Zanzalintinib Plus Atezolizumab Improves Overall Survival in Previously Treated Microsatellite-Stable Metastatic Colorectal Cancer
Clinical Summary:
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Design/Population: The open-label, phase 3 STELLAR-303 trial compared zanzalintinib plus atezolizumab with regorafenib in patients with previously treated metastatic colorectal cancer (mCRC) without microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) tumors.
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Key Outcomes: Zanzalintinib plus atezolizumab significantly improved overall survival compared with regorafenib. The combination was associated with a higher incidence of grade ≥3 treatment-related adverse events, although the safety profile was consistent with the known toxicities of the individual agents.
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Clinical Relevance: These findings support zanzalintinib plus atezolizumab as the first immunotherapy-based regimen to demonstrate an overall survival benefit in a phase 3 trial of previously treated microsatellite-stable mCRC, providing a new chemotherapy-free treatment option for this difficult-to-treat population.
Results from the phase 3 STELLAR-303 trial demonstrated that zanzalintinib plus atezolizumab significantly improved overall survival (OS) compared with regorafenib in patients with previously treated metastatic colorectal cancer (mCRC) without microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) tumors.
In this open-label trial, 901 patients who had previously received standard-of-care therapy were randomized 1:1 to receive 100 mg of once daily zanzalintinib plus 1200 mg of atezolizumab once every 3 weeks (n = 451) or 160 mg of regorafenib once daily on days 1 through 21 of each 28-day cycle (n = 450). Randomization was stratified by geographic region, RAS mutation status, and liver metastases. The primary end point was OS. Safety was a key secondary end point.
After a median follow-up of 18 months, median OS was 10.9 months in the zanzalintinib plus atezolizumab arm compared with 9.4 months in the regorafenib arm (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.69 to 0.93; P = .0045). Among patients without liver metastases, median OS was 15.9 months with zanzalintinib plus atezolizumab and 12.7 months with regorafenib. however, this subgroup analysis was not statistically significant.
Grade ≥3 treatment-related adverse events occurred in 60% of patients receiving zanzalintinib plus atezolizumab compared with 37% of those receiving regorafenib. Five treatment-related deaths occurred in the combination arm and one occurred in the regorafenib arm.
“STELLAR-303 is the first phase 3 trial to show a significant improvement in [OS] 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
