Zanzalintinib (VEGFR/MET) + Nivolumab Yields 63% ORR in Front-Line ccRCC; Triplet With Relatlimab Lags

Zanzalintinib (zanza; XL092) is an oral multi-kinase TKI targeting VEGFR, MET, and TAM receptors; in the Phase 1b STELLAR-002 expansion (NCT05176483), 40 untreated metastatic Clear Cell Renal Carcinoma (ccRCC) patients received zanza 100 mg daily plus nivolumab 480 mg every 4 weeks, while another 40 added the LAG-3 blocker relatlimab. After 16.1 mo and 11.9 mo follow-up, investigator-assessed ORR hit 63% (4 CRs, 21 PRs) with the zanza + nivolumab doublet versus 33% with the zanza + nivolumab + relatlimab triplet, albeit identical 90% disease control. Six- and 12-month PFS rates were 83% and 64% for the doublet and 80% and 59% for the triplet; median PFS is not yet mature. Grade 3–4 AEs were mainly hypertension (30% vs 13%) and diarrhea (15% vs <5%), prompting discontinuation in 5% and 18%; ≥G3 palmar-plantar erythrodysesthesia (PPE), also known as hand-foot syndrome, stayed under 8%. Efficacy fits between cabozantinib + nivolumab (55% ORR) and lenvatinib + pembrolizumab (71% ORR), with a numerically lower PPE burden than most VEGFR TKIs.