Zanzalintinib Plus Atezolizumab Significantly Improves OS in Relapsed or Refractory Metastatic Colorectal Cancer

Key Clinical Takeaways:

• Design/Population: STELLAR-303 is a global, randomized, open-label phase 3 trial that enrolled patients with relapsed or refractory metastatic colorectal cancer who had received prior standard-of-care therapy and did not have microsatellite instability–high or mismatch repair–deficient tumors. 
• Key Outcomes: Treatment with zanzalintinib plus atezolizumab significantly improved overall survival compared with regorafenib in the intention-to-treat population. The combination was associated with a higher incidence of grade 3 or higher treatment-related adverse events than regorafenib.
• Clinical Relevance: These findings establish zanzalintinib plus atezolizumab as an immunotherapy-based, chemotherapy-free option that improves survival in heavily pretreated patients with microsatellite-stable metastatic colorectal cancer, a population with limited effective treatment options.

Results from the STELLAR-303 trial demonstrated that zanzalintinib, a multitargeted tyrosine-kinase inhibitor, plus atezolizumab significantly improved overall survival (OS) compared with regorafenib among patients with relapsed or refractory metastatic colorectal cancer (mCRC) without microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) tumors. 

In this open-label study, 901 patients who received standard-of-care therapy were randomized 1:1 to receive either 100 mg of once daily zanzalintinib plus 1200 mg of atezolizumab once every 3 weeks (n = 451) or 160 mg of regorafenib on days 1 through 21 of each 28-day cycle (n = 450). Patients were stratified based on location, RAS status, and presence of liver metastases. The primary end point was overall survival (OS). A key secondary end point was safety. 

At a median follow-up of 18 months, median OS was 10.9 months in the zanzalintinib plus atezolizumab arm and 9.4 months in the regorafenib arm (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.69 to 0.93; P = .0045). Median OS in patients without liver metastases was 15.9 months in the zanzalintinib plus atezolizumab arm and 12.7 months in the regorafenib arm (HR, 0.79; 95% CI, 0.61 to 1.03; P = .087).

Grade ≥ 3 treatment-related adverse events were reported in 60% of patients in the zanzalintinib plus atezolizumab arm and 37% of patients in the regorafenib arm. Five treatment-related deaths were reported in the zanzalintinib plus atezolizumab arm and 1 was reported in the regorafenib arm.

“STELLAR-303 is the first phase 3 trial to show a significant improvement in overall survival with an immunotherapy-based regimen, zanzalintinib [plus] atezolizumab, in patients with relapsed or refractory [mCRC] that is not MSI-H or dMMR,” concluded Dr Hecht et al. “This combination represents a chemotherapy-free treatment option with a novel mechanism of action for heavily pretreated patients in need of improved therapies.”

Source: 

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. The Lancet. Published online: October 19, 2025. doi:10.1016/S0140-6736(25)02025-2