Zanzalintinib Combined with Checkpoint Inhibitors Shows Robust Clinical Response in Advanced Kidney Cancer: New STELLAR-002 Data at ASCO 2025

At the 2025 American Society of Clinical Oncology Annual Meeting, researchers will present compelling interim findings from the STELLAR-002 trial, demonstrating that zanzalintinib paired with immune checkpoint inhibitors delivers meaningful therapeutic benefit for patients with advanced clear cell renal cell carcinoma (RCC) who have not received prior systemic treatment.

Striking Clinical Efficacy Observed in Combination Strategy

The expansion cohort of STELLAR-002 evaluated two treatment arms in treatment-naive patients with unresectable or metastatic RCC. Among 40 patients receiving zanzalintinib with nivolumab, the objective response rate reached 63% (95% CI: 46-77%), while disease control was achieved in 90% of participants across both treatment strategies. The alternative arm combining zanzalintinib with a fixed-dose nivolumab-relatlimab formulation showed an objective response rate of 40% (95% CI: 25-57%), with matching 90% disease control rates.

Durability of response emerged as a notable finding, with 73.4% of patients in the zanzalintinib-nivolumab combination maintaining their therapeutic response at the 12-month mark. Median progression-free survival extended to 18.5 months for the nivolumab arm and 13.0 months for the triple-agent combination, based on median follow-up periods of 20.1 and 15.9 months respectively.

Safety Profile Aligns with Expected Toxicity Pattern

Treatment-related adverse events occurred universally among study participants. Hypertension emerged as the most frequently reported grade 3 or 4 adverse event in the zanzalintinib-nivolumab cohort, affecting 13 patients, followed by diarrhea in 6 patients. The zanzalintinib with fixed-dose nivolumab-relatlimab arm reported hypertension and rash as the predominant grade 3/4 events, each occurring in 6 patients. Two grade 5 adverse events were documented in each arm, with none attributed to study medication. Treatment discontinuation due to adverse events occurred in 8% of the nivolumab-combination group and 20% of the triple-therapy group.

Dose Optimization from Phase 1b Escalation Data

Supporting data from dose-escalation cohorts analyzed 68 patients with various advanced solid tumors receiving different zanzalintinib doses. These patients represented diverse cancer histologies, including colorectal, prostate, and lung malignancies in addition to RCC. The toxicity profile proved manageable and consistent with the known safety characteristics of each individual agent. Pharmacokinetic and preliminary efficacy assessments supported selection of the 100 mg zanzalintinib dose for ongoing expansion cohorts.

Addressing an Unmet Clinical Need

Approximately 33,700 patients with advanced kidney cancer will require systemic therapy in the United States during 2025, with over 21,400 candidates for first-line interventions. While recent therapeutic advances have improved outcomes, disease progression remains common in intermediate- and poor-risk disease populations, where 75% of this trial cohort was classified. The five-year survival for metastatic RCC remains substantially lower than early-stage disease, highlighting the clinical imperative for more effective early-line options.

Zanzalintinib represents a third-generation oral tyrosine kinase inhibitor targeting VEGF receptors, MET, AXL and MER—mechanisms implicated in angiogenesis, metastatic progression and resistance to immunotherapy. The compound builds upon Exelixis’ established expertise with cabozantinib while offering pharmacokinetic refinements. Beyond RCC, ongoing STELLAR-002 investigations are evaluating zanzalintinib combinations across neuroendocrine tumors, castration-resistant prostate cancer, urothelial carcinoma, hepatocellular carcinoma, non-small cell lung cancer, colorectal cancer and head and neck squamous cell carcinoma.