Exelixis and Natera Launch Phase 3 Trial Testing Zanzalintinib in MRD-Positive Colorectal Cancer Patients
Key Insights
Exelixis and Natera announced collaboration on STELLAR-316, a phase 3 pivotal trial evaluating zanzalintinib in patients with resected stage II/III colorectal cancer (search) who test positive for molecular residual disease (MRD).
The trial will use Natera's Signatera assay to identify MRD-positive patients for enrollment and monitor response to therapy, targeting approximately 20% of stage II/III CRC patients who remain MRD-positive after definitive therapy.
If successful, zanzalintinib could become the first MRD-guided treatment for this high-risk patient population, addressing a significant unmet medical need with no currently approved therapies.
Exelixis and Natera have announced a strategic collaboration on STELLAR-316, a randomized phase 3 pivotal trial that will evaluate zanzalintinib, Exelixis' novel oral kinase inhibitor, with and without an immune checkpoint inhibitor in patients with resected stage II/III colorectal cancer (search) (CRC). The trial represents a precision medicine approach, using Natera's Signatera test to identify patients with molecular residual disease (MRD) for enrollment.
Targeting High-Risk MRD-Positive Patients
The STELLAR-316 trial will enroll patients who test positive for MRD using Natera's Signatera assay following completion of definitive therapy and have no radiographic evidence of disease. This approach targets a specific high-risk population, as approximately 20% of the 89,000 stage II/III colorectal cancer (search) cases projected for 2035 are expected to remain MRD-positive following definitive therapy.
"Patients with colorectal cancer (search) who are MRD-positive following definitive therapy face a high risk of recurrence, underscoring the urgent need for new treatment options that can help prevent clinical metastatic progression," said Dana T. Aftab, Ph.D., Executive Vice President, Research and Development at Exelixis.
The primary endpoint of STELLAR-316 is disease-free survival, with Signatera also being used for longitudinal monitoring of circulating tumor DNA clearance as one of the secondary endpoints. Exelixis expects to initiate the trial in mid-2026.
Addressing Unmet Medical Need
Patients with stage II/III CRC who are MRD-positive have been shown to experience worse outcomes in multiple clinical studies, yet there are no established or approved therapies for this specific patient population in the United States. The collaboration aims to address this gap by potentially making zanzalintinib the first MRD-guided treatment for these patients.
"STELLAR-316 is our second pivotal trial of zanzalintinib in patients with CRC and represents our continued commitment to addressing unmet needs in this patient population by conducting rigorous trials with the potential to improve standards of care," Aftab added.
Zanzalintinib's Mechanism and Development
Zanzalintinib is a novel oral kinase inhibitor that inhibits the activity of the TAM kinases (TYRO3 (search), AXL (search), MER (search)), MET and VEGF (search) receptors. These kinases play important roles in oncogenic processes including tumor cell proliferation, metastasis, angiogenesis, drug resistance and evasion of antitumor immunity. Exelixis designed zanzalintinib to build upon its extensive experience with cabozantinib while improving key characteristics, including pharmacokinetic half-life.
The company recently submitted a New Drug Application to the U.S. Food & Drug Administration for zanzalintinib in combination with atezolizumab for previously treated metastatic colorectal cancer (search), based on positive results from the phase 3 STELLAR-303 pivotal trial.
Supporting Evidence for MRD-Guided Treatment
The collaboration is supported by recent data published in JAMA Oncology from the randomized, phase III CALGB (Alliance)/SWOG 80702 study, which assessed the predictive value of postoperative personalized circulating tumor DNA in patients with stage III colorectal cancer (search). The study included 940 patients with available post-surgical plasma samples who were randomized to receive FOLFOX (search) with or without celecoxib.
Key findings showed that adding celecoxib to conventional chemotherapy in Signatera-positive patients reduced the risk of cancer recurrence and death by approximately 40%. Celecoxib improved disease-free survival (adjusted HR=0.61, 95% CI 0.42-0.89; 3-year 41.0% vs. 22.6%) and overall survival (adjusted HR=0.62, 95% CI 0.40-0.96; 5-year: 61.6% vs. 39.9%) compared to placebo in Signatera-positive patients, while no benefit was observed in Signatera-negative patients.
Strategic Partnership Benefits
"Exelixis and Natera's collaboration on STELLAR-316 underscores both companies' commitment to advancing new approaches to treat CRC," said John Simmons, Ph.D., Global Vice President, Biopharma at Natera. "Leveraging Signatera to inform trial enrollment will help to identify high-risk patients earlier, enabling intervention when disease burden is lower – and importantly, with the potential to improve clinical outcomes."
The trial will be fully enrolled with patients who are receiving commercial Signatera testing as part of their routine standard of care, working directly with patients and their providers to streamline enrollment and ensure real-world applicability of the results.