Are immune-related adverse events associated with the efficacy of immune checkpoint inhibitors in patients with cancer? A systematic review and meta-analysis

Abstract

Background: A number of studies have reported an association between the occurrence of immune-related adverse events (irAEs) and clinical efficacy in patients undergoing treatment with immune checkpoint inhibitors (ICIs), but the results remain controversial.

Methods: Under the guidance of a predefined protocol and Preferred Reporting Items for Systematic Reviews and Meta-analyses statement, this meta-analysis included cohort studies investigating the association of irAEs and efficacy of ICIs in patients with cancer. The primary outcome was overall survival (OS), and the secondary outcome was progression-free survival (PFS). Subgroup analyses involving the cancer type, class of ICIs, combination therapy, sample size, model, landmark analysis, and approach used to extract the data were performed. Specific analyses of the type and grade of irAEs were also performed.

Results: This meta-analysis included 30 studies including 4971 individuals. Patients with cancer who developed irAEs experienced both an OS benefit and a PFS benefit from ICI therapy compared to patients who did not develop irAEs (OS: hazard ratio (HR), 0.54, 95% confidence interval (CI), 0.45-0.65; p < 0.001; PFS: HR, 0.52, 95% CI, 0.44-0.61, p < 0.001). Subgroup analyses of the study quality characteristics and cancer types recapitulated these findings. Specific analyses of endocrine irAEs (OS: HR, 0.52, 95% CI, 0.44-0.62, p < 0.001), dermatological irAEs (OS: HR, 0.45, 95% CI, 0.35-0.59, p < 0.001), and low-grade irAEs (OS: HR, 0.57, 95% CI, 0.43-0.75; p < 0.001) yielded similar results. The association between irAE development and a favorable benefit on survival was significant in patients with cancer who were undergoing treatment with programmed cell death-1 inhibitors (OS: HR, 0.51, 95% CI, 0.42-0.62; p < 0.001), but not cytotoxic T-lymphocyte antigen-4 inhibitors (OS: HR, 0.89, 95% CI, 0.49-1.61; p = 0.706). Additionally, the association was significant in patients with cancer who were treated with ICIs as a monotherapy (OS: HR, 0.53, 95% CI, 0.43-0.65; p < 0.001), but not as a combination therapy (OS: HR, 0.62, 95% CI, 0.36-1.05; p = 0.073).

Conclusions: The occurrence of irAEs was significantly associated with a better ICI efficacy in patients with cancer, particularly endocrine, dermatological, and low-grade irAEs. Further large-scale prospective studies are warranted to validate our findings.

Systematic review registration: PROSPERO CRD42019129310.

Keywords: Cancer; Efficacy; Immune checkpoint inhibitors; Immune-related adverse events.

Fig. 1

Flowchart of study selection process. Abbreviations: OS, overall survival; PFS, progression-free survival; NSCLC, non-small cell lung cancer; RCC, renal cell carcinoma

Fig. 2

Forest plot (random effects model) of the association between immune-related adverse event development and overall survival. The sizes of the squares indicate the weight of the study. Abbreviations: HR, hazard ratio; irAEs, immune-related adverse events; non-irAEs, non-immune-related adverse events. ^aResults for grade 1–2 immune-related adverse events (irAEs). ^bResults for grade 3–4 irAEs

Fig. 3

Meta-analyses of the association between immune-related adverse event development and outcome. Abbreviations: HR, hazard ratio; irAEs, immune-related adverse events; non-irAEs, non-immune-related adverse events. Low grade indicates grades 1–2; severe grade indicates a grade greater than or equal to 3. ^aThe HR was directly presented without pooling because only one study was available

Fig. 4

Subgroup analyses of the association between immune-related adverse event development and overall survival. Abbreviations: OS, overall survival; HR, hazard ratio; NSCLC, non-small cell lung cancer; ICIs, immune checkpoint inhibitors; anti-PD-1, anti-programmed cell death-1; anti-CTLA-4, anti-cytotoxic T-lymphocyte antigen-4. ^aThis group included four multiple cancer types and 1 renal cell carcinoma. ^bThe study reported by Owen et al. was not included in subgroup analysis regarding class of ICIs because it is the only one study investigating anti-PD-1/anti-PD-L1 drug. ^cYes indicates studies that combined ICIs with other therapy, including peptide vaccine (n = 2), radiotherapy (n = 1) and Vemurafenib (n = 1). ^dNo indicates studies that adopted ICIs as monotherapy