salivary gland cancer in combination with trastuzumab.
In a sixth aspect, the invention concerns the use of the pertuzumab in the preparation of a medicament for treating a human patient with advanced lung cancer that is HER2 positive, HER2 amplified, or HER2 mutated in combination with trastuzumab.
In a seventh aspect, the invention concerns the use of the pertuzumab in the preparation of a medicament for the treatment of a human patient with HER2 positive, HER2 amplified, or HER2 mutated advanced pancreatic cancer in combination with trastuzumab.
In an eighth aspect, the invention concerns the use of the pertuzumab in the manufacture of a medicament for treating a human patient with advanced ovarian cancer having HER2 positive, HER2 amplified, or HER2 mutation in combination with trastuzumab.
In a ninth aspect, the invention concerns the use of the pertuzumab in the manufacture of a medicament for treating a human patient with HER2 positive, HER2 amplified, or HER2 mutated advanced prostate cancer in combination with trastuzumab.
In a tenth aspect, the invention concerns the use of the pertuzumab in the manufacture of a medicament for treating a human patient with an advanced skin (apocrine) cancer that is HER2 positive, HER2 amplified, or HER2 mutated in combination with trastuzumab.
These and other aspects will be apparent from the disclosure herein, including the examples.
Brief Description of Drawings
FIG. 1 provides a schematic representation of the structure of HER2 protein, and the amino acid sequences of domains I-IV of its extracellular domain (SEQ ID Nos. 1-4, respectively).
FIGS. 2A and 2B depict an alignment of the amino acid sequences of: variable lightness (V) of murine monoclonal antibody 2C4L) (FIG. 2A) and variable weight (V)H) (FIG. 2B) domains (SEQ ID Nos. 5 and 6, respectively); variant 574/V of pertuzumabLAnd VHDomains (SEQ ID Nos. 7 and 8, respectively), and human VLAnd VHConsensus framework (hum κ 1, light kappa subgroup I; humIII, heavy subgroup III) (SEQ ID Nos. 9 and 10, respectively). Asterisks indicate the variable domains between pertuzumab and murine monoclonal antibody 2C4 or the variable domains of pertuzumab and human frameworkThe difference between them. Complementarity Determining Regions (CDRs) are in parentheses.
FIGS. 3A and 3B show the amino acid sequences of the pertuzumab light chain (FIG. 3A; SEQ ID No.11) and heavy chain (FIG. 3B; SEQ ID No. 12). The CDRs are shown in bold. The calculated molecular weights of the light and heavy chains are 23,526.22Da and 49,216.56Da (cysteine in reduced form). The carbohydrate module is attached to Asn 299 of the heavy chain.
FIGS. 4A and 4B show the amino acid sequences of the trastuzumab light (FIG. 4A; SEQ ID No.13) and heavy (FIG. 4B; SEQ ID No.14) chains, respectively. The boundaries of the variable light and variable heavy fields are indicated by arrows.
FIGS. 5A and 5B depict a variant pertuzumab light chain sequence (FIG. 5A; SEQ ID No.15) and a variant pertuzumab heavy chain sequence (FIG. 5B; SEQ ID No.16), respectively.
FIG. 6 shows the main study protocol for the MyPathway clinical trial.
Figure 7 shows the study design of the study described in example 1.
Figure 8 shows an algorithm for resolving asymptomatic LVEF drop.
Figure 9 shows treatment time for patients with HER2 amplified/overexpressed mCRC (n ═ 34). + indicates that treatment is ongoing; k indicates that the patient has a KRAS mutation; dashed lines indicate 4 months.
Figure 10 shows the optimal percent change from baseline in target lesion size in patients with HER2 amplified/overexpressed mRCR (n-31). + indicates that treatment is ongoing; k indicates that the patient has a KRAS mutation.aThree patients were excluded from this figure: 2 patients (including 1 with KRAS mutation) showed discontinuation of treatment due to clinical progression, no post-baseline tumor assessments, and 1 person discontinued treatment due to a new lesion and lacked three-quarters of the target lesion assessments.b"percent change from baseline" represents the maximum reduction/minimum increase in the size of the target lesion, or the appearance of one or more new lesions. Patients with a 30% reduction in target lesion size fit PR; targetPatients with lesions of at least 20% increase in size or with one or more new lesions are eligible for PD.
Figure 11 shows PFS in patients with HER2 amplified/overexpressed mCRC.
Figure 12 shows OS in patients with HER2 amplified/overexpressed mCRC.
Figure 13 shows a waterfall plot of treatment response in patients with HER2 amplified/overexpressed cholangiocarcinoma (N ═ 8)
Figure 14 shows a cascade of treatment responses (N-8) in patients with HER2 amplified/overexpressed bladder cancer.
Figure 15 shows treatment time (n-12) in patients with HER2 amplified/overexpressed or HER2 mutant metastatic urothelial cancer (mUC).
Figure 16 shows the optimal percent change from baseline for the target lesion size in patient scores.
Fig. 17A to C show CT scans of complete tumor response in patients with HER2 positive mUC at different time points.
A) Year 2015, 4 months: a baseline scan. The maximal metastatic pool was found in the front of the middle of the transverse colon and measured at 3.5cm x1.6 cm.
B) Month 6in 2015: the first post-baseline scan showed that the omental implant had shrunk since the last CT and had no measurable disease. The soft tissue mass in the reticulum is reduced by the arrow definition, and only one linear soft tissue strand is left.
C) Year 2016 for 12 months: there was no evidence of recurrent or metastatic disease.
Detailed Description
I. Definition of
"survival" means that the patient remains alive and includes Overall Survival (OS) as well as Progression Free Survival (PFS).
"overall survival" or "OS" refers to the patient remaining alive for a defined period of time, such as 1 year, 5 years, 10 years, 12 years, 15 years, etc., from the time of diagnosis or treatment. For the purposes of the clinical trial described in the examples, Overall Survival (OS) is defined as the time from the date the patient population was randomized to the date of death for any reason.
By "progression free survival" or "PFS" is meant that the patient remains alive and the cancer does not progress or worsen. For the purposes of the clinical trial described in the examples, Progression Free Survival (PFS) was defined as the time from randomization of the study population to the first documented progressive disease or unmanageable toxicity or death by whatever cause, whichever occurred first. Disease progression can be documented by any clinically accepted method, such as, for example, radiographic progressive disease as determined by response assessment criteria (RECIST) in solid tumors (Therasse et al, J Natl Ca Inst 2000; 92(3): 205-.
By "extended survival" is meant that the overall or progression-free survival in a patient treated according to the invention is extended relative to an untreated patient and/or relative to a patient treated with one or more approved antineoplastic agents but not treated according to the invention. In a specific example, "extending survival" means extending Progression Free Survival (PFS) and/or Overall Survival (OS) of a cancer patient receiving a combination therapy of the invention (e.g., a combination therapy with pertuzumab, trastuzumab, and chemotherapy) relative to a patient treated with trastuzumab and chemotherapy alone. In another specific example, "extending survival" means extending Progression Free Survival (PFS) and/or Overall Survival (OS) of a cancer patient receiving a combination therapy of the invention (e.g., a combination therapy with pertuzumab, trastuzumab, and chemotherapy) relative to a patient treated with pertuzumab and chemotherapy alone.
"Objective response" OR "OR" refers to a measurable response, including a Complete Response (CR) OR a Partial Response (PR).
By "complete response" or "CR" is meant that all symptoms of the cancer disappear in response to treatment. This does not always mean that the cancer is cured.
"partial response" or "PR" refers to the reduction in the size of one or more tumors or lesions or the extent of cancer in the body in response to treatment.
The "HER receptor" is a receptor protein tyrosine kinase belonging to the HER receptor family, including the EGFR, HER2, HER3 and HER4 receptors. HER receptors will typically comprise an extracellular domain that can bind a HER ligand and/or dimerize with another HER receptor molecule; a lipophilic transmembrane domain; a conserved intracellular tyrosine kinase domain; and a carboxy-terminal signaling domain containing several tyrosine residues that can be phosphorylated. The HER receptor may be a "native sequence" HER receptor or an "amino acid sequence variant" thereof. Preferably, the HER receptor is a native sequence human HER receptor.
The expressions "ErbB 2" and "HER 2" are used interchangeably herein and refer to, for example, the human HER2 protein (Genebank accession number X03363) as described in Semba et al, PNAS (USA)82: 6497-. The term "erbB 2" refers to the gene encoding human ErbB2, while "neu" refers to the gene encoding rat p185neuThe gene of (1). Preferred HER2 is native sequence human HER 2.
Herein, "HER 2 extracellular domain" or "HER 2 ECD" refers to the HER2 domain, including fragments thereof, anchored to the cell membrane or outside the cell in circulation. The amino acid sequence of HER2 is shown in figure 1. In one embodiment, the extracellular domain of HER2 may comprise 4 domains: "Domain I" (amino acid residues from about 1 to 195; SEQ ID NO:1), "Domain II" (amino acid residues from about 196-319; SEQ ID NO:2), "Domain III" (amino acid residues from about 320-488; SEQ ID NO:3) and "Domain IV" (amino acid residues from about 489-630; SEQ ID NO:4) (NO numbering of the residues of the signal peptide). See Garrett et al mol.cell..11:495-505(2003), Cho et al Nature 421: 756-.
"HER 3" or "ErbB 3" refers herein to receptors as disclosed, for example, in U.S. Pat. Nos. 5,183,884 and 5,480,968 and Kraus et al, PNAS (USA)86: 9193-.
A "low HER 3" cancer is one that expresses HER3 at a level below the median level for HER3 expression in that cancer type. In one embodiment, the low HER3 cancer is epithelial ovarian cancer, peritoneal cancer or fallopian tube cancer. HER3DNA, protein and/or mRNA levels in the cancer can be assessed to determine whether the cancer is a low HER3 cancer. See, e.g., U.S. patent No.7,981,418 for more information about low HER3 cancer. Optionally, a HER3mRNA expression assay is performed to determine that the cancer is a low HER3 cancer. In one embodiment, HER3mRNA levels in the cancer are assessed, for example using Polymerase Chain Reaction (PCR), such as quantitative reverse transcription PCR (qRT-PCR). Optionally, the cancer expresses HER3 at a concentration ratio equal to or lower than about 2.81, as by qRT-PCR, e.g., using COBASAnd (4) evaluating.
"HER dimer" refers herein to a non-covalently associated dimer comprising at least two HER receptors. Such complexes may form when cells expressing two or more HER receptors are exposed to a HER ligand and may be isolated by immunoprecipitation and analyzed by SDS-PAGE as described, for example, in Sliwkowski et al, J.biol.chem.269(20):14661-14665 (1994). Other proteins, such as cytokine receptor subunits (e.g., gp130), may be associated with the dimer. Preferably, the HER dimer comprises HER 2.
"HER heterodimer" herein refers to a non-covalently associated heterodimer comprising at least two different HER receptors, such as EGFR-HER2, HER2-HER3, or HER2-HER4 heterodimers.
A "HER antibody" is an antibody that binds to a HER receptor. Optionally, the HER antibody further interferes with HER activation or function. Preferably, the HER antibody binds to the HER2 receptor. The HER2 antibodies of interest herein are pertuzumab and trastuzumab.
"HER activation" refers to the activation or phosphorylation of any one or more HER receptors. In general, HER activation results in signal transduction (e.g., by phosphorylation of tyrosine residues in a HER receptor or substrate polypeptide, caused by an intracellular kinase domain of the HER receptor). HER activation may be mediated by HER ligands that bind to HER dimers comprising the HER receptor of interest. HER ligands that bind to HER dimers may activate the kinase domain of one or more HER receptors in the dimer and thereby cause phosphorylation of tyrosine residues in one or more HER receptors and/or phosphorylation of tyrosine residues in other substrate polypeptides such as Akt or MAPK intracellular kinases.
"phosphorylation" refers to the addition of one or more phosphate groups to a protein, such as a HER receptor or substrate thereof.
An antibody that "inhibits HER dimerization" is an antibody that inhibits or interferes with HER dimer formation. Preferably, such antibodies bind HER2 at its heterodimeric binding site. The most preferred dimerization inhibitory antibody herein is pertuzumab or MAb 2C 4. Other examples of antibodies that inhibit HER dimerization include antibodies that bind EGFR and inhibit dimerization thereof with one or more other HER receptors (e.g., EGFR monoclonal antibody 806, MAb 806, which binds activated or "untethered" EGFR; see Johns et al, J.biol.chem.279(29):30375-30384 (2004)); an antibody that binds to HER3 and inhibits dimerization thereof with one or more other HER receptors; and antibodies that bind to HER4 and inhibit dimerization thereof with one or more other HER receptors.
A "HER 2 dimerization inhibitor" is an agent that inhibits the formation of dimers or heterodimers comprising HER 2.
A "heterodimer binding site" on HER2 refers to a region of the extracellular domain of HER2 that contacts a region of the extracellular domain of EGFR, HER3 or HER4 or that interfaces with a region of the extracellular domain of EGFR, HER3 or HER4 when forming a dimer with EGFR, HER3 or HER 4. The region has been found in domain II of HER2 (SEQ ID NO: 15). Franklin et al, Cancer Cell5: 317-.
A HER2 antibody that "binds to the heterodimer binding site of HER 2" binds to residues in domain II (SEQ ID NO:2) and optionally also to other domains of the extracellular domain of HER2, such as residues in domains I and III (SEQ ID NO:1 and 3), and at least to some extent sterically hinders the formation of HER2-EGFR, HER2-HER3 or HER2-HER4 heterodimers. Franklin et al, Cancer Cell5: 317-.
An antibody that "binds domain II of HER 2" binds to residues in domain II (SEQ ID NO:2) and optionally other domains of HER2, such as residues in domains I and III (SEQ ID NO:1 and 3, respectively). Preferably, the antibody that binds domain II binds to HER2 at the junction between domains I, II and III.
For purposes herein, "pertuzumab" and "rhuMAb 2C 4" which are used interchangeably refer to antibodies comprising the variable light and variable heavy chain amino acid sequences in SEQ ID NOS: 7 and 8, respectively. Where pertuzumab is an intact antibody, it preferably comprises an IgG1 antibody; in one embodiment, it 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. Optionally, the antibody is produced by recombinant Chinese Hamster Ovary (CHO) cells. The terms "pertuzumab" and "rhuMAb 2C 4" are herein covered with the names adopted in the United States (USAN) or international non-proprietary name (INN): biologically similar forms of the drug of pertuzumab.
For purposes herein, "trastuzumab" and "rhuMAb 4D 5" which are used interchangeably refer to antibodies comprising variable light and variable heavy chain amino acid sequences from SEQ ID NOS: 13 and 14, respectively. Where trastuzumab is an intact antibody, it preferably comprises an IgG1 antibody; in one embodiment, comprises the light chain amino acid sequence of SEQ ID NO.13 and the heavy chain amino acid sequence of SEQ ID NO. 14. Optionally, the antibody is produced by Chinese Hamster Ovary (CHO) cells. The terms "trastuzumab" and "rhuMAb 4D 5" are herein intended to cover a compound having a U.S. adopted name (USAN) or an international non-proprietary name (INN): biologically similar forms of trastuzumab.
The term "antibody" is used herein in the broadest sense and specifically covers monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired biological activity.
"humanized" forms of non-human (e.g., rodent) antibodies refer to chimeric antibodies that contain, at a minimum, sequences derived from non-human immunoglobulins. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or nonhuman primate having the desired specificity, affinity, and capacity. In some instances, Framework Region (FR) residues of the human immunoglobulin are replaced with corresponding non-human residues. In addition, humanized antibodies may comprise residues not found in the recipient antibody or in the donor antibody. These modifications are made to further improve the performance of the antibody. Typically, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin sequence. Optionally, the humanized antibody will also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For more details see Jones et al, Nature 321:522-525 (1986); riechmann et al, Nature 332: 323-E329 (1988); and Presta, curr, Op, Structure, biol.2:593-596 (1992). Humanized HER2 antibodies include trastuzumabAs described in table 3 and as defined herein of U.S. patent 5,821,337 (expressly incorporated herein by reference); and a humanized 2C4 antibody, pertuzumab as described and defined herein.
