Zanzalintinib/Atezolizumab Misses Survival End Point in Non-MSI-H mCRC Subgroup

Zanzalintinib plus atezolizumab (Tecentriq) did not meet the dual primary end point of the phase 3 STELLAR-303 trial (NCT05425940), eliciting a non-statistically significant overall survival (OS) advantage over regorafenib (Stivarga) in the non-liver metastases subgroup of patients with previously treated non-microsatellite instability–high (MSI-H) metastatic colorectal cancer, according to a news release from Exelixis.¹

Results from the final analysis showed a non-statistically significant trend in OS, with a median OS of 15.9 months with the combination vs 12.7 months with regorafenib (HR, 0.83; 95% CI, 0.66–1.05; P = .1185). The safety profile of the zanzalintinib plus atezolizumab was consistent with previously reported findings from the intention-to-treat (ITT) population, with no new safety signals observed.

Detailed findings from the non-liver metastases subgroup analysis will be submitted for presentation at an upcoming medical conference.

What were the ITT population OS results from STELLAR-303?

STELLAR-303 previously met its other dual primary end point, demonstrating a statistically significant improvement in OS in the ITT population, which included all randomly assigned patients regardless of the presence of active liver metastases (HR, 0.80; 95% CI, 0.69-0.93; P = .0045).² At a median follow-up of 18.0 months, median OS was 10.9 months with the combination compared with 9.4 months with regorafenib. An OS benefit was consistently observed across pre-specified subgroups, including geographic region, RAS status, liver involvement, and prior anti-VEGF therapy. Those results were presented at the 2025 European Society for Medical Oncology (ESMO) Congress and published in The Lancet.

In that analysis, it was shown that grade 3 and 4 adverse events (AEs) occurred in 59% of patients who received the experimental combination vs 37% who received regorafenib. The most common grade 3 or 4 treatment-related AEs were hypertension (15% vs 9%), fatigue (6% vs 2%), diarrhea (6% vs 2%), and proteinuria (6% vs 2%). AEs led to treatment discontinuation in 18% vs 15% of patients, respectively. Two deaths each were deemed by investigators to be related to zanzalintinib and atezolizumab individually, 1 was due to the combination regimen, and 1 was due to regorafenib.

What is the STELLAR-303 trial design?

STELLAR-303 is a global, multicenter, randomized, phase 3, open-label study that enrolled and randomly assigned patients 1:1 to either zanzalintinib in combination with atezolizumab (n = 451) or regorafenib (n = 450). The study included patients with previously treated non-MSI-H metastatic colorectal cancer. The dual primary end points were OS in the ITT population and OS in the non-liver metastases subgroup. Secondary end points include progression-free survival, objective response rate, and duration of response in both the ITT population and the non-liver metastases subgroup.

What is zanzalintinib and how does it work?

Zanzalintinib is a novel oral kinase inhibitor that targets TAM kinases (TYRO3, AXL, and MER), MET, and VEGF receptors, all pathways involved in tumor cell proliferation, metastasis, angiogenesis, drug resistance, and evasion of antitumor immunity. Zanzalintinib is also being evaluated in ongoing pivotal trials in clear cell and non-clear cell renal cell carcinoma and neuroendocrine tumors, as well as earlier-stage investigations in meningioma, lung cancer, and castration-resistant prostate cancer.

What is the regulatory status of zanzalintinib in metastatic colorectal cancer?

CancerNetwork® previously covered the FDA’s acceptance of the new drug application (NDA) for zanzalintinib in combination with atezolizumab for the treatment of patients with metastatic colorectal cancer who had been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and, if RAS wild-type, an anti-epidermal growth factor receptor (EGFR) therapy.³ The FDA assigned a Prescription Drug User Fee Act (PDUFA) target action date of December 3, 2026.

References

1. Exelixis provides update on the phase 3 STELLAR-303 trial evaluating zanzalintinib in combination with an immune checkpoint inhibitor in patients with metastatic colorectal cancer. News release. Exelixis, Inc. June 22, 2026. Accessed June 23, 2026. https://tinyurl.com/2bbw5maa
2. Exelixis announces detailed results from phase 3 STELLAR-303 pivotal trial evaluating zanzalintinib in combination with an immune checkpoint inhibitor in metastatic colorectal cancer presented at ESMO 2025 and published in The Lancet. News release. Exelixis, Inc. October 20, 2025. Accessed June 23, 2026. https://tinyurl.com/455f9y22
3. Exelixis announces U.S. FDA acceptance of new drug application for zanzalintinib in combination with atezolizumab for previously treated metastatic colorectal cancer. News release. Exelixis, Inc. February 2, 2026. Accessed June 23, 2026. https://tinyurl.com/4fkupzrk