Safety of immune checkpoint modulators beyond PD-1/PD-L1 and CTLA-4 in solid tumors: a meta-analysis

BACKGROUND: Novel agents targeting immune checkpoints are under development to overcome resistance to PD-1/PD-L1 and CTLA-4 blockade. Incidences of immune-related adverse events (irAEs) and toxicity profiles of novel agents remain unelucidated.

METHODS: We searched PubMed/MEDLINE, Embase, and Web of Science for clinical trials evaluating agents targeting co-inhibitory (B7-H3, CD47, TIGIT, LAG-3, and TIM-3) or co-stimulatory checkpoints (OX40, 4-1BB, CD27, ICOS, GITR, CD70, and CD40) in solid tumors. Incidences of any-grade and grade 3-5 (G3-5) treatment-related AEs (trAEs) and irAEs were extracted from phase 2 and 3 trials, and phase 1/2 trials with safety information reported at the recommended phase 2 dose. Odds ratios (ORs) from 2-arm studies evaluating the addition of LAG-3 or TIGIT blockade to control-arm therapy were pooled, and AE incidences across immunotherapy subtypes were reported using a random-effects meta-analysis.

RESULTS: A systematic review identified 27 clinical trials comprising 3946 patients. The addition of LAG-3 blockade increased G3-5 trAEs (OR = 1.79, 95% confidence interval [CI] = 1.26 to 2.54, P = .001), adrenal insufficiency (G3-5: OR = 8.43, 95% CI = 1.04 to 68.37, P = .046; any-grade: OR = 4.81, 95% CI = 1.81 to 12.78, P = .002) and any-grade arthralgia (OR = 2.07, 95% CI = 1.29 to 3.30, P = .002). Adding TIGIT blockade increased any-grade rash (OR = 2.32, 95% CI = 1.01 to 5.34, P = .048). Meta-analyses revealed varying irAE patterns: G5 trAEs (0.9%-2.9%), G3-5 pneumonitis (0.5%-5.5%, highest in TIM-3), G3-5 colitis (0.2%-5.4%, highest in LAG-3), G3-5 hepatitis (1.5%-5.5%, highest in TIM-3), and G3-5 adrenal insufficiency (1.7%-8.4%, highest in TIGIT).

CONCLUSIONS: This study highlights the distinct toxicity profiles of novel immunotherapy agents, providing essential safety data to support clinicians as these therapies approach approval.