FDA Accepts NDA of Zanzalintinib Combo for Pretreated Metastatic CRC

The FDA has accepted for review a new drug application (NDA) for zanzalintinib (formerly XL092) combined with atezolizumab (Tecentriq) for treatment of adult patients with metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy and, if RAS wild-type, an anti-EGFR therapy.¹ A Prescription Drug User Fee Act (PDUFA) target action date has been set for December 3, 2026.

The primary evidence for the NDA originates from the pivotal phase 3 STELLAR-303 trial (NCT05425940), which evaluated the efficacy and safety of the combination vs regorafenib (Stivarga) in pretreated adult patients with microsatellite stable (MSS) or microsatellite instability-low metastatic colorectal cancer.² The acceptance of the NDA marks a significant regulatory milestone for a patient population that has traditionally seen limited benefit from chemotherapy-based regimens.

“We are encouraged by this meaningful progress toward addressing the needs of patients with previously treated metastatic colorectal cancer, for whom effective therapies have been limited and treatment outcomes remain poor,” said Dana T. Aftab, PhD, executive vice president of Research and Development at Exelixis, in a news release.¹ “Zanzalintinib has the potential to become an important advancement in a challenging treatment landscape, and if approved, zanzalintinib in combination with atezolizumab would provide a novel mechanism of action for patients with previously treated metastatic colorectal cancer. We are deeply grateful to the patients, caregivers and investigators contributing to the clinical research in support of this application, and we look forward to collaborating with the FDA during the review process for our first NDA for zanzalintinib.”

Clinical Rationale and Relevance

Zanzalintinib is a third generation, multitargeted tyrosine kinase inhibitor that inhibits MET, AXL, and VEGF receptors. These pathways are integral to tumor angiogenesis, metastasis, and the maintenance of an immunosuppressive tumor microenvironment. Atezolizumab is a monoclonal antibody that targets PD-L1, intended to reinvigorate the antitumor T-cell response.

The rationale for the combination lies in the "cold" nature of MSS metastatic colorectal cancer, which represents a majority of metastatic cases. While immune checkpoint inhibitors have historically failed as monotherapy in this setting, the addition of a multikinase inhibitor like zanzalintinib is hypothesized to modulate the tumor microenvironment, making it more permissive to immunotherapy by reducing myeloid-derived suppressor cells and enhancing T-cell infiltration.

Pending the FDA’s decision, this regimen could provide a crucial new chemotherapy-free alternative for clinicians and patients in the refractory setting.

STELLAR-303 Trial: Clinical Data

In the global, randomized, STELLAR-303 trial, a total of 901 patients were randomly assigned 1:1 to receive either 100 mg of oral zanzalintinib plus intravenous atezolizumab at 1200 mg every 3 weeks (n = 451), or oral regorafenib at 160 mg daily on days 1 to 21 of each 28-day cycle (n = 450). The trial had dual primary end points of overall survival (OS) in the intention-to-treat population as well as in the subgroup of patients without liver metastases.

According to data presented at the 2025 European Society for Medical Oncology (ESMO) Annual Congress and published in The Lancet, the trial met its co-primary end point of OS in the intention-to-treat population.³ The combination of zanzalintinib and atezolizumab demonstrated a statistically significant improvement in median OS, reaching 10.9 months vs 9.4 months in the regorafenib arm. This represents a 20% reduction in the risk of death (HR, 0.80; 95% CI, 0.69-0.93; P =.0045).

Subgroup analyses further revealed that patients without liver metastases experienced a more pronounced survival benefit, with a median OS of 15.9 months in the combination arm vs 12.7 months in the regorafenib group (HR, 0.79; 95% CI, 0.61-1.03; P =.087). While the study also showed an improvement in progression-free survival (PFS)—3.7 months for the combination vs 2.0 months for regorafenib (HR, 0.68)—statistical significance for this secondary end point was not reached at the time of the primary analysis due to the hierarchical testing structure.

Regarding safety, the adverse event (AE) profile observed in STELLAR-303 was generally consistent with the established profiles of both agents. Grade 3 or worse treatment-related AEs occurred in 60% of patients in the combination arm compared with 37% in the regorafenib arm. The most common AEs across both arms included diarrhea, hypertension, fatigue, nausea, and decreased appetite.

REFERENCES

1. Exelixis announces U.S. FDA accepted the new drug application for zanzalintinib in combination with an immune checkpoint inhibitor for patients with metastatic colorectal cancer. News release. Exelixis. February 2, 2026. Accessed February 2, 2026. https://tinyurl.com/y6py4m4m

2. Study of XL092 + atezolizumab vs regorafenib in participants with metastatic colorectal cancer (STELLAR-303). ClinicalTrials.gov. Updated October 23, 2025. Accessed February 2, 2026. https://clinicaltrials.gov/study/NCT05425940

3. Hecht JR, Park YS, Tabernero J, et al. Zanzalintinib plus atezolizumab versus regorafenib in refractory colorectal cancer (STELLAR-303): a randomised, open-label, phase 3 trial. Lancet. 2025;406(10517):2360-2370. doi:10.1016/s0140-6736(25)02025-2