First-in-human phase 1 study of the anti-TIGIT antibody vibostolimab as monotherapy or with pembrolizumab for advanced solid tumors, including non-small-cell lung cancer☆

Abstract

Background: In this first-in-human phase 1 study (NCT02964013; MK-7684-001), we investigated the safety and efficacy of the anti-TIGIT (T cell immunoglobulin and ITIM domain) antibody vibostolimab as monotherapy or in combination with pembrolizumab.

Patients and methods: Part A enrolled patients with advanced solid tumors, and part B enrolled patients with non-small-cell lung cancer (NSCLC). Patients received vibostolimab 2.1-700 mg alone or with pembrolizumab 200 mg in part A and vibostolimab 200 mg alone or with pembrolizumab 200 mg in part B. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective response rate (ORR) per RECIST v1.1.

Results: Part A enrolled 76 patients (monotherapy, 34; combination therapy, 42). No dose-limiting toxicities were reported. Across doses, 56% of patients receiving monotherapy and 62% receiving combination therapy had treatment-related adverse events (TRAEs); grade 3-4 TRAEs occurred in 9% and 17% of patients, respectively. The most common TRAEs were fatigue (15%) and pruritus (15%) with monotherapy and pruritus (17%) and rash (14%) with combination therapy. Confirmed ORR was 0% with monotherapy and 7% with combination therapy. In part B, 39 patients had anti-PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1)-naive NSCLC (all received combination therapy), and 67 had anti-PD-1/PD-L1-refractory NSCLC (monotherapy, 34; combination therapy, 33). In patients with anti-PD-1/PD-L1-naive NSCLC: 85% had TRAEs-the most common were pruritus (38%) and hypoalbuminemia (31%); confirmed ORR was 26%, with responses occurring in both PD-L1-positive and PD-L1-negative tumors. In patients with anti-PD-1/PD-L1-refractory NSCLC: 56% receiving monotherapy and 70% receiving combination therapy had TRAEs-the most common were rash and fatigue (21% each) with monotherapy and pruritus (36%) and fatigue (24%) with combination therapy; confirmed ORR was 3% with monotherapy and 3% with combination therapy.

Conclusions: Vibostolimab plus pembrolizumab was well tolerated and demonstrated antitumor activity in patients with advanced solid tumors, including patients with advanced NSCLC.

Keywords: MK-7684; advanced solid tumors; immune checkpoint inhibitor; non-small-cell lung cancer; pembrolizumab; vibostolimab.

Conflict of interest statement

Disclosure JN reports personal fees from AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Exelixis, Immvira, Johnson & Johnson, Merck, Mirati Therapeutics, and Takeda, outside the submitted work. CM-D reports personal fees from Bristol Myers Squibb, Biomica, MSD, and Pfizer, outside the submitted work. DHL reports personal fees from AbbVie, AstraZeneca, BC Pharma, Blueprint Medicine, Boehringer Ingelheim, Bristol Myers Squibb, ChongKeunDang, CJ Healthcare, Eli Lilly, Genexine, Janssen, Menarini, Merck, MSD, Mundipharma, Novartis, Ono, Pfizer, Roche, Samyang Biopharm, ST Cube, and Takeda; and non-financial support from Blueprint Medicine and Takeda, outside the submitted work. D-WK reports a grant from Merck to his institution for the work under consideration; grants from Alpha Biopharma, Amgen, AstraZeneca, Boehringer Ingelheim, Bridge BioTherapeutics, ChongKeunDang, Daiichi-Sankyo, GSK, Hanmi, Janssen, Merus, Mirati, Novartis, ONO, Pfizer, Roche, Takeda, TP Therapeutics, Xcovery, and Yuhan, outside the submitted work; and personal fees from Amgen and Daiichi-Sankyo, outside the submitted work. MV reports personal fees from Astra-Zeneca outside the submitted work. HCC reports grants to his institution from Amgen, Bristol Myers Squibb-ONO, GSK, Incyte, Lilly, MSD, Merck-Serono, Neigene, Taiho, and Zymework, outside the submitted work; and personal fees from Amgen, Bristol Myers Squibb, Celltrion, Gloria, Lilly, Merck-Serono, MSD, Taiho, and Zymework, outside the submitted work. KM has participated in advisory boards for AstraZeneca, Bayer, Bristol Myers Squibb, and Takeda and speakers' bureaus for Merck, outside the submitted work. UV reports grants and personal fees from Merck for the work under consideration; grants from Astellas and Bristol Myers Squibb, outside the submitted work; and personal fees from AAA, Alkermes, Astellas, Bayer, Bristol Myers Squibb, Exelixis, and Pfizer, outside the submitted work. DR reports research funding from Merck for the work under consideration and research funding from Arcus and Compugen, outside the submitted work. TG reports research funding to his institution from AstraZeneca and MSD; has received honoraria from MSD and Rafael Pharmaceuticals; served as consultant or advisor to AbbVie, AstraZeneca, Bayer, MSD, and Teva; and received travel expenses from AstraZeneca and MSD, outside the submitted work. TMB reports a grant from Merck for the work under consideration and grants to his institution from AbbVie, Aileron Therapeutics, Amgen, ARMO Biosciences, Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Calithera Biosciences, Clovis Oncology, Daiichi Sankyo, Deciphera, Five Prime Therapeutics, Foundation Medicine, Genentech, GlaxoSmithKline, Ignyta, Immunocore, Immunogen, Incyte, Jacobio, Janssen, Karyopharm Therapeutics, Kolltan Pharmaceuticals, Leap Therapeutics, Lilly, Loxo, MabVax, Medpacto, Merck, Merrimack, Millennium, Mirati Therapeutics, MedImmune, Moderna Therapeutics, Novartis, Onyx, Peleton, Pfizer, Phosplatin Therapeutics, Principa Biopharma, Roche, Sanofi, Stemline Therapeutics, Takeda, and Top Alliance BioScience, outside the submitted work; personal fees from AstraZeneca, Bayer, Blueprint Medicines, Bristol Myers Squibb, Exelixis, Foundation Medicine, Guardant Health, Lilly, Loxo, and Pfizer, outside the submitted work; nonfinancial support from Bayer, Bristol Myers Squibb, Foundation Medicine, Guardant Health, Ignyta, Lilly, Loxo, and Moderna Therapeutics, outside the submitted work; and payments to institution for consulting from Ignyta, Leap Therapeutics, Moderna Therapeutics, and Pfizer, outside the submitted work. AJ reports research funding to institution from Debiopharm, Iovance, Khar, Merck, Moderna, Pfizer, and SQZ, outside the submitted work. VC reports a grant from Merck outside of the submitted work and personal fees from AstraZeneca, Coherus, Ipsen, and Pfizer, outside the submitted work. M-JA reports personal fees from Alpha Pharmaceutical, AstraZeneca, Bristol Myers Squibb, Lilly, Merck, MSD, Takeda, and Yuhan, outside the submitted work. EC and JAH are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. All other authors have declared no conflicts of interest. Data sharing Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD) is obligated to protect the rights and privacy of trial patients. To fulfill the company's obligation, MSD has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with qualified external scientific researchers. 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Copyright © 2021 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, The Author(s). Published by Elsevier Ltd.. All rights reserved.