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

Abstract

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.

Radiological dynamics and SITC-defined resistance types of advanced melanoma during anti-PD-1 monotherapy: an independent single-blind observational study on an international cohort

“…Additionally, the PD pattern has not been well described, particularly in the setting of primary/refractory versus secondary/acquired resistance, and based on maximal tumor regression. 14 This report represents the first international effort incorporating melanoma patients with detailed longitudinal radiological data, specifically focusing on disease kinetics at crucial time points during anti-PD-1 monotherapy, and demonstrates for the first time that time course and disease kinetics are associated with survival outcomes.…”

“…Finally, we evaluated the resistance subtype (primary vs secondary) based on a previously reported resistance definition that emerged from the SITC Immunotherapy Resistance Taskforce. 14 Of note, patients included in this study are heterogeneous, 39% had prior immunotherapy, 12% had prior targeted therapy; 16% had brain metastasis; and 29% were with acral, mucosal, or ocular melanomas which are known to be less responsive to immunotherapy. Therefore, the proportion of primary resistance observed in this cohort may be higher than in the general melanoma population with anti-PD-1 monotherapy as the first-line treatment.…”

“…Among patients who experienced PD, those who had PD or SD for <6 months as their best response were categorized into primary resistance; otherwise, PD was designated secondary. 14 …”

228 Radiological dynamics and resistance types in patients with advanced melanoma treated with anti-PD-1 monotherapy

“…As per the SITC Taskforce, primary resistance was defined as a best response of stable disease (SD) lasting less than six months or disease progression (PD), secondary as PD following an initial partial or complete response (PR/CR) or SD lasting 6 months or greater. 1 Results The most dramatic tumor reduction occurred within the first 3 months after anti-PD-1 initiation. A subpopulation of patients who had SD (28.6%, all with tumor shrinkage) experienced further tumor reduction and upgraded to CR/PR and 11.1% of patients with initial PR upgraded to CR.…”

417 Design and rationale of a phase 1 study evaluating AMG 256, a novel, targeted, IL-21 receptor agonist and anti-PD-1 antibody, in patients with advanced solid tumors

“…Background Checkpoint inhibitors are a promising therapy for patients with solid tumors; however, many patients require additional therapies to maximize clinical benefit or overcome resistance. 1 The type-1 cytokine interleukin-21 (IL-21) is a promising candidate for combination and has shown clinical activity in melanoma and renal cell cancer. 2 IL-21 has also shown improved efficacy when combined with anti-programmed death (PD)-1 antibodies in preclinical models.…”