Zanzalintinib Plus Atezolizumab Boosts OS in Previously Treated, Non–MSI-H mCRC

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Ashling Wahner & MJH Life Sciences Using AI

Treatment with the combination of zanzalintinib (XL092) and atezolizumab (Tecentriq) led to a statistically significant improvement in overall survival (OS) compared with regorafenib (Stivarga) in patients with previously treated, non–microsatellite instability–high (MSI-H) metastatic colorectal cancer (mCRC), according to topline data from the phase 3 STELLAR-303 trial (NCT05425940).1

The OS benefit was observed in the trial’s intention-to-treat (ITT) population, which comprised patients with and without liver metastases. This OS analysis was the final one being conducted by the trial’s independent data monitoring committee for the ITT population; data for the study’s other primary end point—OS in patients without liver metastases—in a future final analysis of the data.

The safety of the combination was consistent with previously reported findings for each individual agent, and no new safety signals were reported.

Full data from this analysis will be submitted for presentation at an upcoming medical meeting.

“The STELLAR-303 results, which showed a survival benefit with the combination of zanzalintinib and atezolizumab versus regorafenib across all randomized patients with previously treated metastatic colorectal cancer, marks an important first milestone for our zanzalintinib pivotal development program,” Amy Peterson, MD, Executive Vice President, Product Development & Medical Affairs, and Chief Medical Officer, Exelixis said in a news release. “We look forward to discussing the findings with regulatory authorities and presenting the detailed results at an upcoming medical conference.”

STELLAR-303 Background

Zanzalintinib is a third-generation, oral TKI designed to inhibit the activity of VEGF, MET, AXL, and MET. Along with CRC, the investigational agent is being evaluated in the treatment of kidney cancer, head and neck cancer, and neuroendocrine tumors.

The multicenter, randomized, open-label, controlled, phase 3 study enrolled patients at least 18 years of age with histologically or cytologically confirmed adenocarcinoma of the colon or rectum.2 Known RAS status was required, but patients could have RAS-mutated or wild-type disease. Confirmation of non–MSI-H or non–mismatch repair–deficient disease was also required per tissue testing. Prior treatment with standard-of-care anticancer therapies for mCRC were required, and patients needed to be refractory or intolerant to prior therapies.

Other key inclusion criteria consisted of measurable disease per RECIST 1.1 criteria, an ECOG performance status of 0 or 1; adequate organ and bone marrow function. Patients needed adverse effects related to prior treatments to recover to baseline or no higher than grade 1 in severity, unless they were are clinically nonsignificant and/or stable on supportive therapy.

Prior treatment with zanzalintinib, regorafenib, trifluridine/tipiracil, or immune checkpoint inhibitors targeting PD-1 or PD-L1 was not allowed. Patients could not have known brain metastases or cranial epidural disease unless they received radiotherapy and/or surgery and were stable for at least 4 weeks prior to randomization.

Other exclusion criteria comprised major surgery within 4 weeks of randomization; receipt of corticosteroids of more than 10 mg per day or other immunosuppressive therapies within 14 days of randomization; treatment with a small molecule kinase inhibitor within 2 weeks of randomization; receipt of radiation therapy for bone metastases within 2 weeks of randomization, or any other radiation within 4 weeks of randomization.

Investigators randomly assigned patients 1:1 to receive zanzalintinib at 100 mg once per day plus atezolizumab at 1200 mg once every 3 weeks; or regorafenib at 160 mg per day during the first 21 days of each 28-day cycle.1,2

OS is serving as the trial’s primary end point.2 Secondary end points include progression-free survival, objective response rate, and duration of response.

References

1. Exelixis announces zanzalintinib in combination with an immune checkpoint inhibitor improved overall survival in STELLAR-303 phase 3 pivotal trial in patients with metastatic colorectal Cancer. News release. Exelixis. June 22, 2025. June 23, 2025. https://ir.exelixis.com/news-releases/news-release-details/exelixis-announces-zanzalintinib-combination-immune-checkpoint
2. Study of XL092 + atezolizumab vs regorafenib in subjects with metastatic colorectal cancer (STELLAR-303). ClinicalTrials.gov. Updated July 5, 2024. Accessed June 23, 2025. https://clinicaltrials.gov/study/NCT05425940