Safety and Efficacy of Rechallenge With Immune Checkpoint Inhibitors in Advanced Solid Tumor: A Systematic Review and Meta-Analysis

Background: Immune checkpoint inhibitors (ICIs) have drastically shifted the current landscape toward a wide variety of malignancies. However, ICIs are interrupted owing immune-related adverse events (irAEs), therapy completion, and disease progression. The risk-benefit of rechallenged ICIs remains inconclusive. Herein, a systematic review and meta-analysis were conducted to evaluate the safety and efficacy of ICI rechallenge in the treatment of advanced solid tumor. Methods: PubMed, Web of Science, Embase, and Cochrane Library were searched to analyze the efficacy and safety of ICI rechallenge. The study protocol was approved by the PROSPERO International Register of Systematic Reviews (CRD42022372222). The last updated search date was March 2, 2024. Objective response rate (ORR), disease control rate (DCR), overall survival (OS), and incidence rates of all- and high-grade irAEs were evaluated. Results: A total of 41 retrospective studies comprising 2343 patients were ultimately enrolled for qualitative and quantitative assessments. A total of 1200 (51.2%) individuals were male and the median age was 66 years (range 18-97 years). The majority of the tumors was lung cancer (n = 898, 38.3%). The occurrence rates of all-grade and high-grade (grade 3 or 4) irAEs between initial and readministration ICIs were not significantly different (all-grade: OR, 0.75, 95% CI: 0.39-1.45, p = 0.40; I-2 = 87%; high-grade: OR, 0.96, 95% CI: 0.62-1.49, p = 0.87, I-2 = 65%). ICIs restart presented a decreased ORR and DCR compared to initial ICI administration (ORR: OR, 0.36, 95% CI: 0.23-0.56, p < 0.00001; I-2 = 67%; DCR: OR, 0.62, 95% CI: 0.43-0.89, p = 0.010; I-2 = 53%). Seven studies with 513 patients for survival analysis revealed a nonsignificant difference in OS between the ICIs rechallenge and discontinuation cohorts (hazard ratio [HR]: 0.68, 95% confidence interval (CI): 0.35 to 1.35, p = 0.27). Conclusion: Rechallenging immunotherapy is feasible, and patients should be carefully evaluated by a multidisciplinary team prior to initial therapy for close monitoring and assessment of the risk-benefit ratio. Therefore, prospective trials are essential to guide clinicians in the decision-making process.