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A Phase 1B/2 Study of Ramucirumab in Combination with Emibetuzumab in Patients with Advanced Cancer

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A Phase 1B/2 Study of Ramucirumab in Combination with Emibetuzumab in Patients with Advanced Cancer Author Manuscript Published OnlineFirst on May 29, 2019; DOI: 10.1158/1078-0432.CCR-18-4010 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. A Phase 1b/2 Study of Ramucirumab in Combination with Emibetuzumab in Patients with Advanced Cancer James J. Harding1,2, Andrew X. Zhu3, Todd M. Bauer4, Toni K. Choueiri5, Alexander Drilon1,2, Martin H. Voss1,2, Charles Fuchs5, Ghassan K. Abou-Alfa1,2, Sameera Wijayawardana6, Xuejing A Wang6, Brian Moser6 Arantxa Uruñuela6, Volker Wacheck6, Johanna Bendell4 1 Memorial Sloan Kettering Cancer Center New York, New York 2 Weill Cornell Medical College, New York, New York 3Massachusetts General Hospital/ Harvard Medical School, Boston, Massachusetts4 4Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee 5Yale Cancer Center, Smilow Cancer Hospital, New Haven, Connecticut 6Eli Lilly and Company, Indianapolis, Indiana Running Title: Phase 1b/2 of ramucirumab plus emibetuzumab Keywords: Antibodies, phase Ib/2, emibetuzumab plus ramucirumab, MET protein, advanced or metastatic cancers. Conflicts of Interest: J.J.H was in part supported through the NIH/NCI Cancer Center Support Grant P30 CA008748. J.J.H has received consulting fees from Bristol Myers Squibb, Eli Lilly, CytomX, and Eisai, and research funds from Bristol Myers Squibb. C.S.F. reports consulting role for Agios, Bain Capital, Bayer, Celgene, Dicerna, Five Prime Therapeutics, Gilead Sciences, Eli Lilly, Entrinsic Health, Genentech, KEW, Merck, Merrimack Pharmaceuticals, Pfizer, Sanofi, Taiho, and Unum Therapeutics. He also serves as a Director for CytomX Therapeutics and owns unexercised stock options for CytomX and Entrinsic Health. A.E.D. received honoraria from Medscape, OncLive, PeerVoice, Physicians Education Resources, Tyra Biosciences, Targeted Oncology, MORE Health, Research to Practice, Foundation Medicine, Peerview, AstraZeneca, Genentech/Roche, Bayer; Consulting and Advisory role in Ignyta, Loxo, TP Therapeutics, AstarZeneca, Pfizer, Blueprint Medicines, Genentech/Roche, Takeda, Helsinn Therapeutics, BeiGene, Hengrui Therapeutics, Exelixis and Bayer. SW, XAW, BM, AU and VW are employees and shareholders of Eli Lilly and Company. This study was funded by Eli Lilly and Company. 1 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 29, 2019; DOI: 10.1158/1078-0432.CCR-18-4010 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Corresponding author James J. Harding Address: 300 East 66th Street Memorial Sloan Kettering Cancer Center, New York, Untied States of America. Phone: 646-888-4314 Fax: 646-888-4255 E-mail: [email protected] Target journal: Clinical Cancer Research 2 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 29, 2019; DOI: 10.1158/1078-0432.CCR-18-4010 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Statement of Translational Relevance: Mesenchymal epithelial transition factor proto-oncogene receptor tyrosine kinase (MET) signaling supports oncogenic processes including cell proliferation, invasion, and metastasis. MET activation also contributes to resistance to VEGF/VEGFR targeting agents. This phase 1b/2 study demonstrates a favorable safety profile for emibetuzumab, a humanized, bivalent monoclonal antibody targeting MET, when administered with the VEGFR2 antibody ramucirumab. Exploratory data suggest that baseline tumoral MET expression is associated with clinical anti-tumor activity for this combination in HCC. Patients with high MET expression exhibited an approximate 3-fold longer PFS relative to HCC patients with low MET expression. Given the negative prognosis associated with MET-high HCCs (1), the median PFS of 8.1 months observed herein is of interest as it exceeds previously reported median PFS of 2.0 months for MET high HCC patients treated with MET targeted therapy (2). These translational data warrant additional studies to investigate MET inhibition as an antiangiogenic treatment in HCC. Word count: (current 149/max 150 words) 3 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 29, 2019; DOI: 10.1158/1078-0432.CCR-18-4010 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract: Purpose: Inhibition of the vascular endothelial growth