Intratumoral mature TLSs to predict response to ICI rechallenge in non–clear cell renal cell carcinoma.

Abstract

450 Background: While immune checkpoint inhibitor (lCl)-based therapy has shown promising efficacy in patients with metastatic non-clear cell renal cell carcinoma (nccRCC) in the first-line setting, the optimal treatment following disease progression remains undefined. We aimed to investigate the efficacy, safety and predictive markers of ICl rechallenge in this population. Methods: Thirty-three patients with metastatic nccRCC who received ICI rechallenge were enrolled. Key outcomes included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Whole exome sequencing, bulk RNA sequencing and multiplex immunofluorescence were performed to further explore potential biomarker associated with efficacy of ICI-rechallenge among nccRCC. Results: Following ICI-rechallenge, the cohort demonstrated a median PFS of 11.8 months, an ORR of 16.7% and a DCR of 70%. Among clinicopathological variables, the FH-dRCC subtype was the only factor associated with the potential clinical benefit from ICI-rechallenge. Transcriptomic analysis revealed that an enrichment of B cells and central memory T cells signatures was associated with longer PFS (21.3 vs. 7.9 months). Notably, patients with a higher mature intratumoral tertiary lymphoid structure (m-iTLS) score assessed by mIF showed higher ORR (50% vs. 11%) and longer PFS (28.2 vs. 5.3 months) compared to those with a lower m-iTLS score. In terms of safety, ICI rechallenge was generally well tolerated, with no accumulation, or treatment-related deaths observed. Conclusions: ICI rechallenge may offer favorable clinical benefit and acceptable safety in patients with metastatic nccRCC. Higher density of mature intratumoral TLSs correlated with the efficacy of ICI-rechallenge but warrants further validation.