Outcomes of Patients with Metastatic Non–clear Cell Renal Cell Carcinoma Receiving Contemporary or Traditional First-line Therapies: Results from the International Metastatic Renal Cell Carcinoma Database Consortium

BACKGROUND AND OBJECTIVE: Real-world evidence on the effectiveness of first-line immuno-oncology (IO)-based combinations or cabozantinib (CABO) over traditional targeted therapies in metastatic non-clear cell renal cell carcinoma (nccRCC) is limited. This study aims to compare the outcomes of first-line therapies for metastatic nccRCC according to histologic subtypes, including papillary renal cell carcinoma (RCC), unclassified RCC, and chromophobe RCC with or without sarcomatoid dedifferentiation. METHODS: Using the International Metastatic Renal Cell Carcinoma Database Consortium, patients with metastatic nccRCC who received (1) IO plus vascular endothelial growth factor (IOVE) combination therapy, (2) IOIO doublet therapy, (3) CABO monotherapy, (4) sunitinib or pazopanib (SUN/PAZ) monotherapy, or (5) mammalian target of rapamycin (mTOR) monotherapy were included. Baseline patient characteristics, clinician assessment of objective response rates (ORRs), and overall survival (OS) were compared across first-line therapy regimens. KEY FINDINGS AND LIMITATIONS: The most common nccRCC histology was papillary found in 725 (47%), and sarcomatoid dedifferentiation was found in 236 (15%) of the 1551 patients included. Within the papillary RCC cohort, ORRs and median OS were, respectively, 31% and 33.2 mo for IOVE, 26% and 31.9 mo for IOIO, and 37% and 30.7 mo for CABO, as compared with 13% and 17.2 mo for SUN/PAZ and 3.4% and 13.1 mo for mTOR. Within the sarcomatoid dedifferentiation cohort, receipt of IOIO was associated with the highest ORR and the longest median OS (39% and 31.9 mo, respectively). CONCLUSIONS AND CLINICAL IMPLICATIONS: Distinct patient outcomes were observed across histologic subtypes. More histology-specific strategies are required given the differential activity of first-line therapy regimens against each nccRCC histology.