In a phase III trial (STELLAR-303) reported in The Lancet, Hecht et al found that the combination of the multitargeted tyrosine kinase inhibitor zanzalintinib and atezolizumab improved overall survival vs regorafenib in patients with previously treated relapsed or refractory metastatic colorectal cancer without microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) tumors.
Study Details
In the open-label trial, 901 patients from sites in 16 countries were randomly assigned between September 2022 and July 2024 to receive zanzalintinib at 100 mg daily plus atezolizumab at 1,200 mg every 3 weeks (n = 451) or regorafenib at 160 mg daily on days 1 to 21 of 28-day cycles (n = 450). Study treatment was continued if ongoing clinical benefit was observed by investigators or until unacceptable toxicity or the need for alternative anticancer treatment. Among patients with reported race or ethnicity, 58% were White and 38% were Asian. The dual primary endpoints were overall survival in the intention-to-treat population and in the subset of patients without liver metastases.
Key Findings
Median follow-up was 18.0 months (interquartile range = 14.6–21.5 months).
Median overall survival was 10.9 months (95% confidence interval [CI] = 9.9–12.1 months) in the zanzalintinib plus atezolizumab group vs 9.4 months (95% CI = 8.5–10.2 months) in the regorafenib group (stratified hazard ratio [HR] = 0.80, 95% CI = 0.69–0.93, P = .0045). Separation of the Kaplan-Meier curves occurred early and consistently favored zanzalintinib plus atezolizumab thereafter. Rates at 12 and 24 months were 46% vs 38% and 20% vs 10%.
In an interim analysis of overall survival among patients without liver metastases (n = 187 [41%] in the zanzalintinib plus atezolizumab group; n = 197 [44%] in the regorafenib group), median overall survival was 15.9 months (95% CI = 13.5–17.6 months) in the zanzalintinib plus atezolizumab group vs 12.7 months (95% CI = 10.9–15.5 months) in the regorafenib group (stratified HR = 0.79, 95% CI = 0.61–1.03, P = .087).
Grade 3 or worse treatment-related adverse events occurred in 60% of the zanzalintinib plus atezolizumab group vs 37% of the regorafenib group; the most common were hypertension (15% vs 9%), proteinuria (6% vs 2%), fatigue (6% vs 2%), and diarrhea (6% vs 2%). Treatment-related palmar-plantar erythrodysesthesia occurred less commonly in the zanzalintinib plus atezolizumab group (any grade = 16% vs 50%; grade 3 in 3% vs 9%). Serious treatment-related adverse events occurred in 26% vs 10% of patients. Adverse events led to the discontinuation of treatment in 18% vs 15%. Deaths considered treatment-related occurred in five patients in the zanzalintinib plus atezolizumab group (due to intestinal perforation in two patients and pneumonitis, renal failure, and altered state of consciousness in one each) and in one patient in the regorafenib group (due to jejunal perforation).
The investigators concluded: “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.”
Anwaar Saeed, MD, of the Division of Hematology and Oncology, University of Pittsburgh Medical Center and UPMC Hillman Cancer Center, Pittsburgh, is the corresponding author for The Lancet article.
Disclosure: The study was funded by Exelixis. For full disclosures of all study authors, visit thelancet.com.
