International multicenter experience of prognostic factors and treatment outcomes of metastatic non-clear cell renal cell carcinoma

BACKGROUND: Non-clear cell renal cell carcinoma (nccRCC) represents a heterogeneous group of rare malignancies with limited evidence guiding systemic therapy. The recent introduction of immune checkpoint inhibitors (ICIs) and their combinations with tyrosine kinase inhibitors (TKIs) has shown promising results, but real-world data remain scarce. METHODS: We retrospectively collected clinical and pathological data from patients with metastatic nccRCC included in the Italian Meet-URO-23/I-RARE database and from Vall d'Hebron Institute of Oncology (VHIO). Prognostic factors for overall survival (OS) were analyzed using univariate and multivariate Cox regression. Treatment outcomes were assessed by histology and therapeutic regimen. RESULTS: A total of 156 patients were included: papillary (56.4%), chromophobe (22.4%), translocated (10.9%), and unclassified (10.3%) RCC. Median OS was 17.5 months (95%CI 14.7-27.6) and median progression free survival (PFS) 10.2 months (95%CI 7.6-13.7). Patients treated with ICI-combinations (ICI plus ICI or ICI plus VEGF-TKI) showed significantly improved survival (median OS not reached vs 14.7 months for other regimens, p = 0.0053). The overall objective response rate (ORR) and disease free survival (DFS) for ICI+TKI was 53.3% (16/30 evaluable) and 93.3% (28/30), with ORR of 55.5% (10/18) in papillary and 46.1% (6/13) in chromophobe subtypes. In the overall ICI-combination group, ORR was 48%. In multivariate analysis, International Metastatic RCC Database Consortium (IMDC) score, presence of bone metastases, and type of first-line therapy were independently associated with OS. CONCLUSIONS: In this large international real-world cohort, ICI-based combinations demonstrated superior outcomes compared to other regimens in metastatic nccRCC. These results reinforce the role of immunotherapy combinations as a preferred first-line approach and confirm the IMDC score as a reliable prognostic tool in this population.