Zanzalintinib Combo Improves Survival vs Regorafenib in Metastatic CRC

The safety profile of zanzalintinib plus atezolizumab in the STELLAR-303 trial was consistent with prior reports of each agent; no new safety signals were observed.

Combining zanzalintinib with atezolizumab (Tecentriq) significantly prolonged overall survival (OS) compared with regorafenib (Stivarga) among patients with previously treated metastatic colorectal cancer (CRC) that is not microsatellite instability high, according to a press release on top-line data from the phase 3 STELLAR-303 trial (NCT05425940).

A final analysis conducted by an independent data monitoring committee confirmed that the zanzalintinib combination reached the trial’s dual primary end point of OS across the intent-to-treat (ITT) population. The trial will continue with a planned final analysis for the other primary end point of OS among patients without liver metastases.

The safety profile of zanzalintinib plus atezolizumab in the STELLAR-303 trial was consistent with prior reports of each agent; no new safety signals were observed.

Investigators plan to submit detailed findings from the STELLAR-303 trial for presentation at a future medical meeting.

“The STELLAR-303 results, which showed a survival benefit with the combination of zanzalintinib and atezolizumab vs regorafenib across all [randomly assigned] patients with previously treated metastatic [CRC], marks an important first milestone for our zanzalintinib pivotal development program,” Amy Peterson, MD, executive vice president of product development and medical affairs and chief medical officer at Exelixis, the developer of zanzalintinib, stated in the press release.¹ “We look forward to discussing the findings with regulatory authorities and presenting the detailed results at an upcoming medical conference.”

Developers designed zanzalintinib as a third-generation, orally available tyrosine kinase inhibitor that inhibits receptor tyrosine kinases, including VEGF receptors, MET, AXL, and MER. The agent is intended for use in various advanced solid tumors such as CRC, kidney cancer, head and neck cancer, and neuroendocrine tumors. Additionally, the design of zanzalintinib serves to build upon the target profile of cabozantinib (Cabometyx), the developer’s flagship therapy, while improving characteristics such as the pharmacokinetic half-life.

In the international, multicenter, open-label STELLAR-303 trial, 901 patients were randomly assigned 1:1 to receive zanzalintinib at 100 mg daily plus atezolizumab at 1200 mg intravenously once every 3 weeks or regorafenib at 160 mg for the first 21 days of each 28-day cycle.²

The trial’s dual primary end points were OS across the ITT population and among those without liver metastases. Secondary end points included progression-free survival, objective response rate, and duration of response.

Patients 18 years or older with histologically or cytologically confirmed adenocarcinoma of the colon or rectum and radiographical progression on prior standard-of-care therapies for metastatic CRC were eligible for enrollment in the trial. Other eligibility criteria included having measurable disease per RECIST v1.1 guidelines, available archival tumor biopsy material, an ECOG performance status of 0 or 1, and adequate organ and marrow function.

Those who previously received regorafenib, trifluridine/tipiracil (Lonsurf), or anti–PD-L1 or anti–PD-L2 immune checkpoint inhibitors were ineligible for enrollment in the trial. Patients were also unable to enroll if they had treatment with a small molecule kinase inhibitor within 2 weeks before random assignment; radiotherapy for bone metastasis within 2 weeks before random assignment; known brain metastases or cranial epidural disease; uncontrolled, significant intercurrent or recent illness; major surgery within 4 weeks before random assignment; or a history of psychiatric illness that may have interfered with the ability to adhere to protocol requirements. Having an inability to swallow study treatment formulation or receive intravenous therapy or a gastrointestinal condition that may have affected the absorption of study therapy was also grounds for exclusion from the trial.

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 Inc. June 22, 2025. Accessed June 23, 2025. https://tinyurl.com/mpc5eyb6
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://tinyurl.com/yt3nz8az