Exelixis Reports Positive Final STELLAR-303 Survival Data in Metastatic Colorectal Cancer

Exelixis has reported the final analysis of the non-liver metastases (NLM) subgroup from the Phase 3 STELLAR-303 trial (NCT05425940) evaluating zanzalintinib in combination with atezolizumab versus regorafenib in previously treated non-microsatellite instability-high (non-MSI-high) metastatic colorectal cancer (mCRC). The study showed a numerical improvement in overall survival (OS) for patients without active liver metastases, with a median OS of 15.9 months for the combination therapy compared with 12.7 months for regorafenib. However, the difference did not achieve statistical significance (hazard ratio [HR] 0.83; 95% CI, 0.66–1.05; P=0.1185).

Zanzalintinib Targets Multiple Cancer Growth Pathways

Zanzalintinib is an investigational oral kinase inhibitor that blocks several key signaling pathways involved in tumor growth and immune evasion, including VEGF receptors, MET, and the TAM family kinases TYRO3, AXL, and MER. These pathways contribute to tumor proliferation, metastasis, angiogenesis, treatment resistance, and suppression of anti-tumor immune responses.

Metastatic colorectal cancer remains a major treatment challenge. Despite advances in targeted therapies and immunotherapy, outcomes remain poor for many patients after progression on standard chemotherapy. Liver metastases are particularly common in colorectal cancer and are associated with worse survival outcomes.

Final STELLAR-303 Results

STELLAR-303 (NCT05425940) is a global, multicenter, randomized, open-label Phase 3 trial that enrolled 901 patients with previously treated non-MSI-high mCRC. Participants were randomized 1:1 to receive either zanzalintinib plus atezolizumab (n=451) or regorafenib (n=450).

The trial incorporated two dual primary endpoints: overall survival in the intention-to-treat (ITT) population and overall survival in patients without active liver metastases at baseline.

In the final NLM analysis, the combination demonstrated a favorable survival trend but did not meet the predefined threshold for statistical significance. Importantly, the safety profile remained consistent with earlier findings from the overall study population, and investigators reported no new safety signals.

Secondary endpoints included progression-free survival, objective response rate, and duration of response across both the ITT and NLM populations.

Earlier Positive Results Support Regulatory Filing

The NLM findings follow previously reported results showing that STELLAR-303 met its co-primary endpoint in the ITT population. Those data demonstrated a statistically significant improvement in overall survival regardless of liver metastasis status and were presented at the 2025 European Society for Medical Oncology Congress and subsequently published in The Lancet.

The overall survival benefit observed across the broader study population formed the basis of Exelixis’ regulatory submission seeking approval of the combination in previously treated metastatic colorectal cancer.

FDA Decision Expected in December 2026

In February 2026, the U.S. Food and Drug Administration accepted the New Drug Application for zanzalintinib in combination with atezolizumab for patients with metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and anti-EGFR therapy when appropriate for RAS wild-type disease.

The FDA assigned a Prescription Drug User Fee Act (PDUFA) target action date of December 3, 2026. Exelixis plans to submit the detailed NLM subgroup findings for presentation at a future medical meeting while continuing to advance the broader zanzalintinib development program across colorectal cancer, renal cell carcinoma, neuroendocrine tumors, and several other solid tumors.

 Reference

Exelixis Provides Update on the Phase 3 STELLAR-303 Trial Evaluating Zanzalintinib in Combination with an Immune Checkpoint Inhibitor in Patients with Metastatic Colorectal Cancer | Exelixis, Inc.