Impact of Organ-Specific Severe Immune-Related Adverse Events on Long-Term Survival and Treatment Transitions in Metastatic Renal Cell Carcinoma: A 5-Year Multicenter Multistate Analysis.

Abstract

Introduction: Immune-related adverse events (irAEs) frequently occur during combination immune checkpoint inhibition. However, their prognostic impact may vary according to organ involvement and severity. In this study, we exploratorily evaluated whether severe non-endocrine irAEs represent a temporally distinct and prognostically unfavorable clinical phenotype in patients with metastatic renal cell carcinoma (mRCC) treated with ipilimumab plus nivolumab.

Patients and methods: We analyzed 63 patients with mRCC treated with ipilimumab plus nivolumab who were followed for at least 5 years. Patients were categorized into non-irAE, non-severe + severe endocrine irAE, and severe non-endocrine irAE groups. Overall survival (OS) was assessed. Multistate modeling was used to evaluate the transitions between treatment, irAE occurrence, and death. Landmark analyses were performed at 8 and 12 weeks to address immortal time bias.

Results: The severe non-endocrine irAE group was associated with inferior OS. The multistate analysis revealed a potentially increased risk of direct transition from ipilimumab plus nivolumab to death in the severe non-endocrine irAE group. A significantly higher proportion of patients in the severe non-endocrine irAE group experienced irAEs within 30 days. No significant association was observed in the 8- and 12-week landmark analyses.

Conclusion: In this exploratory retrospective study, severe non-endocrine irAEs showed an association with early onset and potentially unfavorable clinical outcomes in patients with mRCC receiving ipilimumab plus nivolumab. Given the limited sample size, these findings should be interpreted cautiously and require confirmation in larger independent cohorts.