FDA Accepts NDA for Zanzalintinib Plus Atezolizumab in Pretreated mCRC

The FDA has accepted a new drug application seeking approval for zanzalintinib (XL092) in combination with atezolizumab (Tecentriq) for the treatment of adult patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and, if RAS wild type, anti-EGFR therapy.¹

The regulatory agency has assigned a Prescription Drug User Fee Act target action date of December 3, 2026.

The NDA is supported by data from the phase 3 STELLAR-303 trial (NCT05425940), which met its dual primary end point of significantly improved overall survival (OS) with zanzalintinib plus atezolizumab vs regorafenib (Stivarga) in the intention-to-treat (ITT) population of patients with previously treated colorectal cancer.

Of note, OS outcomes in patients without active liver metastases, the trial’s other primary end point, were immature at the data cutoff. According to Exelixis, the drug’s developer, the trial is proceeding to the planned final analysis for this end point; these data are expected to read out mid-2026.

“We are encouraged by this meaningful progress toward addressing the needs of patients with previously treated mCRC, 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 a news release. “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 mCRC. 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.”

What Was the Design of the STELLAR Trial?

The global, randomized, open-label trial enrolled patients aged 18 or older with confirmed metastatic adenocarcinoma of the colon or rectum who did not have documented microsatellite instability-high or mismatch repair–deficient status.² Patients were also required to have disease that radiographically progressed on, or was refractory or intolerant to, prior standard-of-care treatment, including fluoropyrimidine plus irinotecan and oxaliplatin with or without an anti-VEGF antibody, an anti-EGFR antibody, and a BRAF inhibitor.

A total of 901 patients were randomly assigned 1:1 to receive either zanzalintinib at 100 mg orally each day plus atezolizumab at 1200 mg intravenously every 3 weeks (n = 451) or regorafenib at 160 mg orally once daily on days 1 to 21 of each 28-day cycle (n = 450).

The trial’s dual primary end points were OS in the ITT population and OS among patients without liver metastases. Key secondary end points included PFS, ORR, and safety.

What Data From STELLAR Supported This NDA?

Data from STELLAR, concurrently presented at the 2025 European Society for Medical Oncology Congress and published in The Lancet, showed that patients in the ITT population who received zanzalintinib plus atezolizumab achieved a median OS of 10.9 months vs 9.4 months with regorafenib (HR, 0.80; 95% CI, 0.69-0.93; P = .0045). Furthermore, in a prespecified interim subgroup analysis of patients without liver metastases, the median OS was 15.9 months vs 12.8 months, respectively (stratified HR, 0.79; 95% CI, 0.61-1.03; P = .0875). Consistent OS benefit was observed across most key subgroups.

The median progression-free survival (PFS) in the ITT population was 3.7 months with the combination vs 2.0 months with regorafenib (HR, 0.68; 95% CI, 0.59-0.79). Statistical significance for PFS could not be formally claimed under the prespecified hierarchical testing strategy. However, PFS improvement was generally consistent across subgroups.

Regarding safety, any-grade treatment-related adverse effects (TRAEs) occurred in 95% of patients receiving zanzalintinib plus atezolizumab and 92% receiving regorafenib; serious AEs occurred in 57% vs 42% of patients in these respective arms. Serious TRAEs occurred in 26% vs 10% of patients, respectively. Treatment-related deaths included intestinal perforation (n = 2) with zanzalintinib, pneumonitis (n = 1) and renal failure (n = 1) with atezolizumab, altered consciousness (n = 1) with the combination, and jejunal perforation (n = 1) with regorafenib.

The most common AEs observed with zanzalintinib plus atezolizumab vs regorafenib were diarrhea (50% vs 24%), hypertension (34% vs 26%), fatigue (33% vs 20%), nausea (31% vs 13%), and decreased appetite (30% vs 20%).

References

1. Exelixis announces US 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://ir.exelixis.com/news-releases/news-release-details/exelixis-announces-us-fda-accepted-new-drug-application
2. Hecht JR, Park YS, Tabernero J, et al; STELLAR-303 study investigators. 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