An "intact antibody" herein is an antibody comprising two antigen binding regions and an Fc region. Preferably, the intact antibody has a functional Fc region.
An "antibody fragment" comprises a portion of an intact antibody, preferably comprising the antigen binding region thereof. Examples of antibody fragments include Fab, Fab ', F (ab')2And Fv fragments; a diabody; a linear antibody; a single chain antibody molecule; and multispecific antibodies formed from antibody fragments.
"native antibodies" are typically heterotetrameric glycoproteins of about 150,000 daltons composed of two identical light chains (L) and two identical heavy chains (H). Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies between heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has a variable domain (V) at one endH) Followed by a plurality of constant domains. Each light chain has a variable domain (V) at one endL) And a constant domain at the other end. The constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the variable domain of the light chain is aligned with the variable domain of the heavy chain. It is believed that specific amino acid residues form the interface between the light and heavy chain variable domains.
The term "hypervariable region" as used herein refers to the amino acid residues of an antibody which are responsible for antigen binding. Hypervariable regions typically comprise amino acid residues from the "complementarity determining regions" or "CDRs" (e.g.residues 24-34(L1), 50-56(L2) and 89-97(L3) in the light chain variable domain and 31-35(H1), 50-65(H2) and 95-102(H3) in the heavy chain variable domain; Kabat et al, Sequences of Proteins of Immunological Interest,5th Ed. public Health Service, National Institutes of Health, Bethesda, 1991)) and/or those from the "hypervariable loops" (e.g.residues 26-32(L1), 50-52(L2) and 91-96(L3) in the light chain variable domain and 26-32(H1), 53-55(H2) and 96-101(H3, H917J., 1987) in the heavy chain variable domain; Bioia: 901). "framework region" or "FR" residues are those variable domain residues other than the hypervariable region residues defined herein.
The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain, including native sequence Fc regions and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain may vary, the human IgG heavy chain Fc region is generally defined as extending from position Cys226, or from the amino acid residue at Pro230, to the carboxy-terminus of the heavy chain. The C-terminal lysine of the Fc region (residue 447 according to the EU numbering system) may be removed, for example, during production or purification of the antibody, or by recombinant engineering of the nucleic acid encoding the heavy chain of the antibody. Thus, a composition of intact antibodies may comprise a population of antibodies from which all K447 residues have been removed, a population of antibodies from which no K447 residues have been removed, and a population of antibodies having a mixture of antibodies with and without K447 residues.
Unless otherwise indicated, the numbering of residues in immunoglobulin heavy chains herein is that of the EU index, as described in Kabat et al, Sequences of Proteins of Immunological Interest,5th Ed. public Health Service, National Institutes of Health, Bethesda, Md (1991), which is expressly incorporated herein by reference. "EU index as in Kabat" refers to the residue numbering of the human IgG1EU antibody.
A "functional Fc region" possesses the "effector functions" of a native sequence Fc region. Exemplary "effector functions" include C1q combinations; complement-dependent cytotoxicity; fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (e.g., B cell receptors; BCR), and the like. Such effector functions generally require that the Fc region be associated with a binding domain (e.g., an antibody variable domain) and can be evaluated using a variety of assays, such as those disclosed herein.
A "native sequence Fc region" comprises an amino acid sequence that is identical to the amino acid sequence of an Fc region found in nature. Native sequence human Fc regions include native sequence human IgG1Fc regions (non-a and a allotypes); a native sequence human IgG2Fc region; a native sequence human IgG3Fc region; and the native sequence human IgG4Fc region, as well as naturally occurring variants thereof.
A "variant Fc region" comprises an amino acid sequence that differs from the amino acid sequence of a native sequence Fc region by at least one amino acid modification, preferably one or more amino acid substitutions. Preferably, the variant Fc region has at least one amino acid substitution as compared to the native sequence Fc region or to the Fc region of the parent polypeptide, e.g., from about 1 to about 10 amino acid substitutions, preferably from about 1 to about 5 amino acid substitutions, in the native sequence Fc region or in the Fc region of the parent polypeptide. The variant Fc region herein will preferably possess at least about 80% homology with the native sequence Fc region and/or the Fc region of the parent polypeptide, most preferably at least about 90% homology therewith, and more preferably at least about 95% homology therewith.
Intact antibodies can be classified into five major classes, IgA, IgD, IgE, IgG and IgM, some of which can be further divided into "subclasses" (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2, the heavy chain constant domains corresponding to the different antibody classes are referred to as α, δ, epsilon, γ and μ, respectively.
"naked antibody" refers to an antibody that is not conjugated to a heterologous molecule, such as a cytotoxic moiety or a radioactive label.
An "affinity matured" antibody refers to an antibody that has one or more alterations in one or more of its hypervariable regions which result in an improvement in the affinity of the antibody for an antigen compared to a parent antibody that does not possess such alterations. Preferred affinity matured antibodies will have nanomolar or even picomolar affinities for the target antigen. Affinity matured antibodies are produced by procedures known in the art. Marks et al Bio/Technology 10: 779-. Random mutagenesis of CDR and/or framework residues is described below: barbas et al Procnnat. Acad. Sci, USA 91: 3809-; schier et al Gene 169:147-155 (1995); yelton et al J.Immunol.155:1994-2004 (1995); jackson et al, J.Immunol.154(7):3310-9 (1995); and Hawkins et al, J.mol.biol.226:889-896 (1992).
An "deamidated" antibody is one in which one or more asparagine residues have been derivatized to, for example, aspartic acid, succinimide, or isoaspartic acid.
The terms "cancer" and "cancerous" refer to or describe a physiological condition in mammals that is characterized by generally unregulated cell growth. The term "cancer" specifically includes, but is not limited to, HER2 positive, HER2 amplified and/or HER2 mutated cancers, such as colorectal cancer, cholangiocarcinoma, urothelial cancer, bladder cancer, salivary gland cancer, lung cancer, e.g. non-small cell lung (NSCLC), pancreatic, ovarian, prostate, and skin (apocrine) cancers.
"colorectal cancer" is cancer that occurs in any part of the colon and/or rectum. The term specifically includes advanced stages, including metastatic and locally advanced colorectal cancer, non-operable (unresectable) colorectal cancer, colorectal cancer that is not amenable to curative therapy, and advanced colorectal cancer that recurs post-operatively, as well as treatment resistant colorectal cancer, including but not limited to histologically confirmed adenocarcinoma, primary colorectal lymphoma, gastrointestinal stromal tumors, leiomyosarcoma, carcinoid tumors, and melanoma. Adenocarcinoma is the predominant form of colorectal cancer.
"bladder cancer" specifically includes all types and stages of bladder cancer, specifically including but not limited to metastatic and locally advanced bladder cancer, inoperable (unresectable) bladder cancer, bladder cancer that is not amenable to curative therapy, and advanced bladder cancer that recurs after surgery, as well as treatment-resistant bladder cancer. The term specifically includes, but is not limited to urothelial cancer, squamous cell carcinoma, and adenocarcinoma, and non-invasive, non-muscle invasive, and muscle invasive forms of bladder cancer. In one embodiment, the bladder cancer is urothelial bladder cancer.
"cholangiocarcinoma" includes all cancers of the bile duct, including in particular but not limited to metastatic and locally advanced cholangiocarcinoma, inoperable (unresectable) cholangiocarcinoma, cholangiocarcinoma not amenable to curative therapy, and advanced cholangiocarcinoma that recurs after surgery, and treatment-resistant cholangiocarcinoma, including but not limited to intrahepatic cholangiocarcinoma.
"gastric cancer" specifically includes metastatic or locally advanced unresectable gastric cancer, including but not limited to histologically confirmed gastric or gastroesophageal junction adenocarcinoma with inoperable (unresectable) locally advanced or metastatic disease not amenable to treatment by curative therapy, and advanced gastric cancer that recurs post-operatively, such as gastric or gastroesophageal junction adenocarcinoma, when surgery is intended to cure the disease.
"advanced" cancer refers to cancer that spreads beyond the original site or organ by local invasion ("local late stage") or metastasis ("metastatic"). Thus, the term "advanced" cancer includes both locally advanced and metastatic disease.
"metastatic" cancer refers to cancer that spreads from one part of the body (e.g., the breast) to another part of the body.
"refractory" cancer refers to a cancer that has progressed despite administration of an anti-tumor agent, such as chemotherapy or biological therapy, such as immunotherapy, to a cancer patient. An example of a refractory cancer is a platinum resistant cancer.
"recurrent" cancer refers to cancer that regrows at the initial or distal site after responding to an initial treatment, such as surgery.
A "locally recurrent" cancer is one that returns after treatment at the same location as the previously treated cancer.
"unresectable" cancers are not removed (resected) by surgery.
"early breast cancer" as used herein refers to breast cancer that has not spread beyond the breast or axillary lymph nodes. Such cancers are typically treated with neoadjuvant or adjuvant therapy.
"neoadjuvant therapy" or "neoadjuvant treatment" or "neoadjuvant administration" refers to systemic therapy given prior to surgery.
"adjuvant therapy" or "adjuvant treatment" or "adjuvant administration" refers to systemic therapy given after surgery.
Herein, a "patient" or "subject" is a human patient. The patient may be a "cancer patient", i.e. a patient suffering from or at risk of suffering from one or more symptoms of cancer, in particular breast cancer.
A "patient population" refers to a group of cancer patients. Such populations may be used to demonstrate statistically significant efficacy and/or safety of drugs such as pertuzumab and/or trastuzumab.
A "relapsed" patient is one who has symptoms or signs of cancer after resolution. Optionally, the patient relapses after adjuvant or neoadjuvant therapy.
A cancer or biological sample that "displays HER expression, amplification or activation" is one that expresses (including overexpresses) a HER receptor, has an amplified HER gene, and/or otherwise displays HER receptor activation or phosphorylation in a diagnostic test.
A cancer or biological sample that "displays HER activation" is one that shows HER receptor activation or phosphorylation in a diagnostic test. Such activation can be determined directly (e.g., by measuring HER phosphorylation by ELISA) or indirectly (e.g., by gene expression profiling or by detecting HER heterodimers, as described herein).
A cancer cell that "overexpresses or amplifies a HER receptor" refers to a cancer cell that has significantly higher levels of a HER receptor protein or gene as compared to a non-cancer cell of the same tissue type. Such overexpression may be caused by gene amplification or increased transcription or translation. Overexpression or amplification of a HER receptor can be determined in a diagnostic or prognostic assay by assessing an increase in HER protein levels present on the surface of a cell (e.g. by immunohistochemical assay; IHC). Alternatively or additionally, the level of HER-encoding nucleic acid in the cell May be measured, for example, by In Situ Hybridization (ISH), including fluorescence in situ hybridization (FISH; see WO 98/45479 published 10.1998) and chromogenic in situ hybridization (CISH; see, e.g., Tanner et al, am. J. Pathol.157(5): 1467-. HER receptor overexpression or amplification can also be studied by measuring shed antigens (e.g., HER extracellular domain) in biological fluids such as serum (see, e.g., U.S. Pat. No.4,933,294, published 6/12 in 1990; WO 91/05264, published 4/18 in 1991; U.S. Pat. No.5,401,638, published 3/28 in 1995; and Sias et al J.Immunol.methods 132:73-80 (1990)). In addition to the above assays, a variety of in vivo assays may be utilized by the skilled practitioner. For example, cells in a patient may be exposed to an antibody that is optionally labeled with a detectable label, such as a radioisotope, and binding of the antibody to cells in the patient may be assessed, for example, by externally scanning for radioactivity or by analyzing a biopsy sample taken from a patient that has been previously exposed to the antibody.
A "HER 2 positive" cancer comprises cancer cells having higher than normal levels of HER 2. Examples of HER2 positive cancers include HER2 positive colorectal cancer, HER2 positive bile duct cancer, HER2 positive urothelial cancer, and HER2 positive bladder cancer. Optionally, the HER2 positive cancer has an Immunohistochemistry (IHC) score of 2+ or 3+ and/or an In Situ Hybridization (ISH) amplification ratio of ≧ 2.0. Optionally, the HER2 positive cancer has HER2 amplification characterized by a HER2/CEP17 ratio >2.0 (fluorescent or chromogenic in situ hybridization [ FISH or CISH ]), or a gene copy number >6(FISH/CISH or next generation sequencing [ NGS ]).
A "HER 2 mutant" cancer comprises cancer cells having HER2 activating mutations, including kinase domain mutations, which can be identified by, for example, Next Generation Sequencing (NGS) or real-time polymerase chain reaction (RT-PCR). "HER 2 mutant" cancers specifically include cancers characterized by an insertion in exon 20 of HER2, a deletion around amino acid residue 755-759 of HER2, any of the mutations G309A, G309E, S310F, D769H, D769Y, V777L, P780-Y781insGSP, V842I, R896C (Bose et al, Cancer Discov 2013; 3:1-14), and the same non-synonymous putative activation mutation (or insertion deletion) previously reported in the COSMIC database found in two or more unique specimens. For further details, see, e.g., Stephens et al, Nature 2004; 431: 525-6; shigematsu et al, Cancer Res 2005; 1642-6; butitta et al, Int J Cancer 2006; 119: 2586-91; li et al, Oncogene 2008; 4702-11 parts by weight; sequist et al, J Clin Oncol 2010; 3076-83 parts by weight; arcila et, Clin Cancer Res 2012; 18: 4910-8; greulich et al, Proc Natl Acad Sci U S2012; 109: 14476-81; and her-Sprie et al, Front Oncol 2013; 3:1-10. The HER2 mutant cancer may be, for example, HER2 mutant colorectal cancer, HER2 mutant bile duct cancer, HER2 mutant urothelial cancer, HER2 mutant bladder cancer, HER2 mutant salivary gland cancer, or HER2 mutant lung cancer.
As used herein, "antineoplastic agent" refers to a drug used to treat cancer. Non-limiting examples of antineoplastic agents herein 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 inhibitory antibodies, cytotoxic agents, antibodies that induce apoptosis, COX inhibitors, farnesyl transferase inhibitors, antibodies that bind oncofetal protein CA125, HER2 vaccine, Raf or ras inhibitors, doxorubicin liposomes, topotecan, taxanes (taxene, taxanes), dual tyrosine kinase inhibitors, TLK286, EMD-7200, pertuzumab, trastuzumab, erlotinib (erlotinib), and bevacizumab (bevacizumab).
"epitope 2C 4" is the region in the extracellular domain of HER2 to which antibody 2C4 binds. To screen for Antibodies that substantially bind the epitope of 2C4, a conventional cross-blocking assay can be performed, as described in Antibodies, A Laboratory Manual, Cold spring harbor Laboratory, Ed harbor, and David Lane (1988). Preferably, the antibody blocks binding of 2C4 to HER2 by about 50% or more. Alternatively, epitope mapping can be performed to assess whether an antibody substantially binds to the 2C4 epitope of HER 2. Epitope 2C4 contained residues from domain II in the extracellular domain of HER2 (SEQ ID NO: 2). 2C4 and pertuzumab bind the extracellular domain of HER2 at the junction of domains I, II and III (SEQ ID NOS: 1,2 and 3, respectively). Franklin et al Cancer Cell5: 317-.
"epitope 4D 5" refers to the region in the extracellular domain of HER2 to which antibody 4D5(ATCC CRL 10463) and trastuzumab bind. This epitope is close to the transmembrane domain of HER2 and within domain IV (SEQ ID NO:4) of HER 2. To screen for Antibodies that substantially bind the epitope of 4D5, a conventional cross-blocking assay can be performed, as described in Antibodies, A Laboratory Manual, Cold spring Harbor Laboratory, Ed Harbor, and David Lane (1988). Alternatively, epitope mapping can be performed to assess whether the antibody substantially 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 ECD; residue numbering includes signal peptide).
"treatment" refers to both therapeutic treatment and protective or prophylactic measures. Those in need of treatment include those already with cancer as well as those in which cancer is to be prevented. Thus, a patient to be treated herein may have been diagnosed as having cancer or may have a predisposition to or susceptibility to developing cancer.
