Safety and efficacy of quavonlimab, a novel anti-CTLA-4 antibody (MK-1308), in combination with pembrolizumab in first-line advanced non-small-cell lung cancer

Abstract

Background: Quavonlimab (MK-1308), a novel anti-CTLA-4 antibody, in combination with pembrolizumab was investigated in a phase I study.

Patients and methods: Dose-escalation (DE) phase: patients with advanced/metastatic solid tumors received an initial flat dose of quavonlimab as monotherapy [25 mg (cohort 1), 75 mg (cohort 2), or 200 mg (cohort 3)] followed by four treatments of the same quavonlimab dose plus pembrolizumab every 3 weeks (Q3W). Dose-confirmation phase (DC): patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) received first-line quavonlimab [25 mg Q3W (arm A), 25 mg Q6W (arm B), 75 mg Q6W (arm C), or 75 mg Q3W (arm E)] plus pembrolizumab. Primary objectives were safety and tolerability and establishment of the recommended phase II dose (RP2D) of quavonlimab when used with pembrolizumab. Objective response rate (ORR) was a secondary endpoint. Efficacy based on PD-L1 expression, tumor mutational burden (TMB), and changes in circulating CD4+/CD8+ cells were exploratory endpoints.

Results: Thirty-nine patients were enrolled in DE [n = 14 (cohort 1); n = 17 (cohort 2); n = 8 (cohort 3)] and 134 in DC [n = 40 (arm A); n = 40 (arm B); n = 40 (arm C); n = 14 (arm E)]. Maximum-tolerated dose was not reached. Grade 3-5 treatment-related adverse events (AEs; graded according to NCI CTCAE v4.03) occurred in 0%, 23.5%, and 75.0% of patients in DE cohorts 1, 2, and 3, respectively, and 35.0%, 30.0%, 35.0%, and 57.1% of patients in DC arms A, B, C, and E, respectively. Efficacy was observed at all dose levels/schedules in patients with NSCLC. ORRs were 40.0% [95% confidence interval (CI), 24.9-56.7; arm A], 37.5% (95% CI, 22.7-54.2; arm B), 27.5% (95% CI, 14.6-43.9; arm C), and 35.7% (95% CI, 12.8-64.9; arm E). PD-L1 expression and total number of circulating CD4+ cells correlated with ORR.

Conclusions: Quavonlimab 25 mg Q6W plus pembrolizumab demonstrated similar efficacy and a better safety profile among all quavonlimab doses/schedules evaluated; this regimen was the chosen RP2D.

Keywords: CTLA-4; MK-1308; immunotherapy; non-small-cell lung cancer; pembrolizumab; quavonlimab.

Conflict of interest statement

Disclosure RP reports a consultant role for Karyopharm Therapeutics and BioLineRx. JB reports an advisory board role for Roche, AstraZeneca, Pfizer, Takeda, Boehringer Ingelheim, and Bayer; and a consultant role for MSD, BMS, Novartis, and AbbVie. DWR reports research grants from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. M-JA reports an advisory board role for AstraZeneca, Lilly, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, ONO, BMS, Takeda, Amgen, Novartis, and Roche; and a consultant role for Alpha Pharmaceutical Company, AstraZeneca, Lilly, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, ONO, BMS, Takeda, Amgen, Novartis, and Roche. KY reports honorarium received from promotional activities from Chugai Pharma, AstraZeneca, Lilly Japan, Novartis, Kirin, Bristol Myers Squibb Japan, and Taiho. D-WK reports travel and accommodation support for advisory board meeting attendance from Amgen and Daiichi Sankyo. AN reports an advisory board role for MSD, BMS, Roche, and AstraZeneca. MS reports honoraria received from promotional activities from AstraZeneca, MSD, Chugai, Taiho, Pfizer, Nippon Kayaku, Boehringer Ingelheim, Bristol Myers Squibb, ONO, Novartis, and Eli Lilly; and research grants from Chugai, AstraZeneca, MSD, Pfizer, Boehringer Ingelheim, Bristol Myers Squibb, ONO, Novartis, Eli Lilly, AbbVie, Ignyta, and Takeda. DHL reports honoraria for lecturing or consulting from AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, ChongKunDang, CJ Healthcare, Eli Lilly, Janssen, Menarini, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Mundipharma, Novartis, Roche, ST Cube, and Takeda; and travel accommodations from Takeda and Blueprint Medicines. DRS reports leadership for Centennial Medical Center; consulting or advisory role for Genentech/Roche, Novartis, Celgene, Bristol Myers Squibb, AstraZeneca, Pfizer, Boehringer Ingelheim, AbbVie, Foundation Medicine, GlaxoSmithKline, Lilly, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Moderna Therapeutics, Nektar, Takeda, Amgen, TRM Oncology, Precision Oncology, Evelo Therapeutics, Illumina, and PharmaMar; research funding (institution) from Genentech/Roche, Novartis, Celgene, Bristol Myers Squibb, Lilly, AstraZeneca, Pfizer, Boehringer Ingelheim, University of Texas Southwestern Medical Center – Simmons Cancer Center, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, AbbVie, GlaxoSmithKline, G1 Therapeutics, Neon Therapeutics, Takeda, Foundation Medicine, Nektar, Celldex, Clovis Oncology, Daiichi Sankyo, EMD Serono, Acerta Pharma, OncoGenex, Astellas Pharm, GRAIL, Transgene, Ipsen, ARMO BioSciences, Amgen, and Millennium; and travel, accommodation, and expenses from AstraZeneca, Boehringer Ingelheim, Celgene, Lilly, EMD Serono, Bristol Myers Squibb, Genentech, Genzyme, Intuitive Surgical, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Pfizer, Purdue Pharma, Spectrum Pharmaceuticals, and Sysmex. SS is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. XL is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. JC is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and has stock ownership interests in Merck & Co., Inc., Kenilworth, NJ, USA. AC is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and has stock ownership interests in Merck & Co., Inc., Kenilworth, NJ, USA. AC is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. RAA is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. BCC reports a speakers bureau role for Novartis; an advisory board role for Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, ONO, Dizal Pharma, and MSD; a consultant role for Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, ONO, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, and MSD; stock ownership interests in TheraCanVac Inc., Gencurix Inc., and BridgeBio Therapeutics; honoraria from promotional activities for Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, ONO, Dizal Pharma, and MSD; research grants from Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD; and royalties, intellectual property or patents with Champions Oncology. All other authors declare no conflicts of interest.

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