A first-in-human study of the anti-LAG-3 antibody favezelimab plus pembrolizumab in previously treated, advanced microsatellite stable colorectal cancer

Abstract

Background: Treatment options are limited for participants with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) that progressed after two or more prior therapies. Studies have shown that blockade of both lymphocyte-activation gene 3 (LAG-3) and programmed cell death protein 1 (PD-1) can improve antitumor activity. Here, we evaluate the antitumor activity of the LAG-3 antibody favezelimab alone or in combination with pembrolizumab in participants with MSS mCRC.

Patients and methods: Eligible participants with MSS PD-1/programmed death-ligand 1 (PD-L1) treatment-naive mCRC that progressed on two or more prior therapies received 800 mg favezelimab, 800 mg favezelimab plus 200 mg pembrolizumab, or 800 mg favezelimab/200 mg pembrolizumab co-formulation, every 3 weeks. The primary endpoint was safety, the secondary endpoint was objective response rate (ORR), and exploratory endpoints included duration of response, progression-free survival (PFS), and overall survival (OS).

Results: At the data cut-off date of 23 October 2020, a total of 20 participants received favezelimab alone, 89 received favezelimab plus pembrolizumab (including as favezelimab/pembrolizumab co-formulation); 48 had PD-L1 combined positive score (CPS) ≥1 tumors. At this interim analysis median follow-up was 5.8 months with favezelimab and 6.2 with favezelimab plus pembrolizumab. Treatment-related adverse events (TRAEs) were 65% with favezelimab and 65.2% with favezelimab plus pembrolizumab. Grade ≥3 TRAEs were 15% with favezelimab and 20% with favezelimab plus pembrolizumab. No grade 5 TRAEs occurred. Common TRAEs (≥15%) included fatigue (20.0%), nausea (15.0%) with favezelimab, and fatigue (16.9%) with favezelimab plus pembrolizumab. Confirmed ORR was 6.3% with favezelimab plus pembrolizumab, with median duration of response of 10.6 months (range 5.6-12.7 months), median OS of 8.3 months (95% confidence interval 5.5-12.9 months), and median PFS of 2.1 months (1.9-2.2 months). In an exploratory analysis of PD-L1 CPS ≥1 tumors, the confirmed ORR was 11.1%, median OS was 12.7 months (4.5 to not reached), and median PFS was 2.2 months (1.8-4.2 months) with favezelimab plus pembrolizumab.

Conclusions: Favezelimab with or without pembrolizumab had a manageable safety profile, with no treatment-related deaths. Promising antitumor activity was observed with combination therapy, particularly in participants with PD-L1 CPS ≥1 tumors.

Keywords: LAG-3; PD-1; advanced; colorectal cancer.

