Zanzalintinib

Exelixis disclosed Friday that the FDA extended its review of a marketing application seeking approval of the oral kinase inhibitor zanzalintinib by three months to March 3 next year. The company said in a filing with the US Securities and Exchange Commission (SEC) that the agency asked for updated safety and efficacy data.Zanzalintinib — which is designed to block tumour growth and immune evasion through inhibition of TAM kinases, MET and VEGF receptors — is viewed by Exelixis as a potential successor to Cabometyx (cabozantinib) and key to its sales ambitions. Speaking recently, CEO Michael Morrissey said that the pending decision on zanzalintinib "represents an important first step towards establishing [it] as our second oncology franchise and a significant driver of future growth."In February, the FDA accepted the submission, which seeks clearance of zanzalintinib, in combination with Roche's anti-PD-L1 drug Tecentriq (atezolizumab), for the treatment of adults with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, and, if RAS wild-type, an EGFR therapy. The regulator had previously assigned the filing a target review date of December 3.The application is based on findings from the Phase III STELLAR-303 trial, in which zanzalintinib in combination with Tecentriq demonstrated a statistically significant improvement in overall survival (OS) versus Bayer's oral multi-kinase inhibitor Stivarga (regorafenib). Data presented at last year's European Society for Medical Oncology (ESMO) meeting showed that the study met one of its two primary endpoints, with a 20% reduction in the risk of death in the intention-to-treat population at the final analysis. Median OS was 10.9 months for the zanzalintinib combination arm versus 9.4 months for Stivarga.However, at the time, concerns were also raised about zanzalintinib's safety. In STELLAR-303, investigators reported five treatment-related deaths among patients — two for zanzalintinib, two for Tecentriq and one for the combo — compared to one in the Stivarga group.More recently, Exelixis announced that STELLAR-303 failed to meet its other primary endpoint. Specifically, the zanzalintinib combination arm showed only a non-statistically significant trend in OS versus Stivarga in the subset of patients without active liver metastases. Median OS in the two groups was 15.9 months and 12.7 months, respectively.Exelixis noted in the SEC filing that its response to the FDA's request has been deemed "a major amendment," leading to the extended review.

The US FDA has extended its review of the New Drug Application (NDA) for zanzalintinib, an oral kinase inhibitor, in combination with atezolizumab (Tecentriq) for previously treated metastatic colorectal cancer (mCRC) by three months, pushing the updated Prescription Drug User Fee Act (PDUFA) action date to March 3, 2027. The FDA classified updated safety and efficacy data submitted by Alameda, California-based Exelixis, Inc. (Nasdaq: EXEL) in response to an agency information request as a major amendment, triggering the extension. The NDA is based on the Phase III STELLAR-303 trial, which randomized 901 patients 1:1 to zanzalintinib plus atezolizumab or regorafenib in previously treated non-microsatellite instability (non-MSI)-high mCRC. The combination demonstrated a statistically significant 20% reduction in the risk of death versus regorafenib in the intention-to-treat (ITT) population (stratified hazard ratio: 0.80; 95% confidence interval: 0.69–0.93; P=0.0045), with median overall survival (OS) of 10.9 months versus 9.4 months. These results were presented at the 2025 European Society for Medical Oncology Congress and published in The Lancet. The trial carried dual primary OS endpoints — one in the full ITT population and one in patients without active liver metastases (non-liver metastases, NLM). The ITT endpoint was met, but the final NLM analysis reported in June 2026 produced a non-statistically significant trend favoring the combination (hazard ratio: 0.83; 95% CI: 0.66–1.05; P=0.1185), with median OS of 15.9 versus 12.7 months. The FDA accepted the NDA in February 2026 on the basis of the ITT result, covering the broader previously treated mCRC population. Zanzalintinib inhibits the TAM kinases (TYRO3, AXL, MER), MET, and VEGF receptors. Exelixis designed the molecule as a successor to its approved cabozantinib (Cabometyx), with an improved pharmacokinetic half-life. The combination with atezolizumab, a PD-L1 checkpoint inhibitor, is intended to reduce immune evasion through TAM kinase blockade while suppressing angiogenesis. In the late-line mCRC setting, approved options include regorafenib, trifluridine/tipiracil (Lonsurf), and fruquintinib (Fruzaqla). For the BRAF V600E-mutant subset, encorafenib-based regimens are approved. The combination of nivolumab and ipilimumab is approved for MSI-high or mismatch repair-deficient CRC, a population excluded from STELLAR-303. Zanzalintinib plus atezolizumab would represent a chemotherapy-free option targeting the larger non-MSI-high population, where STELLAR-303 is the first Phase 3 trial to demonstrate a statistically significant overall survival improvement with an immunotherapy-based regimen. Beyond the mCRC filing, Exelixis is running multiple zanzalintinib pivotal trials, including STELLAR-304 in non-clear cell renal cell carcinoma, STELLAR-311 in neuroendocrine tumors, and STELLAR-316 in resected stage II/III CRC, the latter in collaboration with Merck and Natera. The revised PDUFA date of March 3, 2027 reflects the standard three-month extension applied when an applicant submits new data during an ongoing review cycle. Spot something wrong? Report an issue with this article