Outcomes and prognostic factors of first-line combination of immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) in TFE3-rearranged renal cell carcinoma.

Abstract

429 Background: Due to the rarity of TFE3-rearranged renal cell carcinoma ( TFE3-rRCC) and the poor understanding of its underlying mechanisms, the clinical treatment landscape in TFE3-rRCC is largely undefined. Hence, the optimal therapy for TFE3-rRCC remains to be determined. The diversity of fusion partners leads to the high heterogeneity of TFE3-rRCC, yet no studies have compared responses of patients with different fusion partners to systemic treatment. Methods: Data were collected retrospectively from our institution. Patients with metastatic TFE3-rRCC were eligible. Kaplan-Meier survival analysis and univariate and multivariate analysis were performed to compare survival outcomes. RNA-seq was performed to determine fusion partners and explore the transcriptomic features. Results: A total of 38 patients with metastatic TFE3-rRCC were enrolled in this study. The fusion partners were identified in 33 (87%) patients. Patients receiving first-line ICI plus TKI had longer PFS than those not receiving first-line ICI plus TKI (median PFS: 11.5 vs. 5.1 months, P=0.098). Subgroup analysis demonstrated that patients with ASPSCR1-TFE3 fusion significantly benefited from ICI plus TKI (PFS HR: 0.068, 95% CI: 0.008-0.609, P=0.016), whereas no improvement in PFS was observed in patients with other fusions. Univariate and multivariate cox regression analysis further demonstrated that besides IMDC risk score, ASPSCR1-TFE3 fusion could also serve as an independent prognostic factor for PFS in patients receiving first-line ICI plus TKI. Among patients receiving ICI plus TKI, those with ASPSCR1-TFE3 fusion had longer PFS than those with other fusions (median PFS: not reached vs. 6.5 months, P=0.01). Transcriptomic data revealed that ASPSCR1-TFE3 fusion rearranged RCC harbored higher angiogenesis activity. Additionally, decreased infiltration of immunosuppressive M2-phenotype macrophages and Tregs was observed in tumors with ASPSCR1-TFE3 fusion. Conclusions: Metastatic TFE3-rearranged RCC patients with ASPSCR1-TFE3 fusion could benefit from ICI plus TKI. Higher angiogenesis activity and decreased infiltration of immunosuppressive cells were observed in tumors with ASPSCR1-TFE3 fusions, which may explain the clinical outcome.