Safety and efficacy of immunotherapy rechallenge in solid tumors after discontinuation of immune checkpoint inhibitors for immune-related adverse events: A systematic review and meta-analysis.

11127 Background: Immune-related adverse events (irAEs) often require treatment discontinuation in patients with cancer receiving immune checkpoint inhibitors (ICIs). Given limited subsequent treatment options, ICI rechallenge is frequently considered. We aimed to estimate the incidence of recurrent irAEs and objective response rates (ORR) in patients receiving ICI rechallenge following prior irAEs. Methods: PubMed, Web of Science, and Embase were searched for studies evaluating ICI rechallenge in patients with advanced solid tumors who previously suspended treatment due to irAEs. Outcomes included the incidence of grade 1-5 (Gr1-5), Gr1-2, and Gr3-5 irAEs, recurrent irAEs, new irAEs, ORR, and disease control rate (DCR). Random-effects meta-analyses and subgroup analyses by cancer type were performed. Meta-regression analysis was conducted to evaluate the impact of the grade and type of initial irAEs on response outcomes. Heterogeneity was assessed using I 2 statistics (≥50% considered high). Results: Thirty-seven studies comprising 1,126 patients with initial irAEs (Gr1-2: 62.8%, Gr3-4: 37.2%) leading to suspension of ICIs were included. The most common initial irAEs in the pooled cohort were hepatitis/liver enzyme elevations (20.5%), pneumonitis (16.1%), and nephritis/acute kidney injury (14.8%). Pooled incidences of Gr1-5, Gr1-2, and Gr3-5 irAEs after ICI rechallenge were 42.2% (95% confidence interval CI: 35.3-49.3), 27.1% (95% CI: 22.9-31.7), and 18.8% (95% CI: 14.7-23.8), respectively. Subgroup analysis showed overall higher incidences of irAEs in melanoma (Gr1-5: 54.6%, Gr1-2: 23.2%, Gr3-5: 26.4%) than those in lung cancer (Gr1-5: 39.7%, Gr1-2: 27.4%, Gr3-5: 14.0%) and solid tumors (Gr1-5: 36.7%, Gr1-2: 22.8%, Gr3-5: 20.1%). The same type of irAEs recurred in 23.8% (95% CI: 20.1-28.0) of patients, while new types of irAEs developed in 29.3% (95% CI: 25.2-33.7) of patients undergoing ICI rechallenge. The overall ORR was 45.2% (95% CI: 34.5-56.4), with cancer type-specific ORRs of 60.5% (95% CI: 47.9-71.9) in melanoma, 39.1% (95% CI: 17.4-66.2) in lung cancer, and 39.5% (95% CI: 27.7-52.6) from studies investigating solid tumors. DCR was high across cancer types: 77.3% (95% CI: 67.7-84.7) overall, 68.2% (95% CI: 41.3-86.8) in melanoma, 91.2% (95% CI: 67.7-98.1) in lung cancer, and 72.5% (95% CI: 63.3-80.1) in solid tumors. Meta-regression analysis showed that commonly observed initial irAE types or grades of initial irAEs (Gr1-2 vs. Gr3-4) did not significantly impact ORR or DCR. Conclusions: ICI rechallenge after discontinuation due to irAEs demonstrates clinical activity but carries a substantial risk of both recurrent and new irAEs. These findings highlight the need for predictive biomarkers to optimize patient selection and maximize survival without compromising safety.