The term "effective amount" refers to an amount of a drug effective to treat cancer in a patient. The effective amount of the drug can reduce the number of cancer cells; reducing the size of the tumor; inhibit (i.e., slow to some extent and preferably prevent) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably prevent) tumor metastasis; inhibit tumor growth to some extent; and/or to alleviate to some extent one or more symptoms associated with cancer. To the extent that the drug can prevent growth and/or kill existing cancer cells, it can be cytostatic and/or cytotoxic. An effective amount may prolong progression-free survival (e.g., as measured by response assessment criteria RECIST or CA-125 change for solid tumors), result in an objective response (including a partial response, PR or complete response, CR), increase overall survival time, and/or ameliorate one or more symptoms of cancer (e.g., as assessed by FOSI).
As used herein, the term "cytotoxic agent" refers to a substance that inhibits or prevents the function of a cell and/or causes destruction of a cell. The term is intended toIncluding radioactive isotopes (e.g. At)211，I131，I125，Y90，Re186，Re188，Sm153，Bi212，P32And radioactive isotopes of Lu), chemotherapeutic agents, and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof.
"chemotherapeutic agent" refers to a chemical compound useful for the treatment of cancer. Examples of chemotherapeutic agents used in chemotherapy include alkylating agents such as thiotepa and thiotepaCyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines (aziridines), such as benzotepa (benzodopa), carboquone (carboquone), metoclopramide (meteredopa) and uretepa (uredpa); ethyleneimines and methylmelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethlamelamine; TLK286 (TELCYTA)TM) (ii) a Annonaceous acetogenins (especially bullatacin and bullatacin); delta-9-tetrahydrocannabinol (dronabinol),) β -lapachone (lapachone), lapachol (lapachol), colchicines (colchicines), betulinic acid (betulinic acid), camptothecin (camptothecin) (including the synthetic analogue topotecan (topotecan)CPT-11 (irinotecan),) Acetyl camptothecin, scopolectin (scopolectin) and 9-aminocamptothecin); bryostatin; callystatin; CC-1065 (including its adozelesin (adozelesin), carvelesin (carzelesin) and bizelesin (bizelesin) synthetic analogs); podophyllotoxin (podophylotoxin); podophyllinic acid (podophyllic acid); teniposide (teniposide); cryptophycins (especially cryptophycins 1 and 8); dolastatin (dolastatin); duocarmycins (including synthetic analogs, KW-2189 and CB1-TM 1); eiscosahol (eleutherobin); pancratistatin; sarcodictyin; spongistatin (spongistatin); nitrogen mustards (nitrogen mustards), such as chlorambucil (chlorambucil), chlorambucil (chlorenaphazine), cholorophosphamide (cholorophosphamide), estramustine (estramustine), ifosfamide (ifosfamide), mechlorethamine (mechlorethamine), mechlorethamine hydrochloride (mechlorethamine oxide hydrochloride), melphalan (melphalan), neomustard (novembichin), benzene mustard cholesterol (phenylesterine), prednimustine (prednimustine), trofosfamide (trofosfamide), uracil mustard (uracil mustard); nitrosoureas (nitrosureas) such as carmustine (carmustine), chlorouretocin (chlorozotocin), fotemustine (fotemustine), lomustine (lomustine), nimustine (nimustine) and ramustine (ranimustine); diphosphonates, such as clodronate (clodronate); antibiotics, such as enediynes (enediynes) antibiotics (e.g., calicheamicin, especially calicheamicin γ 1I and calicheamicin ω I1 (see, e.g., Agnew, Chem Intl. Ed. Engl.,33:183-186(1994)) and anthracyclines such as annamycin, AD 32, alcanubicin, daunorubicin (daunorubicin), doxorubicin (doxorubicin), dexrazoxane (dexrazoxane), DX-52-1, epirubicin (epirubicin), GPX-100, idarubicin (idarubicin), valrubicin (valrubicin), KRN5500, melanolide (menoglucil), anthracyclines (including dynein A, epothilone (esperamicin), neomycin (acidin), anthracyclin (xanthatin), chromanchromycin (chromancin), chromanchromycin (chromomycin), chromanchromycin (chromanchromycin), and related chromanchromycinAcids (azaserine), bleomycin (bleomycin), actinomycin C (cactinomycin), carbacidin, carminomycin (carminomycin), carcinomycin (carzinophilin), chromomycin (chromomycin), actinomycin D (dactinomycin), ditobicin (detonbicin), 6-diazepin-5-oxo-L-norleucine,doxorubicin (doxorubicin) (including morpholinodoxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolodoxorubicin, liposomal doxorubicin, and deoxydoxorubicin), esorubicin (esorubicin), marijumycin (marcelomycin), mitomycins (mitomycins) such as mitomycin C, mycophenolic acid (mycophenolic acid), norramycin (nogalamycin), olivomycin (olivomycin), pelomycin (polyplomycin), pofiomycin (potfiromycin), puromycin (puromycin), triiron doxorubicin (quelamycin), rodobicin (rodorubicin), streptonigrin (streptonigrogrin), streptozocin (streptozostacin), tubercidin (rubicin), and zotocin (zostazin); folic acid analogs such as dimethylfolic acid (denopterin), pteroyltriglutamic acid (pteropterin), and trimetrexate (trimetrexate); purine analogs such as fludarabine (fludarabine), 6-mercaptopurine (mercaptoprine), thiamiprine (thiamiprine), and thioguanine (thioguanine); pyrimidine analogs such as ancitabine (ancitabine), azacitidine (azacitidine), 6-azauridine, carmofur (carmofur), cytarabine (cytarabine), dideoxyuridine (dideoxyuridine), deoxyfluorouridine (doxifluridine), enocitabine (enocitabine), and floxuridine (floxuridine); androgens such as carotinone (calusterone), dromostanolone propionate, epitioandrostanol (epitiostanol), mepiquitane (mepiquitane), and testolactone (testolactone); anti-adrenal agents such as aminoglutethimide (aminoglutethimide), mitotane (mitotane), and trilostane (trilostane); folic acid supplements such as folinic acid (leucovorin); acetoglucurolactone (acegultone); antifolic antineoplastic agents such asLY231514 pemetrexed (pemetrexed), dihydrofolate reductase inhibitors such as methotrexate, antimetabolites such as 5-fluorouracil (5-FU) and prodrugs thereof such as UFT, S-1 and capecitabine, and thymidylate synthase inhibitors and glycinamide ribonucleotide formyl transferase inhibitors such as raltitrexed (TOMUDEX)RMTDX); inhibitors of dihydropyrimidine dehydrogenase such as eniluracil; an aldophosphamide glycoside (aldophosphamideglycoside); aminolevulinic acid (aminolevulinic acid); amsacrine (amsacrine); bestrabuucil; bisantrene; edatrexate (edatraxate); desphosphamide (defofamine); dimecorsine (demecolcine); diazaquinone (diaziqutone); elfornitine; ammonium etitanium acetate; an epothilone; etoglut (etoglucid); gallium nitrate; hydroxyurea (hydroxyurea); lentinan (lentinan); lonidamine (lonidainine); maytansinoids (maytansinoids), such as maytansine (maytansine) and ansamitocins (ansamitocins); mitoguazone (mitoguzone); mitoxantrone (mitoxantrone); mopidanol (mopidanmol); diamine nitracridine (nitrarine); pentostatin (pentostatin); methionine mustard (phenamett); pirarubicin (pirarubicin); losoxantrone (losoxantrone); 2-ethyl hydrazide (ethylhydrazide); procarbazine (procarbazine); PSK7 polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane (rizoxane); rhizomycin (rhizoxin); sisofilan (sizofiran); helical germanium (spirogermanium); tenuazonic acid (tenuazonic acid); triimine quinone (triaziquone); 2,2',2 "-trichlorotriethylamine; trichothecenes (trichothecenes), especially the T-2 toxin, verrucin (verrucin) A, bacillocin (roridin) A and snakes (anguidine); urethane (urethan); vindesine (vindesine)Dacarbazine (dacarbazine); mannitol mustard (mannomustine); dibromomannitol (mitobronitol); dibromodulcitol (mitolactol); pipobromane (pipobroman); a polycytidysine; cytarabine (arabine) ("Ara-C"); cyclophosphamide; thiotepa(thiotepa); taxanes (taxanes); chlorambucil (chlorenbucil); gemcitabine6-thioguanine (thioguanine); mercaptopurine (mercaptoprine); platinum; platinum analogs or platinum-based analogs such as cisplatin (cissplatin), oxaliplatin (oxaliplatin) and carboplatin (carboplatin); vinblastine (vinblastine)Etoposide (VP-16); ifosfamide (ifosfamide); mitoxantrone (mitoxantrone); vincristine (vincristine)Vinca alkaloids (vinca alkaloids); vinorelbine (vinorelbine)Oncostatin (novantrone); edatrexate (edatrexate); daunomycin (daunomycin); aminopterin (aminopterin); (xiloda); ibandronate (ibandronate); topoisomerase inhibitor RFS 2000; difluoromethyl ornithine (DMFO); tretinoin (retinoids), such as tretinoin (retinoic acid); and pharmaceutically acceptable salts, acids or derivatives of any of the foregoing; and combinations of two or more of the above, such as CHOP (abbreviation for cyclophosphamide, doxorubicin, vincristine and prednisolone combination therapy) and FOLFOX (oxaliplatin)TM) Abbreviation for treatment regimen combining 5-FU and folinic acid).
Also included within this definition are anti-hormonal agents such as antiestrogens and Selective Estrogen Receptor Modulators (SERMs) which act to modulate or inhibit the action of hormones on tumors, including, for example, tamoxifen (including tamoxifen)Tamoxifen), raloxifene (raloxifene), droloxifene (droloxifene), 4-hydroxytamoxifene, troxifene (tefluxifen)rioxifene), naloxifene (keoxifene), LY117018, onapristone (onapristone), andtoremifene (toremifene), aromatase inhibitors, and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, goserelin and goserelin, and troxacitabine (1, 3-dioxolane nucleoside cytosine analogues), antisense oligonucleotides, in particular those which inhibit gene expression in signalling pathways involving abnormal cell proliferation, such as for example PKC- α, Raf, H-Ras and epidermal growth factor receptor (EGF-R), vaccines, such as gene therapy vaccines, for example EGF-RA vaccine is provided which comprises a vaccine,a vaccine anda vaccine;rIL-2；a topoisomerase 1 inhibitor;rmRH; and pharmaceutically acceptable salts, acids or derivatives of any of the foregoing.
A "taxane" is a chemotherapy that inhibits mitosis and interferes with microtubules. Examples of taxanes include paclitaxel (A)Bristol-Myers Squibb Oncology, Princeton, N.J.); albumin engineering without CremophorIn the form of nanoparticles of paclitaxel or nab-paclitaxel (ABRAXANE)TM(ii) a American Pharmaceutical Partners, Schaumberg, Illinois); and docetaxel (c)Rorer,Antony,France)。
An "anthracycline" is an antibiotic type derived from the fungus Streptococcus peucetius, examples of which include: daunorubicin, doxorubicin, epirubicin, and any other anthracycline chemotherapeutic agent, including those listed previously.
"anthracycline-based chemotherapy" refers to a chemotherapy regimen consisting of or comprising one or more anthracycline antibiotics. Examples include, but are not limited to, 5-FU, epirubicin, and cyclophosphamide (FEC); 5-FU, doxorubicin and cyclophosphamide (FAC); doxorubicin and cyclophosphamide (AC); epirubicin and Cyclophosphamide (EC); dose-intensive doxorubicin and cyclophosphamide (ddAC), among others.
For purposes herein, "carboplatin-based chemotherapy" refers to a chemotherapeutic regimen consisting of or comprising one or more carboplatin. An example is TCH (docetaxel-Carboplatin and trastuzumab-)。
"aromatase inhibitors" inhibit aromatase, which regulates estrogen production in the adrenal gland. Examples of aromatase inhibitors include: 4(5) -imidazole, aminoglutethimide,megestrol acetate (megestrol),exemestane (exemestane), cresol amphetamine (formastanie), fadrozole (fad)rozole)，The compound is vorozole (vorozole),letrozole (letrozole) andanastrozole (anastrozole). In one embodiment, the aromatase inhibitor described herein is letrozole or anastrozole.
"antimetabolite chemotherapy" is the use of agents that are structurally similar to metabolites but are not available to the body in a productive manner. Many antimetabolite chemotherapies interfere with the production of nucleic acids, RNA and DNA. Examples of antimetabolite chemotherapeutic agents include gemcitabine (gemcitabine)5-Fluorouracil (5-FU), capecitabine (Xeloda)TM) 6-mercaptopurine, methotrexate (methotrexate), 6-thioguanine, pemetrexed (pemetrexed), raltitrexed (raltitrexed), cytarabine (arabinylcytosine ARA-C cytarabine)Dacarbazine (dacarbazine)Azacytosine (azocytosine), deoxycytidine (deoxycytosine), pyridmidine, fludarabine (fludarabine)Cladribine (cladribine), 2-deoxy-D-glucose and the like.
"chemotherapy-resistant" cancer refers to a cancer patient that has progressed while receiving a chemotherapy regimen (i.e., the patient is "chemotherapy refractory"), or the patient has progressed within 12 months (e.g., within 6 months) after completion of the chemotherapy regimen.
The term "platinum" as used herein refers to platinum-based chemotherapies, including, but not limited to, cisplatin, carboplatin, and oxaliplatin.
The term "fluoropyrimidine" as used herein refers to an antimetabolite chemotherapy including, but not limited to, capecitabine, floxuridine, and fluorouracil (5-FU).
Herein, a "fixed" (fixed) or "constant" (flat) dose of a chemotherapeutic agent refers to a dose that is administered to a human patient without regard to the patient's body Weight (WT) or Body Surface Area (BSA). Thus, a fixed or constant dose is not intended as a mg/kg dose or mg/m2The dosage is provided, but rather is provided as an absolute amount of the therapeutic agent.
A "loading" dose herein generally includes an initial dose of a therapeutic agent administered to a patient, followed by one or more maintenance doses thereof. Generally, a single loading dose is administered, but multiple loading doses are also contemplated herein. Typically, the amount of loading dose administered exceeds the amount of maintenance dose administered, and/or the loading dose is administered more frequently than the maintenance dose, thereby achieving the desired steady state concentration of the therapeutic agent earlier than if the maintenance dose was used.
A "maintenance" (maintenance) dose refers herein to one or more doses of a therapeutic agent administered to a patient during treatment. Typically, the maintenance dose is administered at a therapeutic interval, for example, about once every week, about once every two weeks, about once every three weeks, or about once every four weeks, preferably once every three weeks.
"infusion" refers to the introduction of a drug-containing solution into the body through a blood vessel for therapeutic purposes. Typically, this is achieved via an Intravenous (IV) bag.
An "intravenous bag" or "IV bag" is a bag capable of holding a solution that can be administered intravenously to a patient. 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 from a polyolefin or polyvinyl chloride.
A "vial" is a container suitable for holding a liquid or lyophilized preparation. In one embodiment, the vial is a disposable vial, such as a 20-cc disposable vial with a stopper.
A "package insert" is a printed leaflet that must be placed within the package for each prescribed medication as commanded by the food and drug administration or other regulatory agency. The leaflet prints generally contain the trademark, common name, and mechanism of action of the drug; indications of indications, contraindications, warnings, prophylaxis, adverse effects and dosage forms; but also instructions for recommended dosages, times and routes of administration.
The expression "safety data" relates to data obtained in controlled clinical trials showing the prevalence and severity of adverse events to guide the user in terms of drug safety, including guidance on how to monitor and prevent adverse reactions to drugs. Table 3 and table 4 herein provide safety data for pertuzumab. Safety data includes any one or more (e.g., two, three, four or more) of the most common Adverse Events (AEs) or adverse reactions (ADRs) in tables 3 and 4. For example, the safety data comprises information about neutropenia, febrile neutropenia, diarrhea and/or cardiotoxicity as disclosed herein.
