Zanzalintinib plus atezolizumab versus regorafenib in refractory colorectal cancer (STELLAR-303): a randomised, open-label, phase 3 trial.

[BACKGROUND] Zanzalintinib is a multitargeted tyrosine-kinase inhibitor that, when combined with atezolizumab, showed promising antitumour activity and manageable toxicity in a phase 1 study. We aimed to compare the efficacy and safety of zanzalintinib-atezolizumab versus regorafenib in patients with previously treated metastatic colorectal cancer.

[METHODS] STELLAR-303 is a global, randomised, open-label, phase 3 trial done at 121 centres (including hospitals, academic medical centres, and specialised cancer research facilities) in 16 countries. Patients aged 18 years and older with confirmed metastatic adenocarcinoma of the colon or rectum, who had previously received standard-of-care therapy, and did not have microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumours were randomly assigned (1:1) in blocks of four to oral zanzalintinib (100 mg daily) plus intravenous atezolizumab (1200 mg every 3 weeks) or oral regorafenib (160 mg daily on days 1-21 of each 28-day cycle) using an interactive response technology system, stratified by geographical region, RAS status, and presence of liver metastases. Dual primary endpoints were overall survival in the intention-to-treat (ITT) population and in the subset of patients without liver metastases. Safety was assessed in all patients who received at least one dose of study drug. This report is based on a planned overall survival analysis (data cutoff April 30, 2025); the trial is active but not recruiting, and continues to the final overall survival analysis in the subset of patients without liver metastases. This trial is registered with ClinicalTrials.gov (NCT05425940).

[FINDINGS] 1325 patients were screened for eligibility; between Sept 7, 2022, and July 15, 2024, 901 patients were randomly assigned to zanzalintinib-atezolizumab (n=451) or regorafenib (n=450). 528 (59%) patients were male and 373 (41%) were female; 485 (54%) were White, 338 (38%) were Asian, 18 (2%) were Black, 24 (3%) were other races, and 36 (4%) had race not reported. At a median follow-up of 18·0 months (IQR 14·6-21·5), zanzalintinib-atezolizumab showed a significant overall survival benefit versus regorafenib in the ITT population (stratified hazard ratio [HR] 0·80 [95% CI 0·69-0·93]; p=0·0045) with a median overall survival of 10·9 months (95% CI 9·9-12·1) versus 9·4 months (8·5-10·2). At the interim analysis of overall survival in the subset of patients without liver metastases, the stratified HR for zanzalintinib-atezolizumab versus regorafenib was 0·79 (95% CI 0·61-1·03); p=0·087 (median overall survival 15·9 months [95% CI 13·5-17·6] vs 12·7 months [10·9-15·5]). Grade 3 or worse treatment-related adverse events occurred in 268 (60%) of 446 patients receiving zanzalintinib-atezolizumab and 161 (37%) of 434 patients receiving regorafenib. There were five (1%) treatment-related deaths in the zanzalintinib-atezolizumab group and one (<1%) in the regorafenib group.

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

[FUNDING] Exelixis.