FDA Accepts NDA for Zanzalintinib/Atezolizumab in Pretreated Metastatic CRC

The FDA has accepted a new drug application (NDA) for the combination of zanzalintinib (XL092) and atezolizumab (Tecentriq) as a treatment for patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, according to a press release from the developer, Exelixis, Inc.¹ The indication also extends to pretreatment with an anti-EGFR therapy if the patient has RAS wild-type disease. The agency has set a Prescription Drug User Fee Act (PDUFA) action date of December 3, 2026.

The submission is supported by results from the pivotal phase 3 STELLAR-303 trial (NCT05425940), which represents the first phase 3 study of an immune checkpoint inhibitor–based combination to demonstrate a statistically significant overall survival (OS) improvement in this specific patient population. These results were shared at the European Society of Medical Oncology (ESMO) 2025 Congress and simultaneously published in The Lancet.^2,3 Zanzalintinib is a novel, oral multi-kinase inhibitor targeting MET, VEGFR, and TAM kinases (TYRO3, AXL, and MER), which may enhance the antitumor activity of immunotherapy.

“We are encouraged by this meaningful progress toward addressing the needs of patients with previously treated metastatic [CRC], for whom effective therapies have been limited and treatment outcomes remain poor,” Dana T. Aftab, PhD, executive vice president of research and development at Exelixis, stated in the press 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 [CRC].”

Clinical Efficacy

In the primary OS analysis of the intention-to-treat (ITT) population, the combination of zanzalintinib and atezolizumab demonstrated a statistically significant improvement in survival compared with regorafenib (Stivarga). The median OS was 10.9 months in the combination arm vs 9.4 months in the regorafenib arm (HR, 0.80; 95% CI, 0.69-0.93; P = .0045). Notably, a trend toward improved OS was observed in the dual primary end point population of patients without liver metastases, with a median OS of 15.9 months for the combination vs 12.7 months for regorafenib (HR, 0.77; 95% CI, 0.59-1.01).

Secondary efficacy end points also favored the combination regimen. The median progression-free survival (PFS) was 3.7 months with zanzalintinib plus atezolizumab compared with 2.0 months with regorafenib (HR, 0.68; 95% CI, 0.59-0.79). The objective response rate (ORR) was 4% (95% CI, 2%-6%) for the combination and 1% (95% CI, 0%-3%) for regorafenib, while the disease control rate (DCR) reached 54% (95% CI, 49%-58%) and 41% (95% CI, 36%-45%), respectively.

Expert Commentary

“STELLAR-303 is the first phase 3 trial to show improved OS with an [immune checkpoint inhibitor]–based combination in metastatic CRC that is not [microsatellite instability–high (MSI-H) or mismatch repair deficient (dMMR)],” said lead study author Anwar Saeed, MD, an associate professor of medicine and the chief of the Gastrointestinal Medical Oncology Program at the University of Pittsburgh Medical Center, and coauthors, in the presentation.² “Zanzalintinib plus atezolizumab represents a potential novel chemotherapy-free treatment option for heavily pretreated patients with metastatic CRC.”

Trial Breakdown

The randomized, open-label, phase 3 STELLAR-303 study enrolled 901 patients with metastatic CRC that was documented as not MSI-H or dMMR. Patients were randomly assigned 1:1 to receive either the combination therapy or regorafenib monotherapy. The experimental regimen consisted of zanzalintinib at a dose of 100 mg administered orally once daily plus atezolizumab at 1200 mg administered intravenously every 3 weeks. Those in the comparator group received regorafenib at 160 mg orally once daily for the first 21 days of each 28-day cycle.

Eligibility criteria required patients to have metastatic CRC that had radiographically progressed on or was refractory or intolerant to prior standard therapies, including fluoropyrimidine, irinotecan, and oxaliplatin with or without an anti-VEGF antibody. Patients with RAS wild-type tumors must have received an anti-EGFR antibody, and those with a known BRAF V600E mutation must have received a BRAF inhibitor.

Safety Results

The safety profile of the combination was generally consistent with the known profiles of the individual agents. Any-grade treatment-related adverse events (TRAEs) occurred in 95% of patients in the combination arm compared with 92% in the regorafenib arm. Grade 3 or higher TRAEs were reported in 59% of patients receiving zanzalintinib plus atezolizumab and 37% of those receiving regorafenib.

The most frequent any-grade TRAEs for the combination included diarrhea (50%), hypertension (34%), fatigue (33%), and nausea (31%). Serious TRAEs were reported in 26% of patients in the combination arm vs 10% in the regorafenib arm. AEs led to the discontinuation of all study treatments in 18% of the combination group and 15% of the regorafenib group. Fatal TRAEs in the combination arm included intestinal perforation (n=2), pneumonitis (n=1), renal failure (n=1), and altered state of consciousness (n=1).

References

1. 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 February 2, 2026. https://tinyurl.com/4fkupzrk
2. Saeed A, Park YS, Tabernero J, et al. Zanzalintinib plus atezolizumab vs regorafenib in patients with previously treated metastatic colorectal cancer: primary overall survival analysis from the randomized, open-label, phase 3 STELLAR-303 study. Presented at: European Society for Medical Oncology Congress 2025; October 17-21, 2025; Berlin, Germany. LBA30.
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. Published online October 19, 2025. doi:10.1016/S0140-6736(25)02025-2