"efficacy data" refers to data obtained in controlled clinical trials that show that a drug is effective in treating a disease, such as cancer.
By "stable mixture" when referring to a mixture of two or more drugs, such as pertuzumab and trastuzumab, is meant that each drug in the mixture substantially retains its physical and chemical stability in the mixture, as assessed by one or more analytical assays. Exemplary analytical assays for this purpose include: color, appearance and clarity (CAC), concentration and turbidity analysis, particle analysis, Size Exclusion Chromatography (SEC), Ion Exchange Chromatography (IEC), Capillary Zone Electrophoresis (CZE), imaging capillary isoelectric focusing (iCIEF) and potency assays. In one embodiment, the mixture has been shown to be stable at 5 ℃ or 30 ℃ for up to 24 hours.
"combined" administration encompasses both combined administration and separate administration, in which case administration of one therapeutic agent may occur prior to, concurrently with, and/or after administration of the other therapeutic agent. As such, combined administration of pertuzumab and trastuzumab (or combined administration of pertuzumab and trastuzumab) encompasses combined administration and separate administration of either order.
A drug that is administered "concurrently" with one or more other drugs is administered during the same treatment cycle, on the same day as the one or more other drugs are treated, and optionally, at the same time as the one or more other drugs. For example, for cancer therapy given every 3 weeks, concurrently administered drugs are each administered on day 1 of a 3-week cycle.
Antibodies and chemotherapeutic compositions
The HER2 antigen to be used for the production of antibodies may be, for example, the HER2 receptor extracellular domain in soluble form or a portion thereof, which contains the desired epitope. Alternatively, cells expressing HER2 at their cell surface (e.g., NIH-3T3 cells transformed to overexpress HER 2; or cancer cell lines such as SK-BR-3 cells, see Stancovski et al, PNAS (USA)88:8691-8695(1991)) can be used to generate antibodies. Other forms of HER2 receptor that can be used to generate antibodies will be apparent to those skilled in the art.
There are a variety of methods in the art for making monoclonal antibodies herein. For example, monoclonal antibodies can be prepared by recombinant DNA methods (U.S. Pat. No.4,816,567) using the hybridoma method first described by Kohler et al, Nature,256:495 (1975).
The anti-HER 2 antibodies trastuzumab and pertuzumab used in accordance with the invention are commercially available.
(i) Humanized antibodies
Methods for humanizing non-human antibodies have been described in the art. Preferably, the humanized antibody has one or more amino acid residues introduced from a non-human source. These non-human amino acid residues are often referred to as "import" residues, which are typically taken from an "import" variable domain. Humanization can be performed essentially following the method of Winter and co-workers (Jones et al, Nature 321:522-525 (1986); Riechmann et al, Nature 332:323-327 (1988); Verhoeyen et al, Science 239:1534-1536(1988)), by replacing the corresponding sequences of a human antibody with hypervariable region sequences. Thus, such "humanized" antibodies are chimeric antibodies (U.S. Pat. No.4,816,567) in which substantially less than the entire human variable domain is replaced with the corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some hypervariable region residues and possibly some FR residues are replaced by residues from analogous sites in rodent antibodies.
The choice of human variable domains, both light and heavy, used to construct humanized antibodies is important for reducing antigenicity. The entire library of known human variable domain sequences is screened with the variable domain sequences of rodent antibodies according to the so-called "best-fit" method. The human sequence closest to the rodent sequence is then selected as the human Framework Region (FR) of the humanized antibody (Sims et al, J.Immunol.151:2296 (1993); Chothia et al, J.mol.biol.196:901 (1987)). Another approach uses specific framework regions derived from the consensus sequence of all human antibodies of a specific subgroup of light or heavy chains. The same framework can be used for several different humanized antibodies (Carter et al, Proc. Natl. Acad. Sci. USA 89:4285 (1992); Presta et al, J. Immunol.151:2623 (1993)).
More importantly, the antibodies retain high affinity for the antigen and other favorable biological properties after humanization. To achieve this goal, according to a preferred method, humanized antibodies are prepared by a method of analyzing the parental sequences and various conceptual humanized products using three-dimensional models of the parental and humanized sequences. Three-dimensional immunoglobulin models are widely available and familiar to those skilled in the art. Computer programs are available that illustrate and display the likely three-dimensional conformational structures of selected candidate immunoglobulin sequences. Examination of these display images allows analysis of the likely role of the residues in the functioning of the candidate immunoglobulin sequence, i.e., the analysis of residues that affect the ability of the candidate immunoglobulin to bind its antigen. In this way, FR residues can be selected from the recipient and import sequences and combined to obtain desired antibody characteristics, such as increased affinity for the target antigen. In general, hypervariable region residues are directly and most substantially involved in the effect on antigen binding.
U.S. patent No.6,949,245 describes the generation of an exemplary humanized HER2 antibody that binds to HER2 and blocks ligand activation of HER receptor.
Humanized HER2 antibodies specifically include trastuzumab as described in table 3 and defined herein of U.S. patent 5,821,337 (herein expressly incorporated by reference); and a humanized 2C4 antibody such as pertuzumab as described and defined herein.
The humanized antibodies herein may, for example, comprise non-human hypervariable region residues which incorporate a human variable domain and may further comprise Framework Region (FR) substitutions at positions selected from the group consisting of: 69H, 71H and 73H using the variable domain numbering system set forth in Kabat et al, sequences of Proteins of Immunological Interest,5th Ed. public Health Service, national institutes of Health, Bethesda, MD (1991). In one embodiment, the humanized antibody comprises FR substitutions at two or all of positions 69H, 71H and 73H.
Exemplary humanized antibodies of interest herein comprise the variable heavy domain complementarity determining residues GFTFTDYTMX (SEQ ID NO:17), wherein X is preferably D or S; DVNPNSGGSIYNQRFKG (SEQ ID NO: 18); and/or NLGPSFYFDY (SEQ ID NO:19), optionally comprising amino acid modifications of those CDR residues, e.g., wherein the modifications substantially maintain or improve the affinity of the antibody. For example, antibody variants for use in the methods of the invention may have from about 1 to about 7 or about 5 amino acid substitutions in the variable heavy CDR sequences described above. Such antibody variants can be prepared by affinity maturation, e.g., as described below.
For example, in addition to those variable heavy domain CDR residues in the previous paragraph, the humanized antibody may further comprise variable light domain complementarity determining residue KASQDVSIGVA (SEQ ID NO: 20); SASYX1X2X3Wherein X is1Preferably R or L, X2Preferably Y or E, and X3Preferably T or S (SEQ ID NO: 21); and/or QQYYIYPYT (SEQ ID NO: 22). Such humanized antibodies optionally comprise amino acid modifications of the CDR residues described above, e.g., wherein the modifications substantially maintain or improve the affinity of the antibody. For example, an antibody variant of interest may have from about 1 to about 7 or about 5 amino acid substitutions in the variable light CDR sequences described above. Such antibody variants can be prepared by affinity maturation, e.g., as described below.
Affinity matured antibodies that bind HER2 are also encompassed by the present application. The parent antibody may be a human or humanized antibody, for example an antibody comprising light and/or heavy chain variable region sequences of SEQ ID NOs: 7 and 8, respectively (i.e., VL and/or VH comprising pertuzumab). Affinity matured variants of pertuzumab preferably bind HER2 receptor with a better affinity than murine 2C4 or pertuzumab (e.g., an increase in affinity of about 2-fold or about 4-fold to about 100-fold or about 1000-fold as assessed using HER2 extracellular domain (ECD) ELISA, for example). Exemplary heavy chain variable region CDR residues for substitution include H28, H30, H34, H35, H64, H96, H99, or a combination of two or more (e.g., 2, 3, 4,5, 6, or 7 of these residues). Examples of CDR residues for the light chain variable region that are altered include L28, L50, L53, L56, L91, L92, L93, L94, L96, L97, or a combination of two or more (e.g., 2 to 3, 4,5, or up to about 10 of these residues).
The murine 4D5 antibody was humanized to generate humanized variants thereof, including trastuzumab, as described in U.S. Pat. Nos. 5,821,337, 6,054,297, 6,407,213, 6,639,055, 6,719,971 and 6,800,738 and Carter et al PNAS (USA),89: 4285-. HuMAb4D5-8 (trastuzumab) binds HER2 antigen 3-fold more tightly than the mouse 4D5 antibody and has the ability to bind to HER 3-fold more tightlySecondary immune function (ADCC) permitting the directed cytotoxic activity of the humanized antibody in the presence of human effector cells. HuMAb4D5-8 comprises incorporation VLVariable lightness of kappa subgroup I consensus framework (V)L) CDR residues, and incorporation of VHVariable weight (V) of subgroup III consensus frameworkH) CDR residues. The antibody further comprises Framework Region (FR) substitutions at the following positions: vH71, 73, 78 and 93 (Kabat numbering of FR residues); and at VLThe FR substitution at position 66 (Kabat numbering of FR residues). Trastuzumab comprises a non-a allotype human gamma 1Fc region.
Various forms of humanized or affinity matured antibodies are contemplated. For example, a humanized antibody or affinity matured antibody may be an antibody fragment. Alternatively, the humanized antibody or affinity matured antibody may be an intact antibody, such as an intact IgG1 antibody.
(ii) Pertuzumab composition
In one embodiment of the HER2 antibody composition, the composition comprises a mixture of the main species pertuzumab antibody and one or more variants thereof. Preferred embodiments of the primary antibody species of pertuzumab herein are antibodies comprising the light and heavy chain variable domain amino acid sequences of SEQ ID nos. 5 and 6, most preferably the light chain amino acid sequence of SEQ ID No.11 and the heavy chain amino acid sequence of SEQ ID No.12 (including deamidated and/or oxidized variants of those sequences). In one embodiment, the composition comprises a mixture of the main species pertuzumab antibody and an amino acid sequence variant thereof comprising an amino-terminal leader extension. Preferably, the amino-terminal leader extension is located on a light chain of the antibody variant (e.g., on one or both light chains of the antibody variant). The main species HER2 antibody or antibody variant may be a full-length antibody or antibody fragment (e.g. Fab or F (ab')2Fragments), but preferably both are full length antibodies. The antibody variants herein may comprise an amino-terminal leader extension on any one or more of its heavy or light chains. Preferably, the amino-terminal leader extension is located on one or both light chains of the antibody. Said amino groupThe terminal leader extension preferably comprises or consists of VHS-. The presence of the amino-terminal leader extension in the composition can be detected by a variety of analytical techniques, including, but not limited to, N-terminal sequence analysis, determination of charge heterogeneity (e.g., cation exchange chromatography or capillary zone electrophoresis), mass spectrometry, and the like. The amount of antibody variant in the composition is generally in the range from an amount that constitutes the detection limit of any assay (preferably N-terminal sequence analysis) used to detect the variant to an amount that is at least the amount of the main species of antibody. Typically, about 20% or less (e.g., from about 1% to about 15%, e.g., from 5% to about 15%) of the antibody molecules in the composition comprise the amino-terminal leader extension. Such percentage amounts are preferably determined using quantitative N-terminal sequence analysis or cation exchange analysis (preferably using a high resolution, weak cation exchange column such as PROPACWCX-10)TMCation exchange column). In addition to amino-terminal leader extension variants, amino acid sequence alterations of the main class of antibodies and/or variants are also contemplated, including but not limited to antibodies comprising a C-terminal lysine residue on one or both of their heavy chains, deamidated antibody variants, and the like.
In addition, the main species antibody or variant may also comprise glycosylation variations, non-limiting examples of which include antibodies comprising a G1 or G2 oligosaccharide structure attached to its Fc region, antibodies comprising carbohydrate moieties attached to its light chain (e.g., one or two carbohydrate moieties, such as glucose or galactose, attached to one or both light chains of the antibody, e.g., attached to one or more lysine residues), antibodies comprising one or two non-glycosylated heavy chains, or antibodies comprising sialylated oligosaccharides attached to one or both heavy chains thereof, and the like.
The composition may be recovered from a genetically engineered cell line expressing the HER2 antibody, such as a Chinese Hamster Ovary (CHO) cell line, or may be prepared by peptide synthesis.
For more information on exemplary pertuzumab compositions, see U.S. patent nos. 7,560,111 and 7,879,325 and US 2009/0202546a 1.
(iii) Trastuzumab composition
Trastuzumab compositions typically comprise a mixture of the major species of antibody (comprising the light and heavy chain sequences of SEQ ID NOs 13 and 14, respectively) and variant forms thereof, particularly acidic variants, including deamidated variants. Preferably, the amount of such acidic variants in the composition is less than about 25%, or less than about 20%, or less than about 15%. See U.S. patent No.6,339,142. See also Harris et al, J.chromatography, B752: 233-245(2001), which relates to a trastuzumab form that can be resolved by cation exchange chromatography, including peak A (deamidation of Asn30 to Asp in both light chains); peak B (deamidation of Asn55 to isoasp in one heavy chain); peak 1(Asn30 deamidation to Asp in one light chain); peak 2(Asn30 deamidated to Asp in one light chain and Asp102 isomerized to iso Asp in one heavy chain); peak 3 (major peak form, or major species antibody); peak 4(Asp102 isomerizes to iso-Asp in one heavy chain); and peak C (Asp102 succinimide (Asu) in one heavy chain). Such variant forms and compositions are encompassed by the invention herein.
Selecting patients for therapy
HER2 expression or amplification assays can be used to select patients for treatment according to the invention. There are several FDA-approved commercial assays for identifying cancer patients that are HER2 positive, HER2 expressive, HER2 overexpressing or HER2 amplified. These methods comprise(Dako) andHER2 (immunohistochemistry (IHC) assay) and PathAnd HER2 FISHHpharmdxTM(FISH assay). The user should refer to information about the validation and performance of each assay in the package insert for the particular assay kit.
For example, HER2 expression or overexpression mayBy IHC analysis, e.g. using(Dako). Paraffin-embedded tissue sections from tumor biopsies can be subjected to IHC assays against the HER2 protein staining intensity criteria as follows:
score 0: no staining was observed or membrane staining was observed in less than 10% of the tumor cells.
Score 1 +: faint/barely detectable membrane staining was detected in more than 10% of tumor cells. The cells have staining in only a portion of their membranes.
And the score is 2 +: weak to moderate complete membrane staining was observed in more than 10% of tumor cells.
Score 3 +: moderate to intense complete membrane staining was observed in more than 10% of tumor cells.
Those tumors with an HER2 overexpression assessment score of 0 or 1+ may be characterized as HER2 negative, while those with a score of 2+ or 3+ may be characterized as HER2 positive.
HER2 overexpressing tumors can be ranked according to an immunohistochemical score corresponding to the number of copies of HER2 molecule expressed per cell, and can be biochemically determined:
0-10,000 copies/cell,
1+ ═ at least about 200,000 copies per cell,
2+ at least about 500,000 copies/cell,
at least about 2,000,000 copies per cell.
Overexpression of HER2 at 3+ levels that leads to ligand-independent activation of tyrosine kinases (Hudziak et al, Proc. Natl. Acad. Sci. USA 84:7159-7163(1987)) occurs in approximately 30% of breast cancers and in these patients, relapse-free survival and overall decreased survival (Slamon et al, Science244:707-712 (1989); Slamon et al, Science 235:177-182 (1987)).
The presence of overexpression of the HER2 protein is highly correlated with gene amplification, and therefore, alternatively/additionally, assays for detecting gene amplification using In Situ Hybridization (ISH), such as Fluorescence In Situ Hybridization (FISH), can also be used to select patients suitable for treatment according to the present invention. FISH assays such as INFORM can be performed on formalin-fixed, paraffin-embedded tumor tissueTM(sold by Ventana, Arizona) or Path(Vysis, Illinois) to determine the extent, if any, of HER2 amplification in tumors.
Most commonly, HER2 positive status was confirmed using archival paraffin-embedded tumor tissue using any of the aforementioned methods.
