Defining tumor resistance to PD-1 pathway blockade: recommendations from the first meeting of the SITC Immunotherapy Resistance Taskforce.

As the field of cancer immunotherapy continues to advance at a fast pace, treatment approaches and drug development are evolving rapidly to maximize patient benefit. New agents are commonly evaluated for activity in patients who had previously received a programmed death receptor 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor as standard of care or in an investigational study. However, because of the kinetics and patterns of response to PD-1/PD-L1 blockade, and the lack of consistency in the clinical definitions of resistance to therapy, the design of clinical trials of new agents and interpretation of results remains an important challenge. To address this unmet need, the Society for Immunotherapy of Cancer convened a multistakeholder taskforce-consisting of experts in cancer immunotherapy from academia, industry, and government-to generate consensus clinical definitions for resistance to PD-(L)1 inhibitors in three distinct scenarios: primary resistance, secondary resistance, and progression after treatment discontinuation. The taskforce generated consensus on several key issues such as the timeframes that delineate each type of resistance, the necessity for confirmatory scans, and identified caveats for each specific resistance classification. The goal of this effort is to provide guidance for clinical trial design and to support analyses of emerging molecular and cellular data surrounding mechanisms of resistance.

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Competing interests: HMK has served as a consultant for Corvus, Nektar, Biodesix, Genentech, Pfizer, Merck & Co., Immunocore, Array Biopharma and Celldex, and has received research support from Merck & Co., Apexigen and Bristol-Myers Squibb. HAT has served as a consultant or an advisory board member for Bristol-Myers Squibb, Novartis, Merck & Co., Genentech, and Array, and has received commercial research grants from Bristol-Myers Squibb, Merck & Co., Genentech, GlaxoSmithKline and Celgene. MLA is a full-time employee of AstraZeneca/MedImmune. MB is a full-time employee of Bristol-Myers Squibb. MKC has served as a consultant and/or advisory board member for AstraZeneca/MedImmune, Incyte, Moderna and Merck &. Co. She has also received research grant funding from Bristol-Myers Squibb, and reports that a family member is currently employeed by Bristol-Myers Squibb. EC is an employee of and has stock in Roche Genentech. CGD has received research funding Aduro Biotech, Bristol-Myers Squibb, Janssen, royalties from Bristol-Myers Squibb, AstraZeneca, and Janssen, has served as a consultant for Agenus, Dendreon, Janssen, Eli Lilly, Merck & Co., Medimmune, Pierre Fabre, and Roche Genentech, and has ownership interest in Compugen, Harpoon, and Kleo. DMF is a full-time employee of Bristol-Myers Squibb. RLF has served as a consultant for Aduro Biotech, Bain Capital Life Sciences, Bristol-Myers Squibb, Iovance Biotherapeutics, Nanobiotix, Ono Pharmaceutical CO. Ltd, Torque Therapeutics, and TTMS, has served on an advisory board for Amgen, Bristol-Myers Squibb, EMD Serono, GlaxoSmithKline, Eli Lilly, Merck & Co., Numab Therapeutics AG, Oncorus, Pfizerv, PPD (Benitec, Immunicum), Regeneron Pharmaceuticals, and Tesaro, has conducted clinical trials in collaboration with AstraZeneca/MedImmune, Bristol-Myers Squibb, Merck & Co., and has received research funding from AstraZeneca/MedImmune, Bristol-Myers Squibb, Tesaro, TTMS, and VentriRx Pharmaaceuticals. SG has served as a consultant and/or an advisory board member for Exelixis, Janssen Biotech, and AstraZeneca. RWH is a full-time employee and stockholder of CytomX Therapeutics. TML holds stock in AstraZeneca, and has institutional support from Bristol-Myers Squibb. DTL has served on an advisory board for Merck & Co. and Bristol-Myers Squibb, has received research funding from Merck & Co., Bristol-Myers Squibb, Aduro Biotech, Curegenix, and Medivir, has received speaking honoraria from Merck & Co., and is an inventor of licensed intellectual property related to technology for mismatch repair deficiency for diagnosis and therapy (WO2016077553A1) from Johns Hopkins University. The terms of these arrangements are being managed by Johns Hopkins. VML has served on an advisory board for FXBiopharma. VAP has received research funding from Checkmate and Incyte, has received personal fees from LOXO Oncology, Araxes Pharma, Takeda, AbbVie, Tesaro, Exelixis, has received both grants and personal fees from Nektar Therapeutics, AstraZeneca, Eli Lilly, Roche, Merck & Co., Bristol-Myers Squibb, Novartis, Janssen, Checkmate, Incyte, and has served on an advisory board for Arrys Therapeutics. MAP has received personal fees from Merck & Co., Bristol-Myers Squibb, Novartis, Array BioPharma, Aduro, Incytem NewLink Genetics, has received non-financial support from Merck & Co., Bristol-Myers Squibb, RGenix, Infinity, AstraZeneca, Novartis, and Array Bio Pharma. ER is an employee of Merck & Co. JMT has received research funding from Bristol-Myers Squibb, has served on an advisory board for Bristol-Myers Squibb, Merck & Co., AstraZeneca, and Amgen. SLT reports grants and non-financial support from Bristol-Myers Squibb; personal fees from AbbVie, ImaginAb, Immunocore, Avidity NanoMedicines LLC, and Merck; and personal fees and non-financial support from Five Prime Therapeutics and Dragonfly Therapeutics, outside the submitted work. In addition, SLT has patents pending. SLT’s spouse has financial relationships with the following entities: Aduro, Amgen, Bayer, Camden Nexus, Compugen, DNAtrix, Dynavax Technolgies, Ervaxx, FLX Bio, Immunomic Therapeutics, Janssen Pharmaceuticals, Jounce Therapeutics, MedImmune/AstraZeneca, Pfizer, Potenza Therapeutics, Rock Springs Capital, Tizona LLC, Trieza Therapeutics, and WindMIL. RZ is the inventor on patent applications related to work on GITR, PD-1 and CTLA-4, and consultant for Leap Therapeutics. MS has received consulting fees from Roche Genentech, Bristol-Myers Squibb, AstraZeneca/Medimmune, Novartis, Seattle Genetics, Nektar Therapeutics, Eli Lilly, Biodesix, Modulate Therapeutics, Newlink Genetics, Molecular Partners, Innate Pharma, Abbvie, Immunocore, Genmab, Almac, Hinge, Allakos, Anaeropharma, and Array, has served on an advisory board for Symphogen, Adaptimmune, Omniox, Lycera, Pieris, and Torque, and holds stock options in Torque. RS has received personal fees from Amgen, Merck & Co., Genentech, Novartis, Compugen, Replimmune, Array, and Syndax, has recieved research funding from Amgen and Merck & Co., has recieved clinical trial support from Merck & Co., Tesaro, Sanofi, Genentech and Novartis.