Sarcomatoid Differentiation in Renal Cell Carcinoma: Clinical and Pathologic Heterogeneity and Outcomes With Immune Checkpoint Inhibitors-Data From the ARON-1 Study

Purpose: Sarcomatoid renal cell carcinoma (sRCC) represents a kidney malignancy with a sarcomatoid component associated with poor prognosis. Immunotherapy (IO)-based combinations demonstrated promising activity in sRCC, yet real-world evidence (RWE) remains limited. We aimed to characterize the clinicopathologic features and outcomes of patients with metastatic sRCC treated with first-line immune-based combinations. Patients and methods: This retrospective analysis from the ARON-1 study included 350 patients with histologically confirmed metastatic sRCC treated with first-line IO + IO, or IO + tyrosine kinase inhibitor across 66 centers in 21 countries (2016-2024). Overall survival (OS) was analyzed using Kaplan-Meier and Cox regression methods. Correlations between 2-year OS and clinical variables were assessed using Pearson's coefficient. Results: After a median follow-up of 19.1 months, median OS was 26.9 months (95% CI, 21.6 to 43.3). OS was longer in males (43.3 v 15.3 months in females; P < .001), in whom underwent nephrectomy (32.3 v 20.7 months; P = .002), and in patients without hepatic (32.3 v 15.3 months; P < .001), without skeletal (41.0 v 20.0 months; P = .007), or without lymph node metastases (43.3 v 24.6 months; P = .037). Median OS varied by International Metastatic RCC Database Consortium (IMDC) risk group: 66.5, 29.4, and 11.7 months in favorable-, intermediate-, and poor-risk patients, respectively (P < .001). Different IO regimens showed variable outcomes by risk subgroup. Limitations include retrospective design and lack of central pathology review. Conclusion: First-line IO-based combinations provide clinically meaningful survival in sRCC, with outcomes affected by sex, metastatic sites, and IMDC risk. This RWE may support a tailored therapeutic approach on the basis of baseline prognostic factors.