The risk of treatment‐related toxicities with PD‐1/PD‐L1 inhibitors in patients with lung cancer

Abstract The risk of treatment‐related toxicities with programmed cell death 1 and its ligand (PD‐1/PD‐L1) inhibitors in patients with lung cancer is unclear and inconclusive. PubMed, EMBASE, and the Cochrane Library databases were systematically searched without language restrictions from inception to May 31, 2024 to identify Phase 3 randomized controlled trials of lung cancer comparing PD‐1/PD‐L1 inhibitors versus placebo/best supportive care (alone or in combination with nontargeted chemotherapy) that had available data regarding treatment‐related adverse events (TRAEs) or incidence and sample size. Random‐effect models were employed to study the pooled relative risk (RR) and 95% confidence intervals (CIs). Finally, 36 trials, involving 19,693 participants, fulfilled the inclusion criteria. PD‐1/PD‐L1 inhibitors significantly augmented the likelihood of developing all‐grade (RR, 1.03; 95% CI, 1.01–1.04, p < .01) and grade ≥3 TRAEs (RR, 1.16; 95% CI, 1.10 to 1.23, p < .01). PD‐1/PD‐L1 inhibitors substantially augmented the odds of developing treatment‐related serious adverse events (SAEs) (RR, 1.48; 95% CI, 1.27–1.71, p < .01) and fatal adverse events (FAEs) (RR, 1.42; 95% CI, 1.11–1.82, p < .01). Subgroup analyses indicated that the RR of SAEs and FAEs were generally consistent, regardless of treatment type, tumor type, treatment setting, PD‐1/PD‐L1 inhibitors type and study design. The most common causes of FAEs were respiratory failure/insufficiency (33.3%), cardiac events (16.1%), and hematological disorders (10.1%). We demonstrated that PD‐1/PD‐L1 inhibitors were significantly correlated with higher possibility of developing treatment‐related toxicities, especially SAEs and FAEs, compared with placebo/best supportive care controls.