Exelixis Reports Positive Phase 3 Results for Zanzalintinib and Atezolizumab Combo in Metastatic Colorectal Cancer
Exelixis, has announced promising topline results from the STELLAR-303 phase 3 pivotal clinical trial, a major milestone in the development of its investigational therapy zanzalintinib. The trial assessed the combination of zanzalintinib, a next-generation tyrosine kinase inhibitor (TKI), with the immune checkpoint inhibitor atezolizumab (marketed as Tecentriq® by Genentech/Roche), in patients with previously treated metastatic colorectal cancer (mCRC) that is not characterized by high microsatellite instability (MSI-high). According to the final analysis conducted by an independent data monitoring committee, the combination significantly improved overall survival (OS) compared to the current standard of care, regorafenib, in the intent-to-treat (ITT) population.
A Significant Milestone for Zanzalintinib
The STELLAR-303 trial represents the first pivotal phase 3 study to read out in the development program for zanzalintinib, a novel compound that has shown promise across various tumor types. The trial enrolled patients with metastatic colorectal cancer who had previously received standard treatment and whose disease had progressed. Importantly, these were patients whose tumors were not MSI-high — a population for whom therapeutic options remain limited and outcomes are typically poor.
Zanzalintinib, when combined with atezolizumab, met one of the dual primary endpoints of the study by demonstrating a statistically significant overall survival benefit in the ITT population. The ITT cohort included all randomized patients, regardless of baseline liver metastasis status. A second primary endpoint — overall survival among patients without liver metastases (referred to as the non-liver metastasis or NLM subgroup) — will be evaluated in a planned final analysis that is still to come.
Context: Why This Matters
Colorectal cancer remains a major public health challenge worldwide, ranking as the third most commonly diagnosed cancer and the second leading cause of cancer-related death globally. For patients with metastatic CRC who have progressed on standard therapies such as fluoropyrimidines, oxaliplatin, irinotecan, anti-VEGF agents, and anti-EGFR monoclonal antibodies (if applicable), treatment options are often limited to regorafenib or trifluridine/tipiracil. These therapies offer only modest benefits and are often associated with challenging side effects.
Adding immunotherapy to the mix has proven transformative for several cancer types, but checkpoint inhibitors have had limited success in microsatellite-stable (MSS) CRC. This has driven strong interest in combination approaches, particularly those that may help make the tumor microenvironment more amenable to immune-mediated attack.
Zanzalintinib, with its potent inhibition of multiple kinases including MET, VEGFR, AXL, and others, has the potential to alter the tumor vasculature and microenvironment, potentially enhancing the efficacy of immunotherapy such as atezolizumab. The encouraging survival benefit seen in the STELLAR-303 study may signal a path forward for patients with MSS metastatic colorectal cancer — a group that currently faces an unmet need.
Detailed Findings and Next Steps
While detailed data on secondary endpoints and subgroup analyses have not yet been released, Exelixis confirmed that the combination therapy’s safety profile was consistent with previously known data. No new safety signals were identified during the study. Both the zanzalintinib plus atezolizumab regimen and the regorafenib comparator arm demonstrated tolerability in line with their established profiles.
In addition to overall survival, secondary endpoints in the STELLAR-303 trial include progression-free survival (PFS), objective response rate (ORR), and duration of response (DoR) — evaluated in both the ITT population and the NLM subgroup. These metrics are critical in understanding how the combination therapy may influence not just survival but disease control and tumor shrinkage over time.
Exelixis stated that it plans to present the full dataset, including secondary and exploratory endpoints, at an upcoming major medical conference. Such a presentation would likely occur at a high-profile oncology meeting such as the European Society for Medical Oncology (ESMO) or the American Society of Clinical Oncology (ASCO).
Regulatory Implications
Given the statistically significant improvement in overall survival demonstrated in the ITT population, the STELLAR-303 results could potentially serve as the basis for a regulatory submission. Exelixis has indicated that it will engage with regulatory agencies in the near future to discuss next steps, which could include seeking accelerated or full approval for the combination of zanzalintinib and atezolizumab in this setting.
Amy Peterson, M.D., Executive Vice President of Product Development & Medical Affairs and Chief Medical Officer at Exelixis, emphasized the significance of this milestone:
“The STELLAR-303 results, which showed a survival benefit with the combination of zanzalintinib and atezolizumab versus regorafenib across all randomized patients with previously treated metastatic colorectal cancer, marks an important first milestone for our zanzalintinib pivotal development program,” she said. “We look forward to discussing the findings with regulatory authorities and presenting the detailed results at an upcoming medical conference.”
Building on the STELLAR Clinical Program
The STELLAR-303 trial is part of a broader clinical development strategy for zanzalintinib, which Exelixis is evaluating in multiple tumor types. As an investigational agent, zanzalintinib builds upon the company’s experience with cabozantinib (Cabometyx®), a multi-kinase inhibitor already approved for the treatment of renal cell carcinoma, hepatocellular carcinoma, and medullary thyroid cancer.
Zanzalintinib was designed with enhanced potency and selectivity, aiming to provide better efficacy and tolerability than earlier-generation TKIs. Its role as a potential immunotherapy sensitizer makes it particularly attractive in the era of combination oncology regimens.
Beyond STELLAR-303, Exelixis is also conducting additional studies of zanzalintinib in combination with checkpoint inhibitors across other tumor types under the broader STELLAR program, which includes both monotherapy and combination therapy trials.
The Path Forward
As the oncology field increasingly embraces biomarker-driven and immune-based treatment strategies, the success of STELLAR-303 signals a meaningful advance. If further data from the NLM subgroup confirm the survival benefit in patients without liver metastases, and if secondary endpoints support a favorable risk-benefit profile, the combination could become a new standard for patients with MSS metastatic colorectal cancer who have exhausted other options.
Pending discussions with regulators and full data presentations, the oncology community will be watching closely to see whether this combination can help reshape treatment paradigms for a historically hard-to-treat patient population.
The STELLAR-303 trial’s positive outcome positions Exelixis’ zanzalintinib, in partnership with atezolizumab, as a potentially game-changing therapeutic approach in the second- or third-line setting for metastatic colorectal cancer. The demonstrated improvement in overall survival across the full trial population reflects the potential of rationally designed combination regimens to break through longstanding therapeutic barriers. While more detailed clinical data are still forthcoming, the topline results already suggest a significant step forward — not just for Exelixis’ pipeline, but for patients seeking renewed hope in the fight against advanced colorectal cancer.
