Safety and tolerability of PD-1/PD-L1 inhibitors in the treatment of non-small cell lung cancer: a meta-analysis of randomized controlled trials

Significant improvement in survival outcome with the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors has been shown in advanced non-small cell lung cancer (NSCLC) patients compared with chemotherapy. However, the full spectrum of toxic events of PD-1/PD-L1 inhibitors was not well characterized. We conducted a comprehensive meta-analysis to state the safety profile of PD-1/PD-L1 inhibitors in NSCLC, and identify the exact incidence and relative risk (RR) of both summary and detailed AEs. Electronic databases (PubMed, EMBASE and the Cochrane library databases) and major conference proceedings were systematically searched for all clinical trials in lung cancer using PD-1/PD-L1 inhibitors. Eligible studies included randomized controlled trials (RCTs) comparing PD-1/PD-L1 inhibitors with chemotherapy in NSCLC patients reporting all-grade (1-4) or high-grade (3-4) AEs [toxic symptoms, hematologic toxicities, and immune-related AEs (irAEs)], treatment discontinuation due to toxicities, or toxic deaths. The pooled incidence, RR, and corresponding 95% confidence interval (CI) of toxicity outcomes were calculated. A total of 4413 patients from 8 RCTs (3 with nivolumab; 2 with atezolizumab, and 3 with pembrolizuma) were included. In terms of summary toxic events, PD-1/PD-L1 inhibitors had a significantly lower risk of any all-grade AEs (66.20 vs. 86.08%; RR 0.77) and high-grade AEs (14.26 vs. 43.53%; RR 0.32), treatment discontinuation (5.94 vs. 13.92%; RR 0.44), and toxic deaths (0.48 vs. 1.12%; RR 0.45) than chemotherapy. With regard to detailed toxic events, the risk of toxic symptoms (including all-grade fatigue, nausea, constipation, diarrhea and peripheral sensory neuropathy; high-grade fatigue, anorexia, diarrhea and peripheral sensory neuropathy) and hematologic toxicities (including all-grade and high-grade neutropenia, thrombocytopenia, and anemia) from PD-1/PD-L1 inhibitors was significantly lower than from chemotherapy. However, there was a small but significantly increased risk of irAEs, including all-grade rash, pruritus, colitis, hypothyroidism, hyperthyroidism, ALT/AST elevations and pneumonitis, as well as high-grade pneumonitis. PD-1/PD-L1 inhibitors are generally safer and better tolerated than chemotherapy for patients with NSCLC with regard to summary toxic events, detailed toxic symptoms and hematologic toxicities. However, PD-1/PD-L1 inhibitors can generate a unique spectrum of irAEs, and several of them can be severe and even life-threatening. Clinicians should be aware of the risk of these AEs, as they may have a potentially negative impact on the patients' quality of life and survival outcome.