Adverse events profile of novel agents targeting immune checkpoints beyond PD-1/PD-L1 and CTLA-4 in solid tumors: A meta-analysis.

Abstract

2642 Background: PD-1, PD-L1, and CTLA-4 blockade are standard therapies in multiple solid tumors, and novel agents targeting alternative co-stimulatory and co-inhibitory immune checkpoints are under development. Immune checkpoint inhibitors are well known to cause immune-related adverse events (irAEs) and multiple studies reported the accurate incidence of irAEs from PD-1, PD-L1, and CTLA-4 blockade. With the increasing investigation and anticipated approval of novel immunotherapy agents, understanding their toxicity profiles is critical. Methods: We systematically searched PubMed/MEDLINE, EMBASE, and Web of Science for clinical trials published up to December 1st, 2024. Studies evaluating the safety of agents targeting co-inhibitory checkpoints (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 were included. Incidence rates of grade 1-5 (G1-5) and grade 3-5 (G3-5) treatment-related adverse events (trAEs) and irAEs were extracted. Toxicity data were derived from phase 2 and 3 trials, as well as phase 1/2 trials with safety information reported at the recommended phase 2 dose. Random-effects meta-analysis was used to pool odds ratios (ORs) from two-arm studies evaluating the addition of LAG-3 or TIGIT blockade to control-arm therapy, and proportional meta-analysis was conducted to analyze AE incidence across immunotherapy subtypes. Results: A systematic review identified 27 clinical trials with 40 cohorts comprising 3,946 patients and evaluating 10 immune checkpoints (B7-H3, LAG-3, TIGIT, CD47, OX40, CD137. TIM-3, CD40, CD27, CD40, ICOS). Meta-analyses showed that the addition of LAG-3 blockade to either PD-1 blockade-based therapy or placebo was associated with increased G3-5 trAEs (OR 1.79, 95% confidence interval [CI]: 1.26–2.54, p = 0.001), G3-5 adrenal insufficiency (OR 8.43, 95% CI: 1.04 - 68.37, p = 0.046), G1-5 adrenal insufficiency (OR 4.81, 95% CI: 1.81-12.78, p = 0.002) and arthralgia (OR 2.07, 95% CI: 1.29-3.30, p = 0.002). The addition of TIGIT blockade to PD-L1 blockade-based therapy was associated with increased G1-5 rash (OR 2.32, 95% CI: 1.01–5.34, p = 0.048) (other outcomes will be shown). Proportional meta-analysis revealed varying irAE patterns across agents: G5 trAEs (0.9-2.9%), G3-5 pneumonitis (0.5-5.5%, highest in TIM-3 blockade), G3-5 colitis (0.2-5.4%, highest in LAG-3 blockade), G3-5 hepatitis (1.5-5.5%, highest in TIM-3 blockade), G3-5 rash (0.8%-18.4%, highest in CD40 agonists), G3-5 adrenal insufficiency (1.7-8.4%, highest in TIGIT blockade) (details of all outcomes will be presented). Conclusions: This study highlights the distinct toxicity profiles of novel immunotherapy agents, providing essential safety data to support clinicians as these therapies move toward anticipated clinical approval.