1912TiP - STELLAR-304: A randomized phase III study of zanzalintinib (XL092) and nivolumab in non-clear cell renal cell carcinoma (nccRCC)

Background

nccRCCs are a heterogenous group of rare histologic subtypes, each with distinct biology and response to treatment. There have been few dedicated randomized phase 3 studies in nccRCC, highlighting an urgent unmet need for effective therapies. Sunitinib is the only TKI to have shown a clinical benefit (vs everolimus) in a broad range of histologic subtypes of metastatic nccRCC (Armstrong et al. Lancet Oncol 2016 ). To date, no single agent or combination has shown a significant overall survival (OS) benefit over sunitinib in any nccRCC subtype. Zanzalintinib (XL092), a novel TKI of VEGFR2, MET, AXL, and MER, has shown antitumor and immunomodulatory activity alone, and synergistic antitumor effect with PD1 inhibition, in animal models (Hsu et al. Mol Cancer Ther 2023 ). In a phase 1 study of metastatic solid tumors including RCC, zanzalintinib showed promising clinical activity and a manageable toxicity profile, alone and with an immune checkpoint inhibitor (ICI) (Sharma et al. ESMO 2022 Abs 481P). STELLAR-304 was designed to assess the efficacy and safety of zanzalintinib + nivolumab versus sunitinib in first-line nccRCC (NCT05678673).

Trial design

STELLAR-304 is a global, randomized, open-label study of adults with unresectable/advanced/metastatic nccRCC that is measurable per RECIST v1.1. The trial includes papillary, unclassified, and translocation-associated histologies (sarcomatoid features are allowed); chromophobe, renal medullary carcinoma, or pure collecting duct histology are excluded. Histologies are confirmed by central pathology review. Prior systemic anticancer therapy for advanced or metastatic nccRCC is not permitted; however, 1 prior systemic adjuvant therapy, including ICI and excluding sunitinib, is allowed for completely resected RCC if recurrence occurred ≥6 months after the last adjuvant therapy dose. Patients (N=291) are randomized 2:1 to zanzalintinib + nivolumab or sunitinib alone. The primary endpoints are PFS and ORR per RECIST v1.1 by blinded independent radiology committee. The secondary endpoint is OS; safety will also be assessed. STELLAR-304 is currently recruiting patients in 29 countries in Europe, North and South America, and the Asia-Pacific region.

Clinical trial identification

NCT05678673.

Editorial acknowledgement

Writing and editorial assistance was provided by Alexus Rivas-John, PharmD (Fishawack Communications Inc., part of Fishawack Health, Conshohocken, PA, USA).

Legal entity responsible for the study

Exelixis, Inc.

Funding

Exelixis, Inc.

Disclosure

S.K. Pal: Financial Interests, Personal, Other, Travel Accommodations/Expenses: Ipsen, CRISPR Therapeutics. T.B. Powles: Financial Interests, Institutional, Research Funding: AstraZeneca, Roche, BMS, Exelixis, Ipsen, MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai; Financial Interests, Personal, Advisory Role: AstraZeneca, BMS, Exelixis, Incyte, Ipsen, MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai, Roche, Mash Up Ltd; Financial Interests, Personal, Other, Travel Accommodations/Expenses: Roche, Pfizer, MSD, AstraZeneca, Ipsen. R. Kanesvaran: Financial Interests, Personal, Advisory Role: MSD, BMS, Eisai, Astellas, J&J, Pfizer, AstraZeneca, Merck; Financial Interests, Personal, Other, Honoraria; Travel Accommodations/Expenses: MSD, Astellas, AZ; Financial Interests, Personal, Other, Honoraria: BMS, Eisai, J&J, Pfizer, Merck. C. Lee: Financial Interests, Institutional, Research Funding: AstraZeneca, BMS, Calithera, Eisai, Exelixis, Merck; Financial Interests, Personal, Advisory Role: Aveo, BMS, Exelixis, Eisai, Merck, Pfizer, EMD Serono, Cardinal Health; Financial Interests, Personal, Other, Honoraria: AiCME, IDEOlogy Health, Intellisphere, Medscape, Research to Practice. Z. Wang: Financial Interests, Personal, Full or part-time Employment: Exelixis, Inc.; Financial Interests, Personal, Stocks/Shares: Exelixis, Inc.. P. Patel: Financial Interests, Personal, Full or part-time Employment: Exelixis, Inc.. C. Suarez Rodriguez: Financial Interests, Personal, Advisory Role: Astellas Pharma, Bayer, Hoffmann-La Roche LTD, Ipsen, Merck Sharp and Dohme, Pfizer S.L.U, Sanofi- Aventis; Financial Interests, Institutional, Advisory Role: BMS. All other authors have declared no conflicts of interest.