The phase III STELLAR-303 trial evaluated the anti-VEGFR–related multitargeted tyrosine kinase inhibitor zanzalintinib in combination with the PD-L1 inhibitor atezolizumab vs the multikinase inhibitor regorafenib in patients with previously treated non–microsatellite instability (MSI)–high metastatic colorectal cancer. These study results were presented by lead trial investigator Anwaar Saeed, MD, at the European Society for Medical Oncology (ESMO) Congress 2025 and were simultaneously published in The Lancet.1,2 Dr. Saeed is Section Chief of Gastrointestinal Oncology at the University of Pittsburgh and Director of the Gastrointestinal Disease Center at UPMC Hillman Cancer Center.
Anwaar Saeed, MD
In a statement issued earlier this year,3 zanzalintinib demonstrated a 20% reduction in the risk of death, one of two study endpoints, with the combination in the intention-to-treat population at the final analysis (stratified hazard ratio [HR] = 0.80; 95% confidence interval [CI] = 0.69–0.93; P = .0045). At a median follow-up of 18 months, median overall survival in the intention-to-treat population was 11 months with zanzalintinib plus atezolizumab vs 9 months with regorafenib. Detailed findings presented during the ESMO Congress included survival outcomes in the intention-to-treat population and in the subset of patients without liver metastases.
About STELLAR-303
STELLAR-303 randomly assigned patients 1:1 to either zanzalintinib in combination with atezolizumab (n = 451) or regorafenib (n = 450). The study includes patients with previously treated non–MSI-high metastatic colorectal cancer. The dual primary endpoints of the study are overall survival in the intention-to-treat population and in the subgroup of patients with no active liver metastases. The intention-to-treat population consisted of all randomly assigned patients, regardless of the presence of liver metastases. Secondary endpoints include progression-free survival, objective response rate, and duration of response in the intention-to-treat population and in the subgroup of patients without active liver metastases.
“While treating non–MSI-high metastatic colorectal cancer remains a challenge, the combination of zanzalintinib and atezolizumab has shown consistent benefits across key subgroups of patients,” said Dr. Saeed in a press release.
Survival Outcomes and Safety
An overall survival benefit with the combination was consistently observed across prespecified subgroups, including geographic region, RAS status, liver involvement, and prior anti-VEGF therapy. The 12- and 24-month landmark overall survival estimates were 46% (95% CI = 41%–51%) and 20% (95% CI = 15%–26%), respectively, for the combination of zanzalintinib and atezolizumab and 38% (95% CI = 34%–43%) and 10% (95% CI = 6%–16%), respectively, for regorafenib. Overall survival data in patients without liver metastases were immature at the data cutoff. A prespecified interim analysis showed a trend in overall survival favoring the combination (15.9 months vs 12.8 months; stratified hazard ratio = 0.79; 95% CI = 0.61%–1.0%; P = .0875) at a median follow-up of 16.8 months. The trial will proceed to the planned final analysis for this endpoint.
The safety profiles of zanzalintinib in combination with atezolizumab and of regorafenib were reported to be generally consistent with what has been previously observed, and no new safety signals were identified, according to the investigators. Grade 3 or 4 treatment-related adverse events occurred in 59% of patients receiving zanzalintinib in combination with atezolizumab and 37% of patients receiving regorafenib. Adverse events leading to discontinuation of all study treatment occurred in 18% vs 15% of patients, respectively. The most common grade 3 or 4 treatment-related adverse events were hypertension (15% vs 9%, respectively), fatigue (6% vs 2%), diarrhea (6% vs 2%), and proteinuria (6% vs 2%). Deaths considered related to treatment by investigators were five for the combination, and one for regorafenib.
“STELLAR-303 is the first immunotherapy-based phase III trial that demonstrated improved overall survival with a differentiated kinase inhibitor compared to a standard of care in this patient population,” Dr. Saeed concluded. “The survival benefit was demonstrated early and was consistent throughout the trial, underscoring the combination’s potential for patients in need of a new and effective treatment option after disease progression.”
DISCLOSURE: Dr. Saeed has received institutional research funding from AstraZeneca, Bristol Myers Squibb, Merck, Exelixis, Actuate Therapeutics, Incyte, Amgen, Oxford BioTherapeutics, Replimune, Phanes Therapeutics, Arcus Biosciences, Regeneron, and Kahr Bio; and has served as an advisor to AstraZeneca, Bristol Myers Squibb, Merck, Exelixis, Pfizer, Xilio Therapeutics, Taiho Pharmaceutical, Amgen, Arcus Therapeutics, Autem Therapeutics, Kahr Bio, Arcus Therapeutics, Regeneron, and Replimune. For full disclosures of all study authors, visit cslide.ctimeetingtech.com.
REFERENCES
1. Saeed A, Park YS, Tabernero J, et al: Zanzalintinib plus atezolizumab vs regorafenib in patients with previously treated metastatic colorectal cancer: Primary overall survival analysis from the randomized, open-label, phase III STELLAR-303 study. ESMO Congress 2025. Abstract LBA30. Presented October 20, 2025.
2. Hecht JR, Park YS, Tabernero J, et al: Zanzalintinib plus atezolizumab versus regorafenib in refractory colorectal cancer (STELLAR-303): A randomised, open-label, phase 3 trial. Lancet. October 20, 2025 (early release online).
3. Exelixis announces zanzalintinib in combination with an immune checkpoint inhibitor improved overall survival in STELLAR-303 phase 3 pivotal trial in patients with metastatic colorectal cancer. June 22, 2015. Available at https://ir.exelixis.com/news-releases/news-release-details/exelixis-announces-zanzalintinib-combination-immune-checkpoint. Accessed October 27, 2025.
