Background: 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.
Materials and methods: 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.
Results: 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.
Conclusion: 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.
Keywords: Chemotherapy; Lung cancer; PD-1; PD-L1.