Immune-related and Common Adverse Events With Programmed Cell Death 1/Programmed Cell Death Ligand 1 inhibitors combined with other Anticancer Therapy for Solid Tumors: A Systematic Review and Meta-analysis

The combination of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors and anticancer therapies has been in the spotlight in recent years. However, the risks associated with these combination therapies are not fully elucidated. The primary objective of this study was to evaluate the relative risk of organ-specific immune-related adverse events (irAEs) and common adverse events (AEs) in patients treated with PD-1/PD-L1 inhibitor–based combination therapies compared to those treated with PD-1/PD-L1 inhibitor monotherapy for solid tumors. An electronic database search was performed using ClinicalTrials.gov, Medline, and American Society of Clinical Oncology (ASCO)/European Society for Medical Oncology (ESMO) annual meeting libraries. We included randomized controlled trials designed to assess the safety of combination therapies using PD-1/PD-L1 inhibitors and other anticancer drugs. All the selected clinical studies included solid tumors and provided information on the incidence of nonserious and serious AEs. The quality of evidence was assessed using the Cochrane risk-of-bias tool. A meta-analysis was performed using random-effect models to pool the results. The primary analysis included 16 relevant clinical studies comprising 4232 patients, of whom 2071 and 2161 patients received PD-1/PD-L1 inhibitor–-based combination therapy and PD-1/PD-L1 inhibitor monotherapy, respectively. Serious organ-specific irAEs were infrequent, even when PD-1/PD-L1 inhibitors were combined with other anticancer drugs. The incidence of serious colitis was significantly higher in the combination therapy group than in the monotherapy group. Among the common AEs associated with PD-1/PD-L1 inhibitors, the incidence of serious pyrexia/fever, nonserious pyrexia/fever, fatigue, nausea, decreased appetite, vomiting, diarrhea, dyspnea, and rash significantly increased in the combination therapy group. In the subgroup analysis based on the modes of action of concomitant anticancer drugs, the combination of PD-1/PD-L1 inhibitors and DNA synthesis inhibitors significantly increased the risk of serious colitis compared to PD-1/PD-L1 inhibitor monotherapy. Organ-specific irAEs occur infrequently when combinations of PD-1/PD-L1 inhibitors and other anticancer drugs are used. However, the risk of serious colitis and certain AEs is higher than that associated with PD-1/PD-L1 inhibitor monotherapy. Vigilant monitoring of AEs and implementation of appropriate clinical m