factor receptor-2 (VEGFR-2) blocks angiogenesis and attenuates tumor growth, but cancers may evade this effect through activation of the hepatocyte growth factor (HGF) receptor MET. Here we report results of the phase 1b/2 study of ramucirumab, a monoclonal anti-VEGFR-2 antibody, plus the anti-MET monoclonal antibody emibetuzumab. Patients and Methods: A 3+3 dose escalation of emibetuzumab plus ramucirumab (Phase 1b) was followed by tumor-specific expansion cohorts. Primary objectives were to determine the recommended phase 2 dose (RP2D) and to evaluate antitumor activity. Secondary objectives included safety, pharmacokinetics, and immunogenicity. Tumoral MET expression was explored by immunohistochemistry. Results: 97 solid tumor patients (6 phase 1b, 16 GEJ, 45 HCC, 15 RCC, and 15 NSCLC) received emibetuzumab at 750 or 2000 mg flat dosing plus ramucirumab at 8mg/kg Q2W. No DLTs were observed. Common AEs were primarily mild or moderate and included fatigue (36.1%), peripheral edema (28.9%), and nausea (14.4%). Emibetuzumab exposures were similar as in previous studies with no apparent drug-drug interactions. Five partial responses (5.2%) were observed across all tumor types. The greatest anti- tumor activity was noted in HCC with a 6.7% ORR, 60% DCR, and 5.42 months (95% CI: 1.64-8.12) PFS. HCC with high MET expression showed improved PFS with approximately threefold increase in PFS (8.1 vs. 2.8 months) relative to low MET expression. 4 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 29, 2019; DOI: 10.1158/1078-0432.CCR-18-4010 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Conclusions: Ramucirumab plus emibetuzumab was safe and exhibited cytostatic antitumor activity. MET expression may help to select patients benefitting most from this combination treatment in select tumor types. Word count: 250 words (max 250 words) 5 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 29, 2019; DOI: 10.1158/1078-0432.CCR-18-4010 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. INTRODUCTION Vascular endothelial growth factor (VEGF) and its receptor, vascular endothelial growth factor receptor-2 (VEGFR-2) have critical roles in the physiologic growth and maintenance of blood vessels. High levels of VEGF and other angiogenic factors are often associated with an increased level of tumor microvessel density, aggressive pathologic features, and poor clinical outcomes in a variety of cancer histology. In preclinical models, blockade of the VEGF/VEGFR-2 axis leads to tumor vascular remodeling and cancer cell death. Pathological dysregulation of angiogenesis is an established hallmark of malignancy, and both VEGFR-2 and its ligand are bona fide therapeutic targets either with selective monoclonal antibodies or via multi-targeted tyrosine kinase inhibitors, in a variety of tumor types, including non-small lung cancer (NSCLC), ovarian cancer, renal cell carcinoma (RCC), and several gastrointestinal malignancies such as colorectal cancer (CRC), gastric or gastroesophageal junction adenocarcinoma (GEJ), and hepatocellular carcinoma (HCC) (3-6). Innate and acquired resistance to anti-angiogenic therapy is frequent and multi- factorial, but is in part mediated by the hepatocyte growth factor (HGF) receptor MET (7- 9). Both ligand-dependent and -independent MET activation is implicated in tumor cell motility, proliferation, survival, invasion, metastasis, and angiogenesis. Indeed, the MET receptor is overexpressed, activated, amplified, or mutated in a wide variety of solid tumors (9-11), and contributes to an aggressive tumor biology (12,13). Importantly, VEGF blockade leads to a reciprocal increase in MET concentration and activation (8), which in turn leads to MET-mediated anti-angiogenic escape (14). Simultaneous pharmacological inhibition of MET and VEGF signaling mitigates MET-mediated escape, thereby slowing 6 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 29, 2019; DOI: 10.1158/1078-0432.CCR-18-4010 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. tumor growth and reducing invasion and metastasis (14). Thus, there is compelling preclinical evidence to support co-targeting VEGF and MET pathways in malignances to enhance the activity of VEGF/VEGFR-2 monotherapy. Clinically the concept MET as a mechanism of anti-angiogenic resistance is also suggested in several correlative programs across multiple tumor types indicating
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