Zanzalintinib Plus Immune Checkpoint Inhibitor Shows Promise in Metastatic Colorectal Cancer: Detailed Results from the STELLAR-303 Trial, Presented at ESMO 2025 and Published in The Lancet

10/20/2025 – 02:30 AM

– Zanzalintinib in combination with atezolizumab improved median overall survival to 10.9 months versus 9.4 months with regorafenib, and significantly reduced the risk of death by 20% in the intention-to-treat population –

– Exelixis plans to complete its first new drug application submission for zanzalintinib in the U.S. in 2025 –

ALAMEDA, Calif. – Exelixis, Inc. (Nasdaq: EXEL) unveiled compelling data from its STELLAR-303 phase 3 trial, a study evaluating zanzalintinib in combination with atezolizumab (Tecentriq^®) versus regorafenib, for patients with previously treated non-microsatellite instability (MSI)-high metastatic colorectal cancer (CRC). The results, presented at the 2025 European Society for Medical Oncology (ESMO) Congress and simultaneously published in *The Lancet*, signal a potential shift in the treatment paradigm for this challenging cancer.

The STELLAR-303 trial met one of its dual primary endpoints, demonstrating a 20% reduction in the risk of death with the combination therapy in the intention-to-treat (ITT) population (stratified hazard ratio [HR]: 0.80; 95% confidence interval [CI]: 0.69-0.93; P=0.0045). With a median follow-up of 18.0 months, median overall survival (OS) in the ITT population reached 10.9 months with the zanzalintinib-atezolizumab combination, compared to 9.4 months with regorafenib.

“The combination of zanzalintinib and atezolizumab has shown consistent benefits across key subgroups of patients,” said Anwaar Saeed, M.D., Section Chief of Gastrointestinal Oncology at the University of Pittsburgh, Director of the Gastrointestinal Disease Center at UPMC Hillman Cancer Center and a lead investigator of the trial. “STELLAR-303 is the first immunotherapy-based phase 3 trial that demonstrated improved overall survival with a differentiated kinase inhibitor compared to a standard of care in this patient population.”

The observed OS benefit with the combination therapy remained consistent across pre-specified subgroups, including geographic region, *RAS* status, liver involvement, and prior anti-VEGF therapy. Landmark OS estimates at 12 and 24 months further underscored the potential of the combination, with 46% (95% CI: 41-51) and 20% (95% CI: 15-26) survival rates, respectively, for zanzalintinib plus atezolizumab, compared to 38% (95% CI: 34-43) and 10% (95% CI: 6-16) for regorafenib.

While the data for the other dual primary endpoint, OS in patients without liver metastases (NLM), remains immature, an interim analysis revealed a promising trend favoring the combination (15.9 months versus 12.8 months; stratified HR: 0.79; 95% CI: 0.61-1.03; P=0.0875), with a median follow-up of 16.8 months. The trial is ongoing and will proceed to the planned final analysis for this endpoint.

“These detailed results from STELLAR-303 offer valuable insights into the potential of the zanzalintinib and atezolizumab combination as a novel approach to improve survival in patients with previously treated metastatic colorectal cancer,” stated Dana T. Aftab, Ph.D., Executive Vice President, Research and Development, Exelixis. “We anticipate completing the submission of our first new drug application for zanzalintinib before the end of this year, as we strive to introduce this combination regimen to a patient population in need of a new and chemotherapy-free option. These data, together with our robust clinical trial program, highlight the advancements we are making toward expanding the range of solid tumor types that zanzalintinib may effectively target.”

In the ITT population, a trend toward improvement in progression-free survival (PFS) was also observed with the combination therapy (stratified HR: 0.68 [95% CI: 0.59–0.79]; median, 3.7 [95% CI: 3.5–3.8] months versus 2.0 [95% CI: 1.9–2.6] months). However, statistical superiority has not yet been established due to the prespecified hierarchical testing strategy.

The safety profiles of the zanzalintinib-atezolizumab combination and regorafenib were consistent with prior observations, and no new safety signals were identified. Grade 3/4 treatment-related adverse events (AEs) were reported in 59% of patients receiving the combination therapy and 37% of those receiving regorafenib. AEs leading to discontinuation of all study treatment occurred in 18% and 15% of patients, respectively.

**Investment Considerations:**

The positive results from the STELLAR-303 trial represent a significant milestone for Exelixis and could potentially drive shareholder value. While further analysis and regulatory review are necessary, the data suggest that zanzalintinib, in combination with atezolizumab, could become a valuable treatment option for patients with previously treated metastatic CRC.

However, investors should be aware of the risks associated with pharmaceutical development, including the possibility of unexpected safety issues, regulatory setbacks, and market competition. The outcome of the planned final analysis for OS in patients without liver metastases will also be crucial in determining the ultimate commercial potential of zanzalintinib.

**About Zanzalintinib:**

Zanzalintinib is an investigational oral kinase inhibitor targeting TAM kinases (TYRO3, AXL, MER), MET, and VEGF receptors. These kinases play pivotal roles in tumor cell proliferation, metastasis, angiogenesis, drug resistance, and evasion of antitumor immunity.

**About CRC:**

Colorectal cancer (CRC) is a major public health concern, ranking as the third most common cancer and the second leading cause of cancer-related deaths in the U.S.

**About Exelixis:**

Exelixis, Inc. is an oncology-focused biotechnology company dedicated to developing innovative medicines for cancer treatment.

Exelixis, the Exelixis logo and CABOMETYX are registered U.S. trademarks of Exelixis.

TECENTRIQ is a registered U.S. trademark of Genentech, a member of the Roche Group.