Article Impact Level: HIGH Data Quality: STRONG Summary of The Lancet https://doi.org/10.1016/S0140-6736(25)02025-2 Dr. Young Suk Park et al.
Points
- STELLAR-303 compared zanzalintinib–atezolizumab versus regorafenib in refractory metastatic colorectal cancer patients.
- Patients with non-MSI-H/dMMR mCRC, previously treated, were randomized to combination therapy or regorafenib.
- Zanzalintinib–atezolizumab significantly improved overall survival in the ITT population, HR 0.80 (95% CI 0.69–0.93; p=0.0045).
- Median overall survival was 10.9 months for the combination versus 9.4 months for regorafenib in the ITT population.
- This trial marks the first phase 3 to show OS benefit with an immunotherapy-based regimen in this specific mCRC population.
Summary
The STELLAR-303 trial, a global, randomized, open-label, phase 3 study, evaluated the efficacy and safety of zanzalintinib plus atezolizumab compared to regorafenib in patients with previously treated metastatic colorectal cancer (mCRC) without microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors. Zanzalintinib, a multitargeted tyrosine-kinase inhibitor, combined with atezolizumab, previously demonstrated promising antitumor activity and manageable toxicity in a phase 1 study. A total of 901 eligible patients (59% male, 41% female; 54% White, 38% Asian, 2% Black) were randomized 1:1 to receive oral zanzalintinib (100 mg daily) plus intravenous atezolizumab (1200 mg every 3 weeks) or oral regorafenib (160 mg daily for 21 days of each 28-day cycle). Stratification factors included geographical region, RAS status, and presence of liver metastases. Dual primary endpoints were overall survival (OS) in the intention-to-treat (ITT) population and in the subset of patients without liver metastases.
At a median follow-up of 18.0 months (IQR 14.6–21.5), zanzalintinib–atezolizumab demonstrated a significant OS benefit over regorafenib in the ITT population (stratified hazard ratio [HR] 0.80 [95% CI 0.69–0.93]; p=0.0045). The median OS for the combination was 10.9 months (95% CI 9.9–12.1) compared to 9.4 months (8.5–10.2) for regorafenib. In the interim analysis for patients without liver metastases, the stratified HR was 0.79 (95% CI 0.61–1.03; p=0.087), with median OS of 15.9 months (95% CI 13.5–17.6) versus 12.7 months (10.9–15.5), though this did not reach statistical significance.
Regarding safety, grade 3 or worse treatment-related adverse events occurred in 268 (60%) of 446 patients in the zanzalintinib–atezolizumab group and 161 (37%) of 434 patients in the regorafenib group. There were five (1%) treatment-related deaths with the combination therapy and one (<1%) with regorafenib. STELLAR-303 is significant as the first phase 3 trial to show a statistically significant improvement in OS with an immunotherapy-based regimen in relapsed or refractory mCRC that is not MSI-H or dMMR, offering a novel, chemotherapy-free treatment option for heavily pretreated patients.
Link to the article: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)02025-2/abstract
References
Hecht, J. R., Park, Y. S., Tabernero, J., Lee, M.-A., Lee, S., Virgili, A. C., Van Den Eynde, M., Fontana, E., Fakih, M., Asghari, G., So, J., Stein, A., Dubreuil, O., Bodnar, L., He, C. S., Wang, G., Smith, R., Eng, C., & Saeed, A. (2025). Zanzalintinib plus atezolizumab versus regorafenib in refractory colorectal cancer (STELLAR-303): A randomised, open-label, phase 3 trial. The Lancet, S0140673625020252. https://doi.org/10.1016/S0140-6736(25)02025-2
