Exelixis has announced encouraging results from the phase 1b/2 STELLAR-002 trial evaluating zanzalintinib in combination with immune checkpoint inhibitors for patients with previously untreated advanced clear cell renal cell carcinoma (RCC). The data will be presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.
The expansion cohort of STELLAR-002 included patients with advanced clear cell RCC who received zanzalintinib in combination with either nivolumab (n=40) or a fixed-dose combination of nivolumab and relatlimab (n=40) in two non-randomized treatment arms. Notably, 75% of patients in the nivolumab arm and 70% in the nivolumab/relatlimab arm had intermediate- or poor-risk disease according to the International Metastatic RCC Database Consortium criteria.
Impressive Efficacy Results
At a median follow-up of 20.1 months for the zanzalintinib plus nivolumab arm, the objective response rate was 63% (95% confidence interval [CI]: 46-77%), with a disease control rate of 90% (95% CI: 76-97%). The 12-month duration of response was 73.4% (95% CI: 50.0-87.1%), and median progression-free survival reached 18.5 months (95% CI: 9.5 months-not estimable).
For patients receiving zanzalintinib with fixed-dose nivolumab and relatlimab, at a median follow-up of 15.9 months, the objective response rate was 40% (95% CI: 25-57%), with a disease control rate of 90% (95% CI: 76-97%). The 12-month duration of response was 74.1% (95% CI: 39.1-90.9%), and median progression-free survival was 13.0 months (95% CI: 7.4 months-not estimable).
"The high rate of durable responses and long progression-free survival observed for zanzalintinib in combination with nivolumab are encouraging and support further evaluation of this regimen," said Dr. Jad Chahoud, Associate Member, Department of Genitourinary Oncology and Medical Director of the Inpatient/Outpatient service at Moffitt Cancer Center in Tampa, Florida, who is presenting the findings.
Safety Profile
Treatment-emergent adverse events (TEAEs) of any grade were reported in all patients. In the zanzalintinib plus nivolumab arm, the most common grade 3/4 TEAEs occurring in at least four patients included hypertension (n=13), diarrhea (n=6), aspartate aminotransferase increase (n=5), alanine aminotransferase increase (n=5), and palmar-plantar erythrodysesthesia (n=4).
For the zanzalintinib plus nivolumab/relatlimab arm, grade 3/4 TEAEs occurring in at least four patients included hypertension (n=6), rash (n=6), lipase increase (n=4), and pulmonary embolism (n=4).
There were two grade 5 TEAEs in each arm, though none were considered related to study treatment. Treatment discontinuation rates due to treatment-related adverse events were 8% in the nivolumab arm and 20% in the nivolumab/relatlimab arm.
Additional Dose-Finding Cohort Results
The ASCO presentation will also include data from multiple dose-escalation cohorts from STELLAR-002, which evaluated zanzalintinib in combination with checkpoint inhibitors across various advanced solid tumors.
This analysis included patients who received zanzalintinib 100 mg with nivolumab (n=19); zanzalintinib 60 mg with fixed-dose nivolumab and relatlimab (n=24); or zanzalintinib 100 mg with fixed-dose nivolumab and relatlimab (n=25). The most common cancer types varied by cohort but included colorectal, prostate, lung, and renal cell cancers, as well as melanoma.
The findings showed that the toxicity profile of these combinations was manageable and consistent with each monotherapy agent. Based on preliminary safety, efficacy, and pharmacokinetic results, the 100 mg dose of zanzalintinib was selected for the ongoing expansion cohorts.
About Zanzalintinib and RCC
Zanzalintinib is a third-generation oral tyrosine kinase inhibitor that inhibits receptor tyrosine kinases implicated in cancer growth and spread, including VEGF receptors, MET, AXL, and MER. Exelixis developed zanzalintinib to build upon its experience with cabozantinib while improving key characteristics such as pharmacokinetic half-life.
Kidney cancer represents a significant health burden, with nearly 81,000 Americans expected to be diagnosed in 2025. Clear cell RCC is the most common type, accounting for approximately 75% of cases. For patients with advanced or late-stage metastatic RCC, the five-year survival rate is only 18%, highlighting the need for more effective treatment options.
"We are pleased to present these preliminary findings from the phase 1b/2 STELLAR-002 study, including early signs of promising activity for zanzalintinib in combination with immune checkpoint inhibitors," said Dr. Amy Peterson, Executive Vice President, Product Development & Medical Affairs, and Chief Medical Officer at Exelixis. "Data emerging from this ongoing study are important to help inform further evaluation of zanzalintinib-based regimens in advanced solid tumors, including renal cell carcinoma."
The STELLAR-002 trial (NCT05176483) is a global, open-label phase 1b/2 study evaluating zanzalintinib alone and in various immunotherapy combinations across multiple tumor types. Exelixis is sponsoring the trial, with Bristol Myers Squibb providing nivolumab, ipilimumab, and the fixed-dose combination of nivolumab and relatlimab.
