Exelixis's STELLAR-001 trial, presented at the ASCO GI 2025 symposium, reveals encouraging results for zanzalintinib, a tyrosine kinase inhibitor, when combined with atezolizumab, an immune checkpoint inhibitor, in treating previously-treated metastatic colorectal cancer (CRC). The study highlights improved progression-free survival (PFS) and overall survival (OS) in a specific subgroup of patients, offering a potential new treatment avenue for this challenging cancer.
The phase 1b/2 STELLAR-001 trial included 107 patients with unresectable, locally advanced or metastatic RAS wild-type CRC. Patients were randomized 1:1 to receive either single-agent zanzalintinib or zanzalintinib in combination with atezolizumab. The median number of prior lines of therapy was 3.0 for patients treated with zanzalintinib alone and 2.5 for patients treated with zanzalintinib in combination with atezolizumab.
Efficacy Outcomes
The addition of atezolizumab to zanzalintinib led to numerical improvements in both PFS and OS. Specifically, in patients without liver metastases, the median PFS was 8.2 months with the combination compared to 3.3 months with zanzalintinib alone (HR 0.37, 95% CI: 0.15-0.91). The median OS in this subgroup was 18.5 months with the combination versus 21.1 months with zanzalintinib alone (HR 0.74, 95% CI: 0.27-2.04). The 6-month survival rate was 87.8% in the combination arm compared to 64.7% in the zanzalintinib alone arm.
| | Zanzalintinib alone | Zanzalintinib + atezolizumab |
|---------------------|----------------------|-------------------------------|
| Patients, n | 17 | 17 |
| Median PFS, months | 3.3 | 8.2 |
| PFS HR (95% CI) | | 0.37 (0.15-0.91) |
| Median OS, months | 21.1 | 18.5 |
| OS HR (95% CI) | | 0.74 (0.27-2.04) |
| 6-month survival rate, % | 64.7 | 87.8 |
| 12-month survival rate, % | 52.3 | 62.7 |
| ORR, % | 5.9 | 18.0 |
| Partial response, n | 1 | 3 |
Biomarker Analysis
A biomarker analysis revealed that a PD-L1 combined positive score greater than 1 was associated with improved PFS and OS in patients treated with the zanzalintinib and atezolizumab combination compared to zanzalintinib alone.
Safety Profile
Grade 3/4 treatment-related adverse events (AEs) occurred in 40% of patients receiving zanzalintinib alone and 48% of patients receiving the combination. One grade 5 treatment-related AE occurred in each group. Zanzalintinib was discontinued in 19% and 30% of patients, respectively. Treatment-related AEs leading to discontinuation of any drug occurred in 8% and 19% of patients, respectively. Common treatment-related adverse events included nausea, diarrhea, and fatigue.
Implications for Future Research
"Data from this randomized expansion cohort reaffirms our decision to initiate STELLAR-303 evaluating zanzalintinib in combination with atezolizumab compared with regorafenib in patients with metastatic colorectal cancer," said Amy Peterson, M.D., Executive Vice President, Product Development & Medical Affairs, and Chief Medical Officer, Exelixis. The STELLAR-303 trial completed enrollment in August 2024, and preliminary results are expected in the second half of 2025, dependent on study event rates.
Colorectal Cancer Landscape
Colorectal cancer remains a significant health challenge, being the third most common cancer and the second leading cause of cancer-related deaths in the U.S. The STELLAR-001 trial offers a promising step forward in addressing the unmet needs of patients with previously-treated metastatic CRC, particularly those without liver metastases.
