Horita, Nobuyuki

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.

ImportanceLip, oral, and pharyngeal cancers are important contributors to cancer burden worldwide, and a comprehensive evaluation of their burden globally, regionally, and nationally is crucial for effective policy planning.ObjectiveTo analyze the total and risk-attributable burden of lip and oral cavity cancer (LOC) and other pharyngeal cancer (OPC) for 204 countries and territories and by Socio-demographic Index (SDI) using 2019 Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study estimates.Evidence ReviewThe incidence, mortality, and disability-adjusted life years (DALYs) due to LOC and OPC from 1990 to 2019 were estimated using GBD 2019 methods. The GBD 2019 comparative risk assessment framework was used to estimate the proportion of deaths and DALYs for LOC and OPC attributable to smoking, tobacco, and alcohol consumption in 2019.FindingsIn 2019, 370 000 (95% uncertainty interval [UI], 338 000-401 000) cases and 199 000 (95% UI, 181 000-217 000) deaths for LOC and 167 000 (95% UI, 153 000-180 000) cases and 114 000 (95% UI, 103 000-126 000) deaths for OPC were estimated to occur globally, contributing 5.5 million (95% UI, 5.0-6.0 million) and 3.2 million (95% UI, 2.9-3.6 million) DALYs, respectively. From 1990 to 2019, low-middle and low SDI regions consistently showed the highest age-standardized mortality rates due to LOC and OPC, while the high SDI strata exhibited age-standardized incidence rates decreasing for LOC and increasing for OPC. Globally in 2019, smoking had the greatest contribution to risk-attributable OPC deaths for both sexes (55.8% [95% UI, 49.2%-62.0%] of all OPC deaths in male individuals and 17.4% [95% UI, 13.8%-21.2%] of all OPC deaths in female individuals). Smoking and alcohol both contributed to substantial LOC deaths globally among male individuals (42.3% [95% UI, 35.2%-48.6%] and 40.2% [95% UI, 33.3%-46.8%] of all risk-attributable cancer deaths, respectively), while chewing tobacco contributed to the greatest attributable LOC deaths among female individuals (27.6% [95% UI, 21.5%-33.8%]), driven by high risk-attributable burden in South and Southeast Asia.Conclusions and RelevanceIn this systematic analysis, disparities in LOC and OPC burden existed across the SDI spectrum, and a considerable percentage of burden was attributable to tobacco and alcohol use. These estimates can contribute to an understanding of the distribution and disparities in LOC and OPC burden globally and support cancer control planning efforts.