FDA Extends Review of Zanzalintinib Combo in Pretreated Metastatic CRC

The FDA has extended its review of the new drug application (NDA) for zanzalintinib (XL092) plus atezolizumab (Tecentriq) as a treatment for patients with previously treated metastatic colorectal cancer (CRC), according to a regulatory filing from Exelixis.¹

The agency extended the Prescription Drug User Fee Act (PDUFA) action date by 3 months, to March 3, 2027, from the prior target of December 3, 2026. The extension followed the submission of updated safety and efficacy data by Exelixis in response to an FDA information request, which the agency classified as a major amendment.

Why did the FDA extend the zanzalintinib review?

Developers disclosed the extension in a regulatory filing, noting that it had submitted updated safety and efficacy data in response to an information request from the FDA. The agency classified the updated submission as a major amendment, which provides the FDA with additional time to review the new information and results in a standard 3-month extension of the review period. As a result, the PDUFA action date moved to March 3, 2027. The extension does not reflect a change in the underlying data supporting the application.

What is the NDA seeking, and what supports it?

Previously, the FDA accepted the NDA for zanzalintinib plus atezolizumab in February 2026 for the treatment of patients with metastatic CRC previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; the sought indication also extends to patients previously treated with an anti-EGFR therapy if they have RAS wild-type disease.² The submission is supported by data from the pivotal phase 3 STELLAR-303 trial (NCT05425940), which the developer has described as the first phase 3 study of an immune checkpoint inhibitor–based combination to demonstrate a statistically significant overall survival (OS) improvement in patients with metastatic CRC that is not microsatellite instability–high (MSI-H) or mismatch repair deficient.

What did the STELLAR-303 trial show?

In the primary OS analysis of the intention-to-treat population, zanzalintinib plus atezolizumab produced a median OS of 10.9 months vs 9.4 months with regorafenib (Stivarga), corresponding to a hazard ratio (HR) of 0.80 (95% CI, 0.69-0.93; P = .0045).³ In the dual primary end point population of patients without liver metastases, a numerical OS improvement was observed with the combination (median OS, 15.9 vs 12.7 months; HR, 0.77; 95% CI, 0.59-1.01), though it did not reach statistical significance. The median progression-free survival was 3.7 months with the combination vs 2.0 months with regorafenib (HR, 0.68; 95% CI, 0.59-0.79).

Grade 3 or higher treatment-related adverse events occurred in 59% of patients in the combination arm vs 37% of those in the regorafenib arm.

In June 2026, developers announced that the STELLAR-303 trial did not reach its dual primary end point of OS in the non–liver metastases subgroup of patients with previously treated metastatic CRC that was not MSI-H.⁴

The randomized, open-label trial enrolled 901 patients who were assigned 1:1 to zanzalintinib at 100 mg orally once daily plus atezolizumab at 1200 mg intravenously every 3 weeks or to regorafenib at 160 mg orally once daily for the first 21 days of each 28-day cycle.

What is zanzalintinib?

Zanzalintinib is a novel, oral, multitargeted tyrosine kinase inhibitor that targets MET, VEGF receptors, and the TAM kinases TYRO3, AXL, and MER—targets that may enhance the antitumor activity of immunotherapy. If approved, zanzalintinib plus atezolizumab would offer a chemotherapy-free regimen with a novel mechanism of action for patients with previously treated metastatic CRC, a population for whom effective treatment options remain limited.

References

1. Roy S. US FDA extends review of Exelixis cancer drug. Reuters. September 11, 2026. Accessed September 14, 2026. https://tinyurl.com/yfezanes
2. 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 September 14, 2026. https://tinyurl.com/4fkupzrk
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. 2026;406(10517):2360-2370. doi:10.1016/S0140-6736(25)02025-2
4. Exelixis provides update on the phase 3 STELLAR-303 trial evaluating zanzalintinib in combination with an immune checkpoint inhibitor in patients with metastatic colorectal cancer. News release. Exelixis Inc. June 22, 2026. Accessed September 14, 2026. https://tinyurl.com/2bbw5maa