Preferably, HER2 positive patients with IHC scores of 2+ or 3+ and/or FISH or ISH positivity are selected for treatment according to the invention. Patients with an IHC score of 3+ and FISH/ISH positivity are particularly suitable for treatment according to the invention.
HER2 mutations have also been identified that are associated with responsiveness to HER 2-directed therapy. Such mutations include, but are not limited to, insertions in exon 20 of HER2, deletions around amino acid residues 755-759 of HER2, any of the mutations G309A, G309E, S310F, D769H, D769Y, V777L, P780-Y781insGSP, V842I, R896C (Bose et al, cancer Discov 2013; 3:1-14), and the same non-synonymous putative activation mutation (or insertion deletion) previously reported in the COSMIC database found in two or more unique specimens.
See also U.S. patent No.7,981,418 for additional assays to screen patients for pertuzumab therapy, and examples.
Pharmaceutical formulations
Therapeutic formulations of the HER2 antibody for use according to the invention are prepared for storage by combining the antibody of the desired purity with an optional pharmaceutically acceptable carrierIn particular, excipients or stabilizers (Remington's pharmaceutical Sciences 16th edition, Osol, a.ed. (1980)), typically in lyophilized form or in aqueous solution. Antibody crystals are also contemplated (see U.S. patent application 2002/0136719). Acceptable carriers, excipients, or 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 (such as octadecyl dimethyl benzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butanol 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) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or nonionic surfactants such as TWEENTM，PLURONICSTMOr polyethylene glycol (PEG). Lyophilized antibody dosage forms are described in WO 97/04801, which is expressly incorporated herein by reference.
Lyophilized antibody dosage forms are described in U.S. Pat. Nos. 6,267,958, 6,685,940 and 6,821,515, which are expressly incorporated herein by reference. It is preferable that(trastuzumab) formulation is a sterile, white to pale yellow preservative-free lyophilized powder for Intravenous (IV) administration comprising 440mg trastuzumab, 400mg α -trehalose dehydrate, 9.9mg L-histidine-HCl, 6.4mg L-histidine and 1.8mg polysorbate 20, usp. with 1.1% benzyl alcohol as a repellentReconstitution of 20mL bacteriostatic water for injection (BWFI) of the preservative to give a multi-dose solution containing 21mg/mL trastuzumab at a pH of about 6.0. See trastuzumab prescription information for more details.
A preferred pertuzumab formulation for therapeutic use comprises 20mM histidine acetate, 120mM sucrose, 0.02% polysorbate 20, 30mg/mL pertuzumab at pH 6.0. An alternative pertuzumab formulation comprises 25mg/mL pertuzumab, 10mM histidine-HCl buffer, 240mM sucrose, 0.02% polysorbate 20, pH 6.0.
The placebo formulation used in the clinical trial described in the examples is equivalent to pertuzumab without active agent.
The formulations herein may also contain more than one active compound necessary for the particular indication to be treated, preferably those active ingredients having complementary activities that do not adversely affect each other. Various drugs that can be combined with HER dimerization inhibitors are described in the methods section below. Such molecules are suitably present in combination in an amount effective for the intended purpose.
Formulations for in vivo administration must be sterile. This can be readily achieved by filtration through sterile filtration membranes.
Methods of treatment
In accordance with the present invention, pertuzumab and trastuzumab are administered in accordance with the applicable prescription information.
Pertuzumab is typically administered by intravenous infusion every three weeks, beginning with 840mg of the first 60 minutes of infusion followed by 420mg of the second and any subsequent 30 to 60 minutes of intravenous infusion. Additional details of suitable administration schedules are given in the pertuzumab prescribing information and in the examples.
Trastuzumab is typically administered by intravenous infusion every three weeks, starting with a loading dose of 8mg/kg for the first 90 minutes, followed by a maintenance dose of 6mg/kg for the second and any subsequent 30 to 60 minutes by intravenous infusion. Further details of suitable administration schedules are given in the trastuzumab prescribing information and in the examples.
Pertuzumab and trastuzumab can be administered in either order during the same visit.
VI. product
In another embodiment of the invention, an article is provided that contains a material useful for treating colorectal, biliary, urothelial, bladder, salivary gland, or lung cancer. The article of manufacture comprises a vial containing a fixed dose of pertuzumab, wherein the fixed dose is about 420mg, about 525mg, about 840mg, or about 1050mg of pertuzumab, such as 420mg or 840mg of pertuzumab. The article preferably further comprises a package insert. The package insert can provide instructions for administering the fixed dose to a patient having HER2 positive, HER2 amplified, or HER2 mutation in colorectal, biliary, urothelial, bladder, salivary gland, or lung cancer, in combination with trastuzumab, as described and claimed herein. In a certain embodiment, the package insert provides instructions for treating colorectal cancer, bile duct cancer, urothelial cancer, bladder cancer, salivary gland cancer, or lung cancer, such as advanced (locally advanced or metastatic) and/or treatment-resistant colorectal, bile duct, urothelium, bladder, salivary glands, or lung cancer.
In one embodiment, the article of manufacture comprises two vials, wherein the first vial contains a fixed dose of about 840mg of pertuzumab, and the second vial contains a fixed dose of about 420mg of pertuzumab.
In another embodiment, the article of manufacture comprises two vials, wherein the first vial contains a fixed dose of about 1050mg of pertuzumab, and the second vial contains a fixed dose of about 525mg of pertuzumab.
One embodiment of the article of manufacture herein comprises an Intravenous (IV) bag containing a stable mixture of pertuzumab and trastuzumab suitable for administration to a cancer patient. Optionally, the mixture is a saline solution; for example, about 0.9% NaCl or about 0.45% NaCl. An exemplary IV bag is a polyolefin or polyvinyl chloride infusion bag, such as a 250mL IV bag. According to one embodiment of the invention, the mixture comprises about 420mg or about 840mg of pertuzumab, and about 200mg to about 1000mg of trastuzumab (e.g., about 400mg to about 900mg of trastuzumab).
Optionally, the mixture in the IV bag is stable at 5 ℃ or 30 ℃ for up to 24 hours. The stability of the mixture can be assessed by one or more assays selected from the group consisting of: color, appearance and clarity (CAC), concentration and turbidity analysis, particle analysis, Size Exclusion Chromatography (SEC), Ion Exchange Chromatography (IEC), Capillary Zone Electrophoresis (CZE), imaging capillary isoelectric focusing (iCIEF) and potency assays.
In another embodiment, the article of manufacture comprises a single dose vial containing about 420mg of pertuzumab.
Preservation of biological Material
The following hybridoma cell lines have been deposited with the American type culture Collection, 10801 Universal boulevard, Manassas, VA 20110-:
TABLE 1
Table of sequences
Description of the invention SEQ ID NO Drawing (A)
HER2 Domain I 1 1
Domain II of HER2 2 1
HER2 Domain III 3 1
HER2 Domain IV 4 1
2C4 variable light weight 5 2A
2C4 variable weight 6 2B
574/pertuzumab alleviality 7 2A
574/variable weights of pertuzumab 8 2B
Human VLCommon frame 9 2A
Human VHCommon frame 10 2B
Pertuzumab light chain 11 3A
Pertuzumab heavy chain 12 3B
Trastuzumab light chain 13 4A
Trastuzumab heavy chain 14 4B
Variant pertuzumab light chain 15 5A
Variant pertuzumab heavy chain 16 5B
GFTFTDYTMX 17
DVNPNSGGSIYNQRFKG 18
NLGPSFYFDY 19
KASQDVSIGVA 20
SASYX1X2X3 21
QQYYIYPYT 22
Further details of the invention are exemplified by the following non-limiting examples. The disclosures of all references in this specification are expressly incorporated herein by reference.
A list of abbreviations and definitions for terms used throughout the specification (including the examples) is provided in the following table.
List of abbreviations and definitions of terms
Example 1
Evaluation of trastuzumab plus pertuzumab for phase IIa clinical study in patients with cancer characterized by HER2 overexpression, amplification, or HER2 activating mutation
This is a multicenter, non-randomized, open label phase IIa study performed in the United states (MyPathway study; ML 28897; NCT 2091141). Four different treatment regimens will be evaluated simultaneously in groups of patients with advanced solid tumors that progress after administration of standard-of-care treatments, or in the absence of standard therapy, or with therapy that would bring clinical benefit and/or is not a suitable option according to the judgment of the attending physician, and the available treatment options that are considered optimal by trials of targeted therapy. The management of patients with solid tumors characterized by overexpression, amplification, or HER2 activating mutations of HER2 is one of the therapeutic regimens studied. The study protocol for this clinical trial is shown in figure 6.
Target
Main object of
The primary goal of this study was to assess efficacy (as measured by the overall response assessed by the investigator) in patients with advanced solid tumors and 1) with molecular alterations (mutations, gene expression abnormalities) that predicted a response to one of these agents, 2) indications that did not have prior approval for the use of these agents, 3) unsuited for the Roche/Genentech initiated aggressive, cumulative intervention trials, and 4) patients who would not have available a therapy of clinical benefit and/or would not be a suitable option at the discretion of the attending physician.
Secondary target
Secondary objectives of this study were as follows:
to evaluate the safety and tolerability of study medication to the tumor type studied
To collect and store molecular profiling data for all patients processed in this study, the aim was to correlate treatment response with the pattern of tumor genetic abnormalities
Exploratory biomarker targets
The exploratory biomarker targets for this study were as follows:
to assess the association of the level and nature and response of somatic tumor-specific mutations identified by blood-based Next Generation Sequencing (NGS) to a study medication (i.e., predictive biomarker), progression to a more severe disease state (i.e., prognostic biomarker), acquired resistance to a study medication, evidence of activity of a study medication, and a standard measure of efficacy.
To assess the correlation of the level and nature of somatic tumor-specific mutations identified by blood-based NGS to better understand disease progression.
Design of research
Inclusion criteria
For study entry, patients must meet the following criteria:
being able to understand the nature of the test and to provide informed consent
Age ≥ 18 years
Willingness and ability to comply with research and follow-up procedures
Life expectancy of 12 weeks or more
Metastatic cancer (solid tumors, excluding hematological malignancies) is histologically documented
Results from molecular testing in a Clinical Laboratory Improvement Amendments (CLIA) -certified laboratory show that tumor tissue exhibits at least one of the following abnormalities:
HER2 overexpression, amplification, or HER2 activating mutation
The results of the molecular test for patient eligibility must be obtained from the most recent tumor biopsy. (Note: No new biopsy is required.)
Patients received standard first line therapy for metastatic cancer (except for tumors where no first line therapy exists) and trials of targeted therapy were considered the best available treatment option. Eligible patients should not have available therapies that would bring clinical benefit and/or are not suitable options according to the judgment of the attending physician.
Treatment with study drugs that have not previously been specifically assigned or any other drug that shares the same target
Progressive cancer at study entry
Measurable or evaluable disease by the 1.1 edition of the solid tumor response assessment criteria (RECIST v1.1)
Eastern cooperative oncology group performance status (ECOG PS) score 0,1, or 2
Adequate hematological function, defined as:
absolute neutrophil count of not less than 1000/μ L
Hemoglobin > 8g/dL (which can be achieved with erythropoietin agents or blood transfusions)
Platelet not less than 75,000/mu L
Adequate renal and hepatic function, defined as:
alanine aminotransferase and aspartate aminotransferase < 2.5 times the Upper Limit of Normal (ULN) (< 5 times ULN if considered due to primary or metastatic liver involvement)
Total bilirubin less than or equal to 1.5 × ULN
Alkaline phosphatase <2 × ULN (< 5 × ULN, if considered to be due to a tumor)
Serum creatinine is less than or equal to 2.0mg/dL or creatinine clearance rate calculated by Cockcroft-Gault formula is more than or equal to 50mL/min
Women with fertility potential (including those with tubal ligation) must have a negative serum pregnancy test < 7 days before the initial trial treatment.
Female patients with fertility potential must agree to use an acceptable method of contraception.
Patients have solid tumors with HER2 overexpression, amplification, or HER2 activating mutations identified by laboratory-conducted assays certified at the Clinical Laboratory Improvement Amendments (CLIA).
Patients with breast, stomach, or gastroesophageal junction cancer must have HER 2-activating mutation.
Will receive tumors that are either HER2 positive as determined by protein overexpression using Immunohistochemistry (IHC), by gene amplification using in situ hybridization (FISH or CISH), or have mutations in the HER2 activating kinase domain identified by Next Generation Sequencing (NGS) or real time polymerase chain reaction (RT-PCR).
An assay using in situ hybridization (FISH or CISH) must indicate the presence of gene amplification of HER2/CEP17 ratio ≧ 2.0 or HER2 gene copy number > 6.0.
Assays using IHC must indicate a score of 3 +.
Assays using NGS or analysis by RT-PCR of genes with known or potential clinically relevant alterations must identify clinically active mutations (those with significant code disruptions leading to amino acid changes that are likely to be detrimental to protein function, including premature stop codons or early frameshift mutations in the coding region).
In the case of multiple assays performed, HER2 positive by any test methodology will qualify the patient as long as the fitness criteria are met.
Left Ventricular Ejection Fraction (LVEF) > 50% or above the lower limit of the normal range of the institution, whichever is lower.
Exclusion criteria
Patients meeting any of the following criteria will be excluded from study entry:
the patient has a hematological malignancy
Concurrent administration of any other anti-cancer therapy (except for male patients with prostate cancer who are receiving androgen blockade): bisphosphonates and denosumab (denosumab) were allowed.
Recent anticancer therapy of 28 days or less and not yet recovered from side effects, except for alopecia
Radiotherapy within 14 days
Active or untreated brain metastases
Patients with treated brain metastases are eligible if they have minimal neurological symptoms, evidence of stable disease (at least 1 month) or response on follow-up scans, and do not require corticosteroid therapy.
History of cancerous meningitis
Uncontrolled concurrent malignancy (early stages are tolerated if no active therapy or intervention is required)
Lactating women
Any of the following cardiovascular events within 6 months prior to study entry: myocardial infarction, malignant hypertension, severe/unstable angina, symptomatic congestive heart failure, cerebrovascular accident, or transient ischemic attack
Pulmonary embolism within 30 days before study entry
Clinically significant history or Presence of > grade 2 ventricular or atrial arrhythmias (national cancer institute, 4.0 edition of the general term for adverse events Standard [ NCI CTCAE v4.0])
Patients with chronic, rate-controlled atrial arrhythmias are eligible without other cardiac abnormalities.
Any other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or that may interfere with interpretation of study results
Psychological, household, social, or geographic conditions not allowing adherence to the protocol
Eligible for another Roche/Genentech initiated aggressive cumulative interventional clinical trial
Breast, stomach, or gastroesophageal junction cancer identified by HER2 amplification or overexpression
Prior treatment with any HER2 targeted therapy
Study treatment
All patients will receive treatment with pertuzumab plus trastuzumab given Intravenously (IV) in cycles of 21 days (3 weeks) duration. The protocol for the study design is presented in figure 7.
All patients will receive:
trastuzumab 8mg/kg Intravenous (IV) loading dose followed by 6mg/kg administered by IV infusion every 3 weeks.
Pertuzumab 840mg IV load dose, followed by 420mg, administered by IV every 3 weeks.
The order of administration of trastuzumab and pertuzumab follows investigator preferences.
Both antibodies will be infused according to the us package insert (USPI).
No routine prior medication is required; however, patients experiencing infusion-related symptoms may be pre-medicated for subsequent infusions following standard institutional practices.
Materials and methods
Trastuzumab
Preparation of
Trastuzumab is a sterile, white to pale yellow, preservative-free, lyophilized powder for IV administration trastuzumab per vial contains 440mg trastuzumab, 9.9mg L-histidine HCl, 6.4mg L-histidine, 440mg α -trehalose dihydrate, and 1.8mg polysorbate 20, USP reconstituted with 20mL of supplied bacteriostatic water for injection (BWFI) USP containing 1.1% benzyl alcohol as a preservative yielding 21mL of a multi-dose solution containing 21mg/mL trastuzumab, pH 6.