Conflict of interest statement

Disclosure EG reports research funding to the institution for clinical studies from Merck Sharp & Dohme (MSD), Novartis, AstraZeneca/MedImmune, Roche, Thermo Fisher Scientific, Taiho Oncology, Affimed Gmbh, Amgen SA, Anaveon AG, AstraZeneca AB, Biontech Gmbh, Catalym Gmbh, Cytomx, F. Hoffmann La Roche Ltd, F-Star Beta Limited, Genentech Inc., Genmab B.V., Hutchison, Medipharma Limited, Icon, Imcheck Therapeutics, Immunocore Ltd, Janssen-Cilag SA, MedImmune LLc, Merck Kgga, S.A – Peptomyc, Ribon Therapeutics, Roche Farma SA, Seattle Genetics Inc., Symphogen A/S, fees for consulting and advisory roles from Roche, Ellipses Pharma, NeoMed, Janssen, Boehringer Ingelheim, Seattle Genetics, TFS, Alkermes, Thermo Fisher Scientific, Bristol Myers Squibb (BMS), mAb Discovery, Anaveon, fees for speakers bureau from MSD, Roche, Thermo Fisher Scientific, Lilly, reimbursement for travel from BMS, Menarini, Glycotope GmbH, MSD; AS reports research funding to the institution from MSD, stock in BMS, Merck, fee for speakers bureau from Merck, Eisai; NJL, AP, YYL, TG report research funding to the institution for clinical studies from MSD; SAI reports research funding to the institution for clinical studies from MSD, AstraZeneca, Eisai, Boryung Pharm, Daewon Pharm, Roche, Pfizer, fees for consulting or advisory role from AstraZeneca, Daiichi Sankyo, Eisai, GlaxoSmithKline, Lilly, MSD, Novartis, Pfizer, Roche; RG reports research funding to the institution for clinical studies from MSD, Novartis, honoraria from BMS, Lilly, Medison, Roche, Novartis, Janssen, Takeda, MSD, Pfizer, Merck, fees for consulting or advisory role from Eisai, AstraZeneca, Bayer, MSD, Novartis, Boehringer Ingelheim, BOL Pharma, Roche, reimbursement for travel from Merck, Bayer, BMS, Medison; MDM reports research funding to the institution from MSD, Roche, Sanofi, PharmaMar, AbbVie, Janssen, Faron, Genentech, MacroGenics, Menarini, Nektar, Novartis; MW reports research funding to the institution for clinical studies, fees for consulting or advisory roles from BMS, Novartis, Kite, Heidelberg Pharma, Roche, Boehringer Ingelheim, honoraria from BMS, Merck, Roche, Novartis, Kite, Boehringer Ingelheim, AstraZeneca, reimbursement for travel from Glenmark, BMS, AstraZeneca; JP, SJ, MC, AA, JH are employees of MSD LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD) and hold stock in Merck & Co., Inc., Rahway, NJ, USA; GSF reports research funding to the institution for clinical studies from 3-V Biosciences, Abbisko, AbbVie, ABL Bio ADC Therapeutics, Aileron, American Society of Clinical Oncology, Amgen, ARMO/Eli Lilly, Artios, AstraZeneca, BeiGene, BioAtla, BioInvent, Biothera, Bicycle, Boehringer Ingelheim, Celldex, Celgene, CicloMed, Curegenix, Curis, Cyteir, Daiichi, DelMar, eFFECTOR, Eli Lilly, EMD Serono, Epizyme, Erasca, Exelixis, Freenome, Fujifilm, Genmab, GlaxoSmithKline, Hutchison MediPharma, IGM Biosciences, Ignyta, ImmunoGen/MacroGenics, Incyte, Jacobio, Jounce, Kolltan, Loxo/Bayer, MedImmune, Millennium, Merck, miRNA Therapeutics, National Institutes of Health, Navire, NiKang, Novartis, OncoMed, Oncorus, Oncothyreon, Poseida, Precision Oncology, Prelude, PureTech, Pyramid, RasCal, Regeneron, Rgenix, Ribon, Samumed, Sapience, Silicon, Strategia, Syndax, Synthorx/Sanofi, Taiho, Takeda, Tarveda, Teneobio, Tesaro, Tocagen, Turning Point Therapeutics, U.T. MD Anderson Cancer Center, Vegenics, Xencor, fees for consulting or advisory role from Fujifilm, Silicon, Navire, Turning Point, Predicine, EMD Serono, reimbursement for travel from BMS, EMD Serono, Fujifilm, Millenium, Sarah Cannon Research Institute, speakers honoraria from Total Health Conferencing, Rocky Mountain Oncology Society.

Copyright © 2022. Published by Elsevier Ltd.

Figures

Figure 1

Study diagram. Study flow for part B cohort A in participants with PD-1/PD-L1 treatment-naive MSS mCRC that progressed on ≥2 prior therapies. HNSCC, head and neck squamous cell carcinoma; mCRC, metastatic colorectal cancer; MSS, microsatellite stable; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; Q3W, every 3 weeks; RP2D, recommended phase II dose.

Figure 2

Kaplan–Meier estimates of (A) progression-free survival (PFS) and (B) overall survival (OS) with favezelimab plus pembrolizumab in patients with MSS mCRC by PD-L1 status. CI, confidence interval; CPS, combined positive score; mCRC, metastatic colorectal cancer; MSS, microsatellite stable; PD-L1, programmed death-ligand 1.