Dr Drakaki on the Investigation of Zanzalintinib in Advanced Non–Clear Cell RCC

Alexandra Drakaki, MD, PhD, associate professor, Division of Hematology-Oncology, David Geffen School of Medicine, University of California, Los Angeles, discusses the potential role of zanzalintinib (XL092) for patients with non–clear cell renal cell carcinoma (RCC).

Zanzalintinib is a novel TKI targeting the VEGFR, MET, and TAM kinases. Drakaki notes that zanzalintinib is currently being investigated as a first-line treatment option for patients with non-clear cell RCC in the phase 3 STELLAR-304 study (NCT05678673), where patients are being randomly assigned 2:1 to receive treatment with zanzalintinib plus nivolumab (Opdivo) or sunitinib (Sutent) alone.

The dual primary end points of the STELLAR-304 trial are progression-free survival (PFS) and objective response rate (ORR) per RECIST 1.1 criteria, assessed by blinded independent central review. Secondary end points include overall survival (OS) and safety. The trial currently recruiting patients across Europe, North and South America, and the Asia-Pacific region.

Drakaki explains that this trial marks the first large-scale, phase 3 randomized study to evaluate a novel TKI combined with immunotherapy in patients with advanced non–clear cell RCC. Unlike clear cell RCC, where an array of immuno-oncology–based combination regimens are the standard of care in the frontline setting, patients with advanced non–clear cell RCC lack similarly robust treatment options due to the distinct molecular and clinical characteristics of this subtype of RCC.

The multi-targeted approach of zanzalintinib aims to disrupt several critical pathways involved in tumor growth and metastasis, including angiogenesis through VEGFR inhibition, MET-driven tumor progression, and TAM kinases' role in the tumor microenvironment.

Drakaki underscores the potential of zanzalintinib to expand treatment options for patients with non–clear cell RCC by targeting the complex biology of non–clear cell subtypes. This phase 3 trial could establish a new standard for combining multi-targeted TKIs with immunotherapy, aiming to improve patient outcomes in this difficult-to-treat setting, she concludes.