Dosage, administration, and storage
Trastuzumab should be administered at a loading dose of 8mg/kg over 90(± 10) minutes. Not as IV bolus or bolus administration. Trastuzumab administration will be based on baseline weight measurements of the patient. The weight will be measured on day 1 of each 3 week treatment cycle. In the case of a weight change of 10% or more, the trastuzumab dose should be recalculated using the new weight. For the first infusion (cycle 1), the patient should be observed for fever and chills, or other infusion-related reactions, for 60 minutes from the end of the infusion. If cycle 1 is tolerated, a 6mg/kg trastuzumab dose for cycle 2 and subsequent day Q21 may be administered over 30(± 10) minutes and the patient will be observed as shown in table 2. All infusion-related symptoms must be resolved prior to administration of pertuzumab (if trastuzumab was first administered) or release of the patient. Patients experiencing infusion-related symptoms may be pre-medicated for subsequent infusions following standard institutional practices.
Variation in trastuzumab dosing was not tolerated at any time except for trastuzumab dose variation due to weight change from baseline weight measurement of ≧ 10%. Trastuzumab can be halted (hold) or discontinued in the event of unacceptable toxicity.
The following sets forth instructions for the administration of trastuzumab.
TABLE 2
Trastuzumab infusion time and post-infusion observation period
aAfter cycle 1, infusion and post-infusion observation times were shortened only in cases where the prior dose was better tolerated.
The vial of trastuzumab was stable at 2 ℃ -8 ℃ (36 ° F-46 ° F) prior to reconstitution. The expiration date of the imprint on the vial is not exceeded. Vials of trastuzumab reconstituted with the supplied BWFI were stable for 28 days after reconstitution when stored refrigerated at 2 ℃ -8 ℃ (36 ° F-46 ° F) and the solution was preserved for multiple uses. Any remaining multiple doses of reconstituted solution were discarded after 28 days. If sterile water for injection is used which is not preserved (not supplied), the reconstituted trastuzumab solution should be used immediately and any unused portion must be discarded. Reconstituted trastuzumab was not frozen.
Solutions of trastuzumab for infusion diluted in polyvinyl chloride or polyethylene bags containing 0.9% sodium chloride for injection, USP, can be stored at 2 ℃ -8 ℃ (36 ° F-46 ° F) for up to 24 hours prior to use. Diluted trastuzumab has been shown to be stable for up to 24 hours at room temperature 15-25 ℃; however, because diluted trastuzumab does not contain an effective preservative, the reconstituted and diluted solution should be stored refrigerated (2-8 ℃).
Dose adjustment
Toxicity will be assessed using the national cancer institute, version 4.0, standard of common terminology for adverse events (NCI CTCAE v 4.0). Toxicity, if it occurs, is graded and appropriate supportive care treatments are applied to reduce signs and symptoms.
Trastuzumab is well tolerated by most patients. If grade 3-4 toxicity due to trastuzumab occurs, further dosing should be suspended until toxicity improves to grade ≦ 1. Trastuzumab should be restarted at the full dose. Trastuzumab should be discontinued if grade 3-4 toxicity occurs again. Patients who benefit from therapy may continue to be treated with trastuzumab at the discretion of their attending physician.
Management of toxicity
The management of specific trastuzumab-related toxicity is discussed below.
a. Hematologic toxicity and neutropenic infection
In clinical trials, an increased incidence of anemia was observed in patients receiving trastuzumab plus chemotherapy compared to patients receiving chemotherapy alone. The severity of these anemic episodes is mostly mild or moderate and reversible. None of these events resulted in discontinuation of trastuzumab therapy.
In clinical trials, the incidence of moderate to severe neutropenia and febrile neutropenia was higher in patients receiving trastuzumab in combination with myelosuppressive chemotherapy than in patients receiving chemotherapy alone. In the post-marketing setting, sepsis-induced death in patients with severe neutropenia was reported in patients receiving trastuzumab and myelosuppressive chemotherapy. However, the incidence of sepsis deaths did not increase significantly in controlled clinical trials (before and after market). The pathophysiological basis for neutropenic exacerbations has not yet been established. The effect of trastuzumab on the pharmacokinetics of chemotherapeutic agents has not been fully evaluated.
b. Management of hematologic toxicity of trastuzumab
Care should be taken to carefully monitor the hematological status of the patient throughout the course of the trial. The use of hematopoietic growth factors to improve hematological toxicity is at the discretion of a physician investigator and should follow the guidelines of the american society of clinical oncologists.
c. Trastuzumab overdose
There is no example of over-dosing of trastuzumab in human clinical trials. A single dose above 500mg trastuzumab has not been tested.
d. Cardiac dysfunction
Signs and symptoms of cardiac dysfunction are observed in some women receiving trastuzumab alone or in combination with chemotherapy (most often anthracycline-based treatments). Cardiac dysfunction was most frequently observed (28%) in patients receiving trastuzumab plus doxorubicin/cyclophosphamide chemotherapy compared to patients receiving doxorubicin/cyclophosphamide alone (7%), trastuzumab plus paclitaxel (11%), paclitaxel alone (1%), or trastuzumab alone (7%). Severe disability or fatal outcome from cardiac dysfunction is observed in approximately 1% of all patients.
In contrast to the irreversible nature of anthracycline-induced cardiomyopathy, the signs and symptoms of trastuzumab-induced cardiac dysfunction are generally responsive to treatment. Full and partial responses were observed in patients with cardiac dysfunction. The risk appears to be independent of the tumor response to therapy. Analysis of clinical databases for predictors of cardiac dysfunction reveals that only aging and exposure to anthracyclines are possible risk factors. In clinical trials, the majority of patients with cardiac dysfunction respond to appropriate medical therapy, often involving discontinuation of trastuzumab. In many cases, patients are able to recover treatment with trastuzumab. In a follow-up study using weekly paclitaxel and trastuzumab as first-line therapy for metastatic breast cancer, the observed incidence of severe cardiac dysfunction was 3% (N ═ 95) (Seidman et al, 2001). Since the occurrence of cardiac dysfunction in trastuzumab plus chemotherapy trials is an unexpected observation, no information is available about the most appropriate method for monitoring cardiac function in patients receiving trastuzumab.
Significant progress has been made in the past few years in the understanding and treatment of Congestive Heart Failure (CHF), and several new drugs have demonstrated the ability to improve cardiac function. Patients who develop symptoms of CHF when taking trastuzumab should be treated according to the american heart failure association (HFSA) guidelines (HFSA 2010).
Since pertuzumab is also associated with a risk of cardiac dysfunction, management of cardiac safety was applied to both drugs for patients receiving both drugs in trials, as described in the next section.
e. Management of cardiac safety
All patients must have a baseline assessment of cardiac function, including LVEF measurement by multi-gate acquisition (MUGA) scan or Echocardiogram (ECHO) prior to entering the study. Only patients with normal LVEF should enter the study. All patients will be monitored regularly with MUGA or ECHO at the time of treatment for LVEF (every 12 weeks or according to clinical instructions).
During the course of therapy with trastuzumab and pertuzumab, patients should be monitored for signs and symptoms of heart failure (i.e., dyspnea, tachycardia, new unexplained cough, jugular vein dilation, hearts, hepatomegaly, paroxysmal nocturnal dyspnea, orthopnea, peripheral edema, and rapidly increasing weight of unknown origin). The same method used to measure LVEF at baseline (either ECHO or MUGA) must be used to confirm the diagnosis.
f. Management of symptomatic cardiac changes
Patients with signs and symptoms of heart failure NCI CTCAE v 4.02, 3, or grade 4 should suspend trastuzumab and pertuzumab and should receive treatment for heart failure as prescribed by HFSA (e.g. ACE inhibitors, angiotensin-II receptor blockers, β -blockers, diuretics, and cardiac glycosides, as needed; HFSA 2010). consideration should be given to obtaining cardiac counseling.
If the treatment addresses the symptoms of heart failure and cardiac function (as measured by ECHO or MUGA) improves, trastuzumab and pertuzumab can be restarted after the discussion with the patient regarding the risk and benefit of continuing therapy. The benefit of continuing therapy may outweigh the risk of cardiac dysfunction if the patient would benefit clinically from HER 2-targeted therapy. Continued supervision with non-invasive measurements of LVEF (MUGA or ECHO) will continue following the protocol if trastuzumab and pertuzumab are restarted.
g. Management of asymptomatic LVEF reduction
Patient management should follow the guidelines shown in fig. 8 if routine LVEF measurements demonstrate a decrease in asymptomatic LVEF during treatment.
Warnings and notices
a. Infusion reactions to trastuzumab
During the first trastuzumab infusion, a symptomatic complex consisting of chills and/or fever was observed in approximately 40% of patients. Other signs and/or symptoms may include nausea, vomiting, pain, stiffness, headache, cough, dizziness, rash, and weakness. The severity of these symptoms is usually mild to moderate and does not occur frequently with subsequent trastuzumab infusions. These symptoms can be treated in compliance with standard institutional practices.
b. Severe infusion-related events of trastuzumab
These events mostly occur during or shortly after the first trastuzumab infusion, severe or moderate infusion-related symptoms can be managed by slowing or stopping trastuzumab infusion and performing supportive therapy with oxygen, β -agonists, antihistamines, or corticosteroids.
If grade 3 or 4 toxicity occurs during the post-infusion observation period, the patient must be evaluated a minimum of 1 hour from the time of first observed toxicity until any severe symptoms resolve.
Patients with infusion-related adverse events of trastuzumab should receive prophylactic treatment with antihistamines and/or corticosteroids prior to all subsequent trastuzumab infusions. For specific preventative pre-medication recommendations seeUSPI。
c. Other trastuzumab-related toxicities
In addition to infusion-related toxicities, some patients reported abdominal pain, dyspepsia, diarrhea, nausea, vomiting, loss of appetite, and dehydration. Allergies are also reported. One patient in one large study developed antibodies against trastuzumab.
Pertuzumab
Preparation of
Pertuzumab was provided as a single-use formulation containing 30mg/mL pertuzumab formulated in 20mM L-histidine (pH 6.0), 120mM sucrose, and 0.02% polysorbate-20. Approximately 420mg of pertuzumab (14.0 mL/vial) was contained in each 20cc vial.
Dosage, administration, and storage
The indicated volume of pertuzumab was removed from the vial and added to a 250cc IV bag of 0.9% sodium chloride injection. The bag was gently inverted to mix the solution. Without vigorous shaking. The solution was visually inspected for particles and discoloration prior to application. The entire volume within the bag should be administered as a continuous IV infusion. The volume contained in the administration tube should be completely flushed with 0.9% sodium chloride injection.
The pertuzumab solution for infusion diluted in polyethylene or non-PVC polyolefin bags filled with 0.9% sodium chloride injection can be stored at 2-8 ℃ (36 ° F-46 ° F) for up to 24 hours prior to use. Diluted pertuzumab has been shown to be stable for up to 24 hours at room temperature (2 ℃ -25 ℃). However, since pertuzumab contains no preservative, the sterile diluted solution should be stored refrigerated (2 ℃ -8 ℃) for no more than 24 hours.
A rate adjustment device may be used for all pertuzumab infusions. When the study drug IV bag is empty, 50mL of 0.9% sodium chloride injection may be added to the IV bag or another bag may be hung and the infusion may be continued to a volume equal to the tubing volume to ensure complete delivery of the pertuzumab.
Administration of pertuzumab should be performed in a setting with emergency equipment and personnel trained to monitor and address medical emergencies. The initial dose of pertuzumab will be administered for 60 minutes and the patient will be monitored for any adverse effects for an additional 60 minutes after the infusion is completed. Infusion should be slowed or interrupted if the patient experiences infusion-related symptoms. If infusion-related symptoms occur, the patient is monitored until the signs and symptoms are completely resolved. Subsequent doses may be administered within 30 minutes if the infusion is well tolerated, and the patient will be observed for additional 30 minutes for infusion-related symptoms as shown in table 3 below.
All infusion related symptoms must be resolved before the patient is discharged. Patients experiencing infusion-related symptoms may then practice pre-medication in compliance with standard institutions.
TABLE 3
Infusion time and post-infusion observation period for pertuzumab
aAfter cycle 1, infusion and post-infusion observation times were shortened only in cases where the prior dose was better tolerated.
Infusion should be stopped in patients with dyspnea or clinically significant hypotension (defined at the investigator's discretion). Patients experiencing NCI CTCAE grade 3 or 4 allergy or acute respiratory distress syndrome should not receive additional pertuzumab.
If the study drug extravasates during infusion, the following steps should be taken:
the infusion was discontinued.
Treatment of extravasation following institutional guidelines for non-caustic extravasation.
Restart infusion on the other side or at a closer site in the same limb if a significant volume of study drug infusion remains.
Storage of
The vials of pertuzumab must be placed in a refrigerator at 2-8 ℃ (36 ° F-46 ° F) immediately upon receipt to ensure optimal retention of physical and biochemical integrity and should be kept refrigerated until just prior to use. Do not freeze and do not shake pertuzumab vials. And (4) avoiding light.
Dose adjustment
Pertuzumab is well tolerated by most patients. If grade 3-4 toxicity due to pertuzumab occurs, further dosing should be suspended until the toxicity improves to grade ≦ 1.
Pertuzumab should be restarted at the full dose. Pertuzumab should be discontinued if grade 3-4 toxicity occurs again. Patients who benefit from therapy may continue to be treated with pertuzumab at the discretion of their attending physician. Management of specific pertuzumab-related toxicity is discussed below.
Pertuzumab warnings and notices
a. Infusion related reactions
Infusion response is defined in randomized trials on metastatic breast cancer as any event described as hypersensitivity, anaphylaxis, acute infusion response, or cytokine release syndrome occurring during or on the day of infusion. An initial dose of pertuzumab was administered the day before trastuzumab and docetaxel to allow for examination of pertuzumab-associated reactions. On the first day, when only pertuzumab was administered, the overall frequency of infusion reactions was 13.0% in the pertuzumab-treated group and 9.8% in the placebo-treated group. Grade 3 or 4 is less than 1%. The most common infusion reactions (> 1.0%) are fever, chills, fatigue, headache, weakness, hypersensitivity, and vomiting.
During the second cycle, the most common infusion reactions (> 1.0%) in the pertuzumab-treated group were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting when all drugs were administered on the same day.
In the randomized trial, the overall frequency of hypersensitivity/anaphylaxis was 10.8% in the pertuzumab-treated group and 9.1% in the placebo-treated group. The incidence of hypersensitivity/anaphylaxis grade 3-4 according to NCI CTCAE v3.0 was 2% in the pertuzumab-treated group and 2.5% in the placebo-treated group. In summary, 4 patients in the pertuzumab-treated group and 2 patients in the placebo-treated group experienced allergies.
Patients were closely observed 60 minutes after the first infusion of pertuzumab and 30 minutes after the subsequent infusion. If a significant infusion-related response occurs, the infusion is slowed or interrupted and appropriate medical therapy is administered in compliance with standard institutional practices. The patient is carefully monitored until signs and symptoms are completely resolved. Permanent discontinuation is considered in patients with severe infusion reactions.
b. Risk of cardiotoxicity
Pertuzumab is directed against the HER2 receptor and is associated with the risk of cardiac dysfunction.
In the pertuzumab single dose phase II study, a LVEF drop of > 10% to LVEF values < 50% was observed in 7% of patients with post-baseline LVEF evaluation. Of these patients 9 received prior anthracycline therapy. In summary, 3 symptomatic heart failure events have been reported in approximately 550 patients treated with pertuzumab across all studies. 2 of these cases occurred in patients with metastatic breast cancer who received a prior anthracycline.
Patients with significant heart disease or baseline LVEF below 50% were not eligible for this study. At this point, the risk factors for pertuzumab-associated cardiac dysfunction are unknown. The risk of cardiac dysfunction should be carefully weighed against the potential benefits in patients who have received a prior anthracycline.
Since pertuzumab and trastuzumab have overlapping potential cardiotoxicity, management of cardiotoxicity in this study arm should consider both treatments.
c. Embryo-fetal toxicity (for trastuzumab or pertuzumab)
There was no clinical study of trastuzumab or pertuzumab in pregnant women. Immunoglobulin G1(IgG1) is known to cross the placental barrier. Studies in animals resulted in oligohydramnios, delayed renal development, and death.
