Immune-related adverse events as potential surrogates of immune checkpoint inhibitors' efficacy: a systematic review and meta-analysis of randomized studies

V Amoroso; F Gallo; A Alberti; D Paloschi; W Ferrari Bravo; A Esposito; D Cosentini; S Grisanti; R Pedersini; F Petrelli; A Berruti

doi:10.1016/j.esmoop.2023.100787

Immune-related adverse events as potential surrogates of immune checkpoint inhibitors' efficacy: a systematic review and meta-analysis of randomized studies

ESMO Open. 2023 Apr;8(2):100787. doi: 10.1016/j.esmoop.2023.100787. Epub 2023 Feb 24.

Authors

V Amoroso¹, F Gallo², A Alberti³, D Paloschi³, W Ferrari Bravo³, A Esposito³, D Cosentini³, S Grisanti³, R Pedersini³, F Petrelli⁴, A Berruti³

Affiliations

¹ Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Medical Oncology Unit, University of Brescia, Azienda Socio Sanitaria Territoriale (ASST) Spedali Civili, Brescia. Electronic address: vitoamoroso@alice.it.
² Clinical Epidemiology Unit, IRCCS, Ospedale Policlinico San Martino, Genova.
³ Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Medical Oncology Unit, University of Brescia, Azienda Socio Sanitaria Territoriale (ASST) Spedali Civili, Brescia.
⁴ Medical Sciences Department, Oncology Unit, Azienda Socio Sanitaria Territoriale (ASST) Bergamo Ovest, Treviglio, Bergamo, Italy.

Abstract

Background: Immune-related adverse events (irAEs) are frequently reported during immune checkpoint inhibitor (ICI) therapy and are associated with long-term outcomes. It is unknown if the irAE occurrence is a valid surrogate of ICIs' efficacy.

Methods: We identified articles reporting the results of randomized trials of experimental ICI therapy in solid tumors with a systematic search. The control arms could be placebo, cytotoxic/targeted therapy, or ICI therapy. We extracted the hazard ratios for overall survival (OS) with the number of OS events per arm and the number and percentages of overall and specific irAEs of grade 1-2 and grade 3-4 per arm. We estimated the treatment effect on the potential surrogate outcome with the odds ratio of the irAE rate between the experimental and the control arm. The statistical analysis consisted of weighted linear regression on a logarithmic scale between treatment effects on irAE rate and treatment effects on OS.

Results: Sixty-two randomized trials were included for a total of 79 contrasts and 42 247 patients. The analyses found no significant association between the treatment effects for overall grade 1-2 or grade 3-4 irAE rates or specific (skin, gastrointestinal, endocrine) irAE rates. In the non-small-cell lung cancer (NSCLC) trial subset, we observed a negative association between treatment effects on overall grade 1-2 irAEs and treatment effects on OS in studies with patients selected for programmed death-ligand 1 expression (R² = 0.55; 95% confidence interval 0.20-0.95; R = -0.69). In the melanoma trial subset, a negative association was shown between treatment effects on gastrointestinal grade 3-4 irAEs and treatment effects on OS in trials without an ICI-based control arm (R² = 0.77; 95% confidence interval 0.24-0.99; R = -0.89).

Conclusions: We found low-strength correlations between the ICI therapy effects on overall or specific irAE rates and the treatment effects on OS in several cancer types.

Keywords: immune checkpoint inhibitors; immune-related adverse events; surrogate endpoints; trial-based meta-analysis.

Publication types

Meta-Analysis
Systematic Review
Review

MeSH terms

Antineoplastic Agents* / therapeutic use
Carcinoma, Non-Small-Cell Lung* / drug therapy
Humans
Immune Checkpoint Inhibitors / adverse effects
Lung Neoplasms* / drug therapy
Melanoma* / drug therapy

Substances

Immune Checkpoint Inhibitors
Antineoplastic Agents