Professor, Dept of Medical Oncology & Therapeutic Research City of Hope Comprehensive Cancer Center, Duarte, CA, USA Duarte, CA, United States
Background: nccRCCs are a group of rare, heterogenous tumors of biologically unique histologic subtypes with distinct responses to treatment. There have been few dedicated randomized controlled studies in nccRCC and treatment decisions are often based on extrapolation of ccRCC data. Sunitinib has shown clinical benefit vs everolimus in a broad range of nccRCC subtypes (Armstrong et al. Lancet Oncol. 2016), and no other treatments in nccRCC have shown an OS benefit over sunitinib. Zanzalintinib, a novel multi-targeted TKI of VEGFR, MET, and the TAM kinases, has demonstrated antitumor and immunomodulatory activity alone and in combination with PD-1 inhibition in preclinical studies (Hsu et al. Mol Cancer Ther. 2023). Furthermore, zanzalintinib has shown encouraging preliminary clinical activity and manageable toxicity, alone and with an immune checkpoint inhibitor in RCC (Sharma et al. ESMO 2022:Abs 481P).
Methods: STELLAR-304 is a global, randomized, open-label study evaluating the efficacy and safety of zanzalintinib + nivolumab versus sunitinib in first-line nccRCC (NCT05678673). Eligible patients are adults with unresectable/advanced/metastatic nccRCC with measurable disease per RECIST v1.1. The trial includes papillary, unclassified, and translocation-associated histology (sarcomatoid features are allowed). Chromophobe, renal medullary carcinoma, or pure collecting duct histology are excluded. Prior systemic anticancer therapy for advanced/ metastatic nccRCC is not permitted except adjuvant therapy in patients with completely resected RCC if recurrence ≥6 months after last dose. Approximately 291 patients will be randomized 2:1 to zanzalintinib + nivolumab or sunitinib. The primary endpoints are PFS and ORR per RECIST v1.1 by blinded independent review. The secondary endpoint is OS; safety will also be assessed. Enrollment is ongoing; patients will be recruited at sites in Europe, North and South America, and the Asia-Pacific region.
