Society for Immunotherapy of Cancer (SITC) consensus definitions for resistance to combinations of immune checkpoint inhibitors with chemotherapy

Sep 24, 2026

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Although immunotherapy can bring major clinical benefit for hard-to-treat cancers, many tumors fail initial treatment with immune checkpoint inhibitors (ICIs) or later progress after initial control. Higher response rates have been shown when ICIs are added to cytotoxic therapies, supporting approvals across multiple solid-tumor indications. Trial design remains difficult without consistent resistance definitions, so SITC convened a 2021 workshop to establish consensus clinical definitions for resistance to multiagent ICI combinations with chemotherapy, supporting analyses of emerging molecular and cellular mechanisms.

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CategoryHealthcare

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Abstract

Introduction

Open access Position article and guidelines Society for Immunotherapy of Cancer (SITC) consensus definitions for resistance to combinations of immune checkpoint inhibitors with chemotherapy Naiyer Rizvi,1 Foluso O Ademuyiwa ,2 Z Alexander Cao,3 Helen X Chen,4 Robert L Ferris,5 Sarah B Goldberg,6 Matthew D Hellmann ,7 Ranee Mehra,8 Ina Rhee,9 Jong Chul Park ,10 Harriet Kluger ,6 Hussein Tawbi ,11 Ryan J Sullivan 10 To cite: Rizvi N, Ademuyiwa FO, Cao ZA, et al. Society for Immunotherapy of Cancer (SITC) consensus definitions for resistance to combinations of immune checkpoint inhibitors with chemotherapy. Journal for ImmunoTherapy of Cancer 2023;11:e005920 . doi:10 . 1136/ jitc-2022-005920 ► Additional supplemental material is published online only. To view, please visit the journal online ([http://dx.doi.org/10](http://dx.doi.org/10) . 1136/jitc-2022-005920) . Accepted 09 January 2023 ► [http://dx.doi.org/10.1136/](http://dx.doi.org/10.1136/)[ ](http://dx.doi.org/10.1136/)jitc-2022-005923 ► [http://dx.doi.org/10.1136/](http://dx.doi.org/10.1136/)[ ](http://dx.doi.org/10.1136/)jitc-2022-005921 © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. For numbered affiliations see end of article. Correspondence to Dr Ryan J Sullivan; [rsullivan7@mgh.harvard.edu](rsullivan7@mgh.harvard.edu) ABSTRACT Although immunotherapy can offer profound clinical benefit for patients with a variety of difficult-to-treat cancers, many tumors either do not respond to upfront treatment with immune checkpoint inhibitors (ICIs) or progressive/recurrent disease occurs after an interval of initial control. Improved response rates have been demonstrated with the addition of ICIs to cytotoxic therapies, leading to approvals from the US Food and Drug Administration and regulatory agencies in other countries for ICI−chemotherapy combinations in a number of solid tumor indications, including breast, head and neck, gastric, and lung cancer. Designing trials for patients with tumors that do not respond or stop responding to treatment with immunotherapy combinations, however, is challenging without uniform definitions of resistance. Previously, the Society for Immunotherapy of Cancer (SITC) published consensus definitions for resistance to single-agent anti-programmed cell death protein 1 (PD-1) . To provide guidance for clinical trial design and to support analyses of emerging molecular and cellular data surrounding mechanisms of resistance to ICI-based combinations, SITC convened a follow-up workshop in 2021 to develop consensus definitions for resistance to multiagent ICI combinations. This manuscript reports the consensus clinical definitions for combinations of ICIsand chemotherapies. Definitions for resistance to ICIs in combination with targeted therapies and with other ICIswill be published in companion volumes to this paper. INTRODUCTION Immune checkpoint inhibitors (ICIs) as single agents or in combinations with chemotherapies and targeted therapies are now the standard of care for patients with a wide range of solid tumors. Despite offering longlasting disease control for a subset of patients, the majority of patients treated with ICI monotherapy either do not respond (ie, de novo or primary resistance) or they progress/ recur after an initial response (ie, acquired or secondary resistance) . Resistance to ICIs is still incompletely understood and the mechanisms of primary and acquired resistance may involve any or all of the steps in the cancerimmunity cycle,1 including loss of neoantigen expression, alternate immune checkpoints, effector cell exclusion, or altered interferon signaling.2–8 Several strategies to enhance therapeutic outcomes are currently under investigation, and combination regimens involving the addition of immunotherapy, targeted therapy, or chemotherapy have advanced through late-stage clinical developmen

FAQs

Why is defining resistance to ICI combinations important for clinical trials?

Designing trials for patients whose tumors do not respond or stop responding is challenging without uniform definitions of resistance.

What is the document’s main purpose regarding SITC guidance?

SITC convened a 2021 follow-up workshop to develop consensus definitions for resistance to multiagent ICI combinations, and the manuscript reports consensus clinical definitions for ICI plus chemotherapy combinations.

How do ICI plus chemotherapy combinations compare with chemotherapy alone?

In phase III trials, ICI combinations with chemotherapy have demonstrated improved overall response rates, progression-free survival (PFS), and overall survival (OS) versus chemotherapy alone.

Sep 24, 2026

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