FDA Delays Decision on Zanzalintinib Combo for mCRC

The FDA has extended the Prescription Drug User Fee Act (PDUFA) action date by 3 months to March 3, 2027, for the new drug application (NDA) for zanzalintinib in combination with atezolizumab for the treatment of patients with metastatic colorectal cancer (mCRC).¹

Exelixis, the developer of zanzalintinib, reported in a filing to the Securities and Exchange Commission that the FDA had notified the company of the extension. The FDA will be using the additional time to review updated efficacy and safety data Exelixis submitted in support of the NDA.

Exelixis reported in February 2026 that the FDA had accepted the NDA and assigned it a standard review with a PDUFA action date of December 3, 2026. The NDA is primarily supported by findings from the phase 3 STELLAR-303 trial (NCT05425940) in which the combination of zanzalintinib and atezolizumab reduced the risk of death by 20% compared with regorafenib (Stivarga) in the intent-to-treat (ITT) population of patients with mCRC.

The study findings showed that at a median follow-up of 18 months (interquartile range, 14.6-21.5), the median overall survival (OS) was 10.9 months with the zanzalintinib combination versus 9.4 months with regorafenib (HR, 0.80; 95% CI, CI 0.69-0.93; P = .0045). In a subset of patients without liver metastases, the median OS was 15.9 months vs 12.7 months, respectively (HR, 0.79; 95% CI, 0.61-1.03); P = .087).

Safety Profile in STELLAR-303 Trial

Overall 268 (60%) of 446 patients receiving zanzalintinib plus atezolizumab experienced grade 3 or worse treatment-related adverse events, compared with 161 (37%) of 434 patients receiving regorafenib. Five treatment-related deaths occurred in the zanzalintinib combination group versus 1 in the regorafenib group.

STELLAR-303 Background and Patient Characteristics

The phase 3 STELLAR-303 trial evaluated zanzalintinib in combination with atezolizumab versus regorafenib in patients with previously treated mCRC. The global, randomized, open-label study was conducted at 121 centers, including hospitals, academic medical centers, and specialized cancer research facilities, across 16 countries.

Adults aged 18 years or older were eligible if they had confirmed metastatic adenocarcinoma of the colon or rectum, had previously received standard-of-care treatment, and had tumors that were not microsatellite instability-high or mismatch repair deficient.

Patients were randomly assigned in a 1:1 ratio to receive either oral zanzalintinib at 100 mg once daily plus intravenous atezolizumab at 1200 mg every 3 weeks or oral regorafenib at 160 mg once daily on days 1 to 21 of each 28-day cycle. Randomization was stratified according to geographic region, RAS status, and the presence of liver metastases.

The trial had 2 primary OS endpoints: overall survival in the ITT population and OS among patients without liver metastases. Safety analyses included patients who received at least 1 dose of either study treatment.

Of 1325 patients screened for eligibility, 901 were randomly assigned between Sept 7, 2022, and July 15, 2024. This included 451 patients assigned to zanzalintinib plus atezolizumab and 450 assigned to regorafenib.

Overall, 528 patients (59%) were male and 373 (41%) were female. By race, 485 patients (54%) were White, 338 (38%) were Asian, 18 (2%) were Black, 24 (3%) were classified as other races, and race was not reported for 36 patients (4%).

“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,” Dana T. Aftab, PhD, executive vice president, Research and Development, Exelixis, stated at the time of the FDA’s initial acceptance of the NDA.²

REFERENCES

1. Exelixis, Inc. Current Report on Form 8-K. US Securities and Exchange Commission. Published September 10, 2026. Accessed September 11, 2026. SEC filing. https://tinyurl.com/tuaa3j44

2. 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 September 11, 2026. https://tinyurl.com/2rh3m9rc