It is not known whether trastuzumab or pertuzumab is excreted in milk. Since maternal IgG1 is excreted in milk and either monoclonal antibody may impair infant growth and development, women should be advised to discontinue lactation during pertuzumab or trastuzumab therapy and not breastfeed for at least 7 months after the last dose of either monoclonal antibody.
d. Follow-up of pregnancy
Infants born to female patients or male patients with female partners who are exposed to trastuzumab/pertuzumab must be tracked for 1 year after birth. The sponsor may require additional information at specific time points during and after pregnancy (i.e. at the end of the sixth trimester of pregnancy, 2 weeks after the expected delivery day, and 3, 6, and 12 months of the baby's life).
e. The most common adverse reactions
The most common adverse reactions (> 30%) seen with pertuzumab in combination with trastuzumab and docetaxel are diarrhea, hair loss, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common orders of 3-4 adverse reactions (> 2%) of NCI CTCAE (v 3.0) are neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, weakness, and fatigue.
The efficacy results of pertuzumab + trastuzumab treatment in patients with multiple HER2 expanding/overexpressing cancer types are shown in table 4 below.
TABLE 4
Efficacy of trastuzumab plus pertuzumab treatment in patients with HER2 amplification/overexpression (N ═ 114 ·)
Included are 12 patients with amplification/overexpression + mutations.
The response occurs in patients with adenocarcinoma of the prostate (1) and skin (apocrine) (1).
CR, complete response; ORR, objective response rate; PR, partial response; SD, stable disease; CI, confidence interval.
Other results are described in the examples below.
Examples2
Pertuzumab + trastuzumab for treating patients with metastatic colorectal cancer (mCRC)
Colorectal cancer is the third leading cause of cancer death in the united states. Colorectal patients have a poor prognosis with a 5-year survival rate of 12.5% (Siegel r.et al, CA Cancer J clin.2014,64: 104-17). In recent advances in precision medicine, HER2 has become a potential therapeutic target for advanced colon cancer, however, no HER2 targeted therapy is currently approved for metastatic colorectal cancer (mCRC).
Study design/treatment
Eligible patients in this assay have mCRC amplified/overexpressed in therapy refractory HER2 as assessed by Next Generation Sequencing (NGS), fluorescence or chromogenic in situ hybridization (FISH or CISH; signal ratio >2.0 or copy number <6), and/or immunohistochemistry (IHC; 3 +). Patients with active brain metastases, concurrent active anti-cancer therapy, pregnancy, or contraindications for pertuzumab or trastuzumab were excluded. Patients received standard doses of pertuzumab + trastuzumab (pertuzumab: 840mg intravenous [ IV ] load dose followed by 420mg IV every 3 weeks; trastuzumab: 8mg/kg IV load dose followed by 6mg/kg IV every 3 weeks) until disease progression or unacceptable toxicity. The primary endpoint was the Objective Response Rate (ORR) assessed by the investigator.
Evaluation and statistical method
Tumor response was assessed by investigators every 6 weeks for the first 24 weeks, and every 12 weeks thereafter. Responses were evaluated by RECIST v 1.1. See example 1 for further details.
Results
By the time the MyPathway (NCT2091141) multicenter, open label, 34 patients enrolled in the phase IIa study with treatment refractory HER2 amplified/overexpressed metastatic colorectal cancer (mCRC) described in example 1 were treated as described above.
TABLE 5
Baseline demographic and clinical characteristics of patients with HER2 amplified/overexpressed mCRC
aOne patient also had mutant HER 2.bSome patients have multiple test types.cThe percentages are calculated based on patients with wild-type KRAS.dThe patient may have received more than one line of anti-EGFR therapy.eOne patient in this group also received cetuximab (cetuximab) monotherapy in a different treatment line.fThree patients in this group also received panitumumab (panitumumab) monotherapy in different treatment lines.
Treatment Exposure and clinical outcome
The median follow-up was 5.6 (range 1.2-22.1) months. The median treatment time was 4.1 (range 0-20.7) months. The treatment time in patient fractions is shown in figure 9.
ORR is 38.2% (n ═ 13, 95% confidence interval [ CI ]; 22.2-56.4) and CBR is 50.0% (n ═ 17; 95% CI, 32.4-64.6). All 13 responders (7 were treating) achieved PR as their best response. The median duration of response was 10.3 (range 1.4-15.7) months. This group included one patient with an accompanying HER2 mutation (S310F).
4 (11.8%) patients (1 being treated) had SD for more than 4 months.
7 (20.5%) patients (1 being treated) had SD less than or equal to 4 months. This group included one patient with an associated EGFR change.
10 (29.4%) patients had Progressive Disease (PD).
The optimal percentage from baseline of the target lesion size in patient scores is shown in figure 10.
TABLE 6
Outcome in clinical features in patients with HER2 amplified or overexpressed mCRC
By data cutoff, 73.5% (n-25) patients experienced PFS events (tumor progression [ n-23 ] or death [ n-2 ]). The median PFS was 4.6 (95% CI, 1.6-9.8) months as shown in table 6 and figure 11. Patients with wild-type KRAS had a higher median PFS (5.7 [ 95% CI, 3.5-12.4] months versus 1.4[ 95% CI, 1.1-2.8] months, respectively) than patients with mutant KRAS.
By the end of the data, 50.0% of patients (n-17) had died. 13 patients died due to disease progression, 1 died from suspected brain metastases, and 3 died from unknown or unspecified causes. The median OS was 10.3 (05% CI, 7.2-22.1) months as shown in table 6 and fig. 12. Patients with wild-type KRAS had a higher median OS (14.0 [ 95% CI, 8.0-22.1] month versus 5.0[ 95% CI, 1.2-10.3] month, respectively) than patients with mutant KRAS.
The safety profile is consistent with the product label for pertuzumab and trastuzumab.
Conclusion
These data suggest that dual HER2 targeted therapy with pertuzumab + trastuzumab (a regimen without chemotherapy) is active in patients with heavily pretreated, HER 2-amplified/overexpressed mCRC. ORR was 38.2%, with a sustained response (median 10.3 months), and CBR was 50.0%. Pertuzumab + trastuzumab treatment appears to have higher activity in patients with wild-type KRAS tumors (ORR 52%, CBR 68%) compared to KRAS mutant cohort (ORR 0%, CBR 0%). Analysis of 3256 patients with CRC indicated that HER2 amplification/overexpression was associated with KRAS wild-type tumor status (Richman SD et al, J Pathol 2016,238: 562-70). Although ORR was lower in patients with right colon cancer (12.5%) compared to left colon (42.9%) or rectal cancer (45.5%), a higher percentage of right colon tumors in this analysis had mutant KRAS (62.5% versus 27.3%, respectively).
Example 3
Pertuzumab + trastuzumab for treating patients with metastatic cholangiocarcinoma
Cholangiocarcinoma has a high mortality rate and limited treatment options. Although HER2 is overexpressed in 9-20% of biliary tract cancers, it has not yet been fully explored as a therapeutic target.
Patients with MyPathway (NCR02091141) open label, multicenter, 11 enrolled in phase IIA studies (HER2 amplified/overexpressed, n-8; HER2 mutated, n-3 [ D277Y/D297Y, S310F, and a775-G776insYVMA ]) with HER2 positive refractory metastatic cholangiocarcinoma who received standard doses of pertuzumab + trastuzumab until disease progression or unacceptable toxicity as described in example 1, either according to gene sequencing, FISH, or IHC with HER2 amplified/overexpressed or putative activating mutations. The primary endpoint was the overall response rate (RECIST v1.1) assessed by the investigator.
At median follow-up 4.2 (range 2.0-12.0) months, 4 patients had Partial Response (PR) and 3 had Stable Disease (SD) >4 months (table 6). The security is consistent with the package inserts. The results are summarized in Table 7.
TABLE 7
aComplete Response (CR) + PR.bThe patient had an extracellular HER2 mutation (D277Y/D297Y).cCR + PR + SD>4 months old
Figure 13 shows a waterfall plot of treatment response in patients with HER2 amplified cholangiocarcinoma (N-8).
The results listed in table 6 above and shown in figure 13 indicate that pertuzumab + trastuzumab is active in HER2 amplified/overexpressed/mutated metastatic bile duct tumors, suggesting that HER2 is a therapeutic target for these rare cancers.
Example 4
Pertuzumab + trastuzumab for treating patients with HER2 positive metastatic bladder cancer (mBC)
Patients with mBC have few treatment options beyond the second-line setting. HER2 was amplified in 5-42% of BC, but limited data on treatment with HER2 targeting agents was available.
MyPathway (NCR02091141) open label, multicenter, 12 patients enrolled in the phase IIa study with platinum resistant HER2 positive mBC (HER2 amplified, n ═ 9; HER2 mutated, n ═ 3) described in example 1 received standard doses of pertuzumab + trastuzumab. At a median follow-up month of 5.4 (range 0.9-14.5), 1 patient had a complete response (CR, ongoing), 2 had a Partial Response (PR), and 2 had Stable Disease (SD) >4 months (table). Security is consistent with product labeling. The results are summarized in Table 8.
TABLE 8
aOne patient also had mutant HER 2.bSome patients have multiple tests.cCR+PR。dCR + PR + SD>4 months.
Figure 14 shows a waterfall plot of treatment response in patients with HER 2-amplified bladder cancer (N-8).
The results shown in table 7 above and in figure 14 indicate that pertuzumab + trastuzumab is active in HER2 amplified/overexpressed/mutated metastatic bladder tumors, suggesting that HER2 is a therapeutic target for these rare cancers.
Example 5
Pertuzumab + trastuzumab for treating patients with HER2 positive metastatic urothelial cancer (mUC)
Patients with metastatic urothelial cancer (mUC) have limited treatment options, consisting primarily of platinum-based chemotherapy as first-line therapy, and atelizumab in the second line. There are no approved beyond second line therapies. Thus, additional treatment options are needed, particularly those with better tolerability.
Alterations in the HER2 receptor have been identified in patients with bladder and urethral epithelial cancers, as shown in table 9 below.
TABLE 9
HER2 altered prevalence in patients with bladder/metastatic urothelial cancer (mUC)
Database with a plurality of databases Tissue of HER2 amplification HER2 mutation
COSMIC1 Urethra 16/419(4％) 59/1133(5％)
cBioPortal2 Urothelium-bladder 6/99(6％) 18/230(8％)
Foundation Medicine3 Urothelium-bladder 86/6535(1％) 79/6535(1％)
Foundation Medicine Bladder of urinary bladder 93/7582(1％) 93/7582(1％)
1http://cancer.sanger.ac.uk/cosmic
2http://www.cbioportal.org
Method of producing a composite material
Patient selection and treatment
Patients in this subset analysis of the clinical trial described in example 1 had metastatic urothelial cancer (mUC) with at least one of the following HER2 changes:
HER2 amplification: next Generation Sequencing (NGS) or fluorescence or chromogenic in situ hybridization (FISH or CISH; signal ratio n >2.0 or copy number >6)
HER2 overexpression: immunohistochemistry (IHC; 3+)
Potential acting HER2 mutations (i.e.insertions in exon 20, deletions around amino acids 755 and 759, known activating mutations, or mutations reported at least twice in the COSMIC database): NGS
Patients received pertuzumab (840mg IV load, followed by 420mg IC every 3 weeks) + trastuzumab (8mg/kg IV load, followed by 6mg/kg IV every 3 weeks) until disease progression or unacceptable toxicity. The primary endpoint was the Objective Response Rate (ORR) assessed by the investigator.
Evaluation of statistical methods
Investigators followed RECIST (v1.1) (Eisenhauer EA, et al, Eur J Cancer, 2009; 45: 228-. No confirmatory tumor assessment is required.
ORR is the percentage of patients with Complete Response (CR) or Partial Response (PR) at any time.
Clinical Benefit Rate (CBR) is the percentage of patients with CR, PR, or Stable Disease (SD) for >4 months.
Response duration is calculated from the day of the first treatment response to the day of disease progression/death (earlier onset), or the day of the last tumor assessment of patients without disease progression/death.
Progression Free Survival (PFS) was calculated as the time from the day of first treatment to the day of progression/death (if any), or to the day of last tumor assessment (if no progressive disease/death).
Overall Survival (OS) is calculated as the time from the day of the first treatment to the day of death, or to the last day if no death was known to be alive.
Results
Patient's health
By the day of the cutoff, 247 patients had received treatment in the MyPathway study, including 12 patients with platinum-resistant HER2 positive mUC who received pertuzumab + trastuzumab therapy. Of these 12 patients, 9 exhibited HER2 amplification/overexpression, and 3 had putative HER2 activating mutations (deletions around S310Y, S310F, and amino acids 755-. One patient in the HER2 amplified/overexpressed cohort also had a HER2 mutation (S310Y). Baseline demographics and clinical outcomes in patient scores are shown in table 10.
Treatment Exposure and clinical outcome
The median follow-up was 4.6 (range 1.0-16.6) months.
In patients with HER2 amplification/overexpression (n ═ 9):
median treatment time 4.6 (range 0.7-16.6) months
ORR is 33.3% (95% confidence interval [ CI ] 7.5-70.1). Three patients responded to pertuzumab + trastuzumab, including one with ongoing CR. The median duration of response was 5.5 (range 0.9-15.2) months. CBR was 55.6% (95% CI 21.2-86.3). Two patients had SD for >4 months. In patients with HER2 mutation (n ═ 3):
median treatment time of 0.7 (range 0-0.8) months
None of the patients experienced objective response or stable disease for >4 months
The treatment time in patient fractions is shown in figure 15.
Baseline characteristics and clinical outcomes of individual patients are shown in table 9.
Watch 10
Baseline characteristics and clinical outcome in patients with HER2 amplified/overexpressed or HER2 mutated mUC
+ indicates that the measurement is in progress.
aAll patients who died as a result of disease progression.
bNot all patients tested all types of changes.
cS310Y。
CBR, clinical benefit rate; CI, confidence interval; CR, complete response; f, female; HER2, human epidermal growth factor receptor 2; m, male; NE, not evaluable; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease.
The optimal percent change from baseline in target lesion size for a patient score is shown in figure 16.
At the end of the data, 77.8% (7/9) of patients in the HERE-HER 2 amplification/overexpression cohort and all patients in the HER2 mutation cohort (3/3) experienced PFS events (disease progression [ n-9 ] or death [ n-1 ].
Median progression-free survival was 5.3 (95% CI, 1.3-NE) months in patients with HER2 amplification/overexpression and 1.3 (95% CI, 0.5-1.4) months in patients with disease with HER2 mutation.
By the time the data was cut off, 55.6% (5/9) of patients with HER2 amplification/overexpression and 100% (3/3) of patients with mutated HER2 died, both due to disease progression. The median overall survival was 8.6 (95% CI, 1.8-NE) months in patients with HER2 amplification/overexpression and 3.7 (95% CI, 1.0-5.6) months in patients with disease with HER2 mutation.
Case study of patients with mUC amplified HER2
A 63-year-old caucasian male patient presented with superficial bladder cancer in 2010 and was treated with multiple cycles of bcg immunotherapy.
At the end of 2012, transurethral resection revealed a T1, grade 3 urothelial cancer. The patient underwent a left distal ureterectomy in 2013, month 1; the excised lymph nodes were negative.
Knot/soft tissue and bone lesions were found throughout the body in 2014 8, suggesting diffuse metastasis. Patients received dose-intensive treatment with methotrexate + vinblastine + doxorubicin + platinum for 7 cycles with near complete response.
Recurrent disease with peritoneal metastasis was found at month 4 in 2015.
Gene sequencing identified HER2 amplification with a copy number of 52, at which time the patient enrolled in MyPathway and began treatment with pertuzumab + trastuzumab.
Responses were observed after 2 cycles of therapy, continuing to become CR, ongoing at the time of the last tumor evaluation (fig. 17A-C).
