Sex-based analysis of first-line immune-based combinations in intermediate/poor-risk papillary, chromophobe, and unclassified renal cell carcinoma: an ARON-1 subanalysis

Background: Non-clear cell renal cell carcinoma (nccRCC) represents a heterogeneous group of malignancies with limited prospective data to guide systemic therapy. Immune-based combination regimens are increasingly used in this setting by extrapolation from clear cell RCC trials. Whether patient sex influences outcomes in metastatic nccRCC treated with first-line immunotherapy (IO)-based combinations remains unknown. Methods: This is a retrospective sub-analysis of the ARON-1 real-world study that included 256 patients with intermediate- or poor-risk metastatic nccRCC treated with first-line IO-based combinations across 56 centers in 17 countries between January 2021 and December 2024. Patients with favorable-risk disease were excluded. The primary objective was to compare overall survival (OS) and time on treatment (ToT) between male and female patients. Tumor responses were assessed per RECIST 1.1 criteria. Survival outcomes were estimated using the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazards regression models were used for univariable and multivariable analyses. Results: Of 256 patients included, 197 (77%) were male and 59 (23%) were female. The median OS in the overall population was 27.8 months (95% CI 22.6-36.5), with a 1-year OS rate of 80%. No statistically significant difference in OS was observed between females and males (31.9 months vs 26.7 months; p = 0.124). In the intermediate-risk subgroup, females demonstrated a longer median OS compared with males (36.1 vs. 27.8 months; HR 0.60; p = 0.041). Among patients with liver metastases, median OS was not reached in females versus 15.0 months in males (1-year OS: 88% vs. 53%; p < 0.001). In patients with papillary histology, females showed a significantly longer OS than males (36.1 vs. 27.8 months; HR 0.52; p = 0.037). Conclusions: In this large real-world study of IO-based combinations in metastatic nccRCC, no statistically significant sex-based difference in OS was observed in the overall population. Exploratory subgroup analyses identified potential sex-based interactions in intermediate-risk disease, liver metastases, and papillary histology that warrant prospective investigation. The underrepresentation of women in this cohort and the retrospective design underscore the need for dedicated, sex-stratified analyses in future trials.