Pretreatment intratumoral mature TLSs in non-clear cell renal cell carcinoma are associated with response to immunotherapy rechallenge

BACKGROUND: While immune checkpoint inhibitor (ICI)-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 ICI rechallenge in this population. METHODS: 39 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. Whole exome sequencing, bulk RNA sequencing, and multiplex immunofluorescence (mIF) were performed to further explore potential biomarkers associated with the efficacy of ICI-rechallenge among nccRCC. RESULTS: Following ICI-rechallenge, the cohort demonstrated a median PFS of 11.8 months, an ORR of 13.9% and a DCR of 69.4%. Among clinicopathological variables, the fumarate hydratase-deficient renal cell carcinoma 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 cell 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 (50.0% vs 0.0%) and longer PFS (28.2 vs 5.0 months) compared with 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 iTLSs correlated with the efficacy of ICI-rechallenge but warrants further validation.