At the time of data cutoff, the patient had received pertuzumab + trastuzumab for 16.6 months (25 cycles).
Safety feature
The safety is consistent with the product label of pertuzumab and trastuzumab. Of all patients, 58.3% (n-7) experienced at least one treatment-related Adverse Event (AE) and 8.3% (n-1) experienced at least one treatment-related AE no less than grade 3.
Conclusion
The disclosed results indicate that pertuzumab + trastuzumab can provide a better tolerated treatment option for patients with previously treated HER2 amplified/overexpressed mUC.
Among patients with HER2 amplified/overexpressed disease, ORR was 33.3% and CBR was 55.6%, with one patient with peritoneal metastasis experienced persistent, ongoing CR (152 + months at data cutoff) and three other patients experienced PR or SD for more than 6 months.
Although the number of patients was small, no activity was observed in patients with mUC having the HER2 mutation. The low rate of significant quality of life impairing toxicity observed for the chemotherapy-free targeting regimen of pertuzumab + trastuzumab may be particularly valuable in patients with mUC-related complications, such as low renal function.
Example 6
Pertuzumab + trastuzumab for treating patients with HER2 positive salivary gland cancer
Salivary gland cancer constitutes < 1% of cancers. Advanced cases have a 5-year survival rate of 40%. Due to their rarity, there are no standard treatment guidelines. However, salivary duct carcinomas have a morphology and gene expression profile similar to breast cancer, and 20-40% of this subset have HER2 alterations.
Method of producing a composite material
Patients have advanced salivary gland cancer with HER2 (amplified, overexpressed, and/or mutated), as applicable, assessed locally by gene sequencing, FISH, or IHC. As described in example 1, patients received a standard dose of pertuzumab + trastuzumab until disease progression or unacceptable toxicity. The primary endpoint was the Objective Response Rate (ORR) assessed by investigators through RECIST v 1.1.
Results
At the data cutoff, 7 patients with HER2 alterations received treatment for salivary gland cancer (both carcinomas). One HER2 patient with no post-baseline tumor assessment by data cutoff failed to assess efficacy. The characteristics and outcomes are shown (table 10). Of the 6 patients with Complete Response (CR) or Partial Response (PR), 5 patients remained receiving study treatment by the time of data cutoff with a median treatment time of 4.6 (range 1.4-12.5) months. There is no new security signal.
TABLE 11
aSix patients had HER2 amplification/overexpression (1 patient with PR also had HER2 mutation [ D769H/L755F)]). Patients that could not be evaluated had HER2 mutation (S310F).
bPTCH-1(Q400)。
cCR+PR。
dAmong 6 evaluable patients.
Conclusion
Among patients with advanced salivary gland cancer characterized by HER2 alterations, 5 achieved CR or PR. These promising results merit the study of these treatments in additional patients.
Example 7
Pertuzumab + trastuzumab for treating patients with HER2 positive lung cancer
Method of producing a composite material
As described in example 1, patients with previously treated advanced NSCLC and alterations (amplifications and/or mutations) in HER2 received a standard dose of pertuzumab + trastuzumab until disease progression or unacceptable toxicity. The primary endpoint was the investigator's evaluation of the objective response rate (ORR, defined as complete response [ CR ] + partial response [ PR ]) by RECIST v 1.1.
Results
The results are summarized in Table 12.
TABLE 12
+ indicates that a response is occurring.
aCR + PR + stable diseases>4 months.
bHER2 amplified and/or mutated.
Conclusion
Targeted therapy is effective in patients with previously treated NSCLC carrying an alteration (amplification and/or mutation) of HER 2.
In summary, the results presented in the examples confirm the efficacy of pertuzumab + trastuzumab targeted therapy for the treatment of a variety of advanced, metastatic, refractory cancers.
While certain embodiments of the present invention have been shown and described herein, it will be understood by those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.
Sequence listing
<110> GeneTak company (GENENTECH, INC.)
Haofume Roche GmbH (F. HOFFMANN-LA ROCHE AG)
<120> treatment of advanced HER2 expressing cancer
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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> sources
<223 >/Annotation = "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> sources
<223 >/Annotation = "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 135140
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 AsnVal 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> sources
<223 >/Annotation = "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 LeuGln 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> sources
<223 >/Annotation = "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> sources
<223 >/Annotation = "description of Artificial sequence-synthetic polypeptide"
<400>15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
1 510 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> sources
<223 >/Annotation = "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 2530
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
<210>17
<211>10
<212>PRT
<213> Artificial sequence
<220>
<221> sources
<223 >/Annotation = "description of Artificial sequence synthetic peptide"
<220>
<221> variants
<222>(10)..(10)
<223 >/replace = "Ser"
<220>
<221> miscellaneous features
<222>(10)..(10)
<223 >/Note = "residues given in sequence have no preference for residues at that position in the annotation"
<400>17
Gly Phe Thr Phe Thr Asp Tyr Thr Met Asp
1 5 10
<210>18
<211>17
<212>PRT
<213> Artificial sequence
<220>
<221> sources
<223 >/Annotation = "description of Artificial sequence synthetic peptide"
<400>18
Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe Lys
1 5 10 15
Gly
<210>19
<211>10
<212>PRT
<213> Artificial sequence
<220>
<221> sources
<223 >/Annotation = "description of Artificial sequence synthetic peptide"
<400>19
Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr
1 5 10
<210>20
<211>11
<212>PRT
<213> Artificial sequence
<220>
<221> sources
<223 >/Annotation = "description of Artificial sequence synthetic peptide"
<400>20
Lys Ala Ser Gln Asp Val Ser Ile Gly Val Ala
1 5 10
<210>21
<211>7
<212>PRT
<213> Artificial sequence
<220>
<221> sources
<223 >/Annotation = "description of Artificial sequence synthetic peptide"
<220>
<221> variants
<222>(5)..(5)
<223 >/replace = "Leu"
<220>
<221> variants
<222>(6)..(6)
<223 >/replace = "Glu"
<220>
<221> variants
<222>(7)..(7)
<223 >/replace = "Ser"
<220>
<221> miscellaneous features
<222>(5)..(7)
<223 >/Note = "residues given in sequence have no preference for residues at that position in the annotation"
<400>21
Ser Ala Ser Tyr Arg Tyr Thr
1 5
<210>22
<211>9
<212>PRT
<213> Artificial sequence
<220>
<221> sources
<223 >/Annotation = "description of Artificial sequence synthetic peptide"
<400>22
Gln Gln Tyr Tyr Ile Tyr Pro Tyr Thr
1 5

Claims (64)

1. A method for treating advanced colorectal cancer, comprising administering to a human patient with HER2 positive, HER2 amplified, or HER2 mutated advanced colorectal cancer an effective amount of a combination of pertuzumab and trastuzumab.
2. A method for treating advanced biliary cancer comprising administering to a human patient with advanced biliary cancer that is HER2 positive, HER2 amplified, or HER2 mutant an effective amount of a combination of pertuzumab and trastuzumab.
3. A method for treating advanced urinary epithelial cancer comprising administering an effective amount of a combination of pertuzumab and trastuzumab to a human patient with HER2 positive, HER2 amplified, or HER2 mutant advanced bladder cancer.
4. A method for treating advanced bladder cancer comprising administering an effective amount of a combination of pertuzumab and trastuzumab to a human patient with HER2 positive, HER2 amplified, or HER2 mutant advanced bladder cancer.
5. A method for treating advanced salivary gland cancer comprising administering an effective amount of a combination of pertuzumab and trastuzumab to a human patient with HER2 positive, HER2 amplified, or HER2 mutant advanced bladder cancer.
6. A method for treating advanced lung cancer comprising administering to a human patient with advanced bladder cancer that is HER2 positive, HER2 amplified, or HER2 mutated an effective amount of a combination of pertuzumab and trastuzumab.
7. A method for treating advanced pancreatic cancer comprising administering an effective amount of a combination of pertuzumab and trastuzumab to a human patient with HER2 positive, HER2 amplified, or HER2 mutant advanced pancreatic cancer.
8. A method for treating advanced ovarian cancer comprising administering an effective amount of a combination of pertuzumab and trastuzumab to a human patient with advanced ovarian cancer that is HER2 positive, HER2 amplified, or HER2 mutant.
9. A method for treating advanced prostate cancer comprising administering an effective amount of a combination of pertuzumab and trastuzumab to a human patient with HER2 positive, HER2 amplified, or HER2 mutated advanced prostate cancer.
10. A method for treating advanced skin cancer comprising administering an effective amount of a combination of pertuzumab and trastuzumab to a human patient with HER2 positive, HER2 amplified, or HER2 mutant advanced skin cancer.
11. The method of any one of claims 1-10, wherein the cancer is HER2 positive.
12. The method of claim 11 wherein the HER2 expression level is IHC2+ or 3 +.
13. The method of any one of claims 1-10, wherein the cancer is HER2 amplified.
14. The method of claim 13, wherein HER2 amplification is determined by Fluorescence In Situ Hybridization (FISH).
15. The method of claim 13 wherein HER2 amplification is determined by Next Generation Sequencing (NGS).
16. The method of any one of claims 1-10, wherein the cancer is HER2 mutant.
17. The method of claim 16, wherein the mutation is a HER2 activation mutation.
18. The method of claim 16, wherein the HER2 mutation is selected from the group consisting of an insertion within exon 20 of HER2, a deletion around amino acid residues 755-759 of HER2, G309A, G309E, S310F, D769H, D769Y, V777L, P780-Y781insGSP, V8421I, R896C and other putative activating mutations found in two or more unique specimens.
19. The method of any one of claims 1-10, wherein the cancer is locally advanced.
20. The method of any one of claims 1-10, wherein the cancer is metastatic.
21. The method of any one of claims 1-20, wherein the cancer is refractory to another treatment regimen.
22. The method of claim 21, wherein the cancer is chemotherapy-resistant.
23. The method of claim 22, wherein the cancer is platinum-resistant.
24. The method of any one of claims 1-23, wherein the patient receives 1 to 5 rounds of prior treatment for the cancer.
25. The method of claim 24, wherein the prior treatment comprises chemotherapy.
26. The method of claim 24 or 25, wherein the prior treatment comprises HER 2-directed therapy.
27. The method of claim 24, wherein at least one of the prior treatments is administered in an advanced stage.
28. The method of claim 24, wherein at least one of the prior treatments is neoadjuvant therapy.
29. The method of claim 24, wherein at least one of the prior treatments is adjuvant therapy.
30. The method of claim 24, wherein the cancer is resistant to at least one of the prior treatments.
31. The method of any one of claims 1-30, wherein the combination of pertuzumab and trastuzumab is administered in the absence of other anti-cancer drugs.
32. The method of claim 31, wherein the combination of pertuzumab and trastuzumab is administered in the absence of chemotherapy.
33. The method of claim 31, wherein the combination of pertuzumab and trastuzumab is administered in the absence of another HER 2-directed therapy.
34. The method of any one of claims 1-33, wherein the treatment consists essentially of combined administration of pertuzumab and trastuzumab in combination.
35. The method of any one of claims 1-34, wherein the administering results in an improved Overall Response Rate (ORR) relative to administration of pertuzumab or trastuzumab as the single agent.
36. The method of any one of claims 1-35, wherein the administration results in an improved Partial Response (PR) relative to administration of pertuzumab or trastuzumab as the single agent.
37. The method of any one of claims 1-35, wherein the administration results in an improved Complete Response (CR) relative to administration of pertuzumab or trastuzumab as the single agent.
38. The method of any one of claims 1-35, wherein the administration prolongs survival of the patient relative to administration of pertuzumab or trastuzumab as the single agent.
39. The method of claim 38, wherein said administering extends Progression Free Survival (PFS).
40. The method of claim 38, wherein the administration prolongs Overall Survival (OS).
41. The method of any one of claims 1-35, wherein the combination of pertuzumab and trastuzumab results in a synergistic effect.
42. The method of any one of claims 1-41, wherein the administering does not result in an increase in side effects relative to monotherapy with pertuzumab or trastuzumab.
43. The method of claim 42, wherein said administering does not result in an increase in cardiac side effects relative to monotherapy with pertuzumab or trastuzumab.
44. An article of manufacture comprising a vial containing pertuzumab and a package insert, wherein the package insert provides instructions for administering the pertuzumab as claimed in any one of claims 1 to 43.
45. A composition of pertuzumab for use in combination with trastuzumab in the treatment of a human patient with HER2 positive, HER2 amplified, or HER2 mutated advanced colorectal cancer.
46. A composition of pertuzumab for use in combination with trastuzumab in treating a human patient with HER2 positive, HER2 amplified, or HER2 mutated advanced biliary cancer.
47. A composition of pertuzumab for use in combination with trastuzumab in treating a human patient with HER2 positive, HER2 amplified, or HER2 mutated advanced urothelial cancer.
48. A composition of pertuzumab for use in combination with trastuzumab in treating a human patient with HER2 positive, HER2 amplified, or HER2 mutated advanced bladder cancer.
49. A composition of pertuzumab for use in combination with trastuzumab in treating a human patient with HER2 positive, HER2 amplified, or HER2 mutated advanced salivary gland cancer.
50. A composition of pertuzumab for use in combination with trastuzumab in treating a human patient with HER2 positive, HER2 amplified, or HER2 mutated advanced lung cancer.
51. A composition of pertuzumab for use in combination with trastuzumab in the treatment of a human patient with HER2 positive, HER2 amplified, or HER2 mutated advanced pancreatic cancer.
52. A composition of pertuzumab for use in combination with trastuzumab in treating a human patient with advanced ovarian cancer having HER2 positive, HER2 amplified, or HER2 mutation.
53. A composition of pertuzumab for use in combination with trastuzumab in treating a human patient with HER2 positive, HER2 amplified, or HER2 mutated advanced prostate cancer.
54. A composition of pertuzumab for use in combination with trastuzumab in treating a human patient with HER2 positive, HER2 amplified, or HER2 mutated advanced skin cancer.
55. Use of pertuzumab in the manufacture of a medicament for treating a human patient having HER2 positive, HER2 amplified, or HER2 mutated advanced colorectal cancer in combination with trastuzumab.
56. Use of pertuzumab in the manufacture of a medicament for treating a human patient with HER2 positive, HER2 amplified, or HER2 mutated advanced bile duct cancer in combination with trastuzumab.
57. Use of pertuzumab in the manufacture of a medicament for treating a human patient with HER2 positive, HER2 amplified, or HER2 mutated advanced urothelial cancer in combination with trastuzumab.
58. Use of pertuzumab in the manufacture of a medicament for treating a human patient with HER2 positive, HER2 amplified, or HER2 mutated advanced bladder cancer in combination with trastuzumab.
59. Use of pertuzumab in the manufacture of a medicament for treating a human patient with HER2 positive, HER2 amplified, or HER2 mutated advanced salivary gland cancer in combination with trastuzumab.
60. Use of pertuzumab in the preparation of a medicament for treating a human patient with HER2 positive, HER2 amplified, or HER2 mutated advanced lung cancer in combination with trastuzumab.
61. Use of pertuzumab in the manufacture of a medicament for treating a human patient with HER2 positive, HER2 amplified, or HER2 mutated advanced pancreatic cancer in combination with trastuzumab.
62. Use of pertuzumab in the manufacture of a medicament for treating a human patient with HER2 positive, HER2 amplified, or HER2 mutated advanced ovarian cancer in combination with trastuzumab.
63. Use of pertuzumab in the manufacture of a medicament for treating a human patient with HER2 positive, HER2 amplified, or HER2 mutated advanced prostate cancer in combination with trastuzumab.
64. Use of pertuzumab in the manufacture of a medicament for treating a human patient having an advanced skin cancer that is HER2 positive, HER2 amplified, or HER2 mutated in combination with trastuzumab.
HK62020002145.4A 2016-12-28 2017-12-14 Treatment of advanced her2 expressing cancer HK40012811A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US62/439,815 2016-12-28
US62/457,672 2017-02-10
US62/519,599 2017-06-14

Publications (1)

Publication Number Publication Date
HK40012811A true HK40012811A (en) 2020-07-31

Family

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