Zanzalintinib Combined with Atezolizumab Shows Survival Advantage Over Regorafenib in Metastatic Colorectal Cancer Trial

Landmark STELLAR-303 Study Delivers Positive Results for Advanced Cancer Treatment

The STELLAR-303 phase 3 clinical trial has yielded encouraging findings for patients battling advanced colorectal cancer. The study evaluated whether zanzalintinib, when used alongside atezolizumab (Tecentriq®), could improve outcomes compared to regorafenib—a standard treatment option. Results from the final analysis conducted by an independent monitoring committee reveal that the zanzalintinib-atezolizumab combination achieved a statistically meaningful reduction in mortality risk across all enrolled patients with previously treated, non-MSI-high metastatic colorectal cancer.

Understanding the Trial Design and Patient Population

The STELLAR-303 investigation enrolled 901 patients across multiple international sites, with participants randomly assigned 1:1 to receive either zanzalintinib (100 mg) combined with atezolizumab or regorafenib monotherapy. The trial was designed to evaluate two distinct patient populations: all randomized patients regardless of liver metastases presence, and a subgroup of patients without active liver involvement at baseline.

The primary endpoints of the study centered on overall survival measured in both the intent-to-treat population and in patients without liver metastases. Secondary efficacy measures included progression-free survival, objective response rates, and duration of clinical benefit in each population segment. Patient stratification by liver metastasis status reflects an important clinical reality: approximately one-quarter of metastatic colorectal cancers present with liver involvement, which significantly impacts long-term survival prognosis.

Clinical Context: Why This Trial Matters

Colorectal cancer represents a substantial public health burden, ranking as the third most prevalent malignancy and second leading cause of cancer mortality in the United States. Approximately 154,000 new diagnoses are anticipated in 2025, with around 53,000 estimated deaths from the disease. The disease disproportionately affects individuals aged 65 to 74 years and occurs more frequently in men and among non-Hispanic American Indian/Alaska Native populations.

The metastatic stage presents particular challenges for patients and clinicians. Nearly 25% of colorectal cancers are identified when distant spread has already occurred, at which point the five-year survival rate drops to just 16.2%. When metastases establish in the liver—the most frequent site of dissemination—median survival becomes even more constrained, with palliative chemotherapy yielding less than 14% five-year survival rates.

The Mechanism Behind Zanzalintinib

Zanzalintinib functions as a third-generation oral tyrosine kinase inhibitor that suppresses multiple receptor pathways implicated in cancer progression and treatment resistance. Specifically, it blocks VEGF receptors, MET, AXL, and MER—molecular targets involved in tumor growth, blood vessel formation, metastatic spread, and resistance to immunotherapy agents like checkpoint inhibitors.

The drug was developed to leverage Exelixis’ extensive experience with cabozantinib, the company’s established oncology medication, while incorporating pharmacokinetic improvements aimed at optimizing therapeutic delivery. Beyond colorectal cancer, zanzalintinib is being investigated across additional solid tumors including renal cell carcinoma, head and neck malignancies, and neuroendocrine neoplasms.

Safety and Next Steps

Both the zanzalintinib-atezolizumab combination and regorafenib demonstrated safety profiles consistent with historical experience in clinical trials. No novel safety signals emerged during the STELLAR-303 analysis. The trial will proceed toward analyzing the second primary endpoint—overall survival benefit in patients without liver metastases at baseline.

Exelixis intends to present comprehensive trial data at an upcoming medical conference and engage with regulatory authorities regarding the findings. The company continues advancing its broader pipeline of small molecule inhibitors, antibody-drug conjugate therapies, and other biotherapeutic approaches targeting diverse tumor types and clinical indications.