Landmark Trial: immunotherapy Combination Substantially Extends survival for Advanced Colorectal Cancer
A novel combination of targeted therapy and immunotherapy has demonstrated a notable advancement in survival rates for patients with metastatic colorectal cancer, offering a beacon of hope for a population with historically limited treatment options. The findings, concurrently published in The Lancet and presented at the European Society for Medical Oncology Congress (ESMO 2025), represent the first time an immunotherapy-based regimen has shown a clear survival benefit for the vast majority of individuals battling this deadly disease.
Metastatic colorectal cancer, the second leading cause of cancer death in the United States, affects approximately 150,000 peopel each year. While immunotherapy has revolutionized cancer treatment, its effectiveness has been largely confined to patients whose tumors exhibit specific genetic markers, MSI-H or dMMR. The remaining 95% have not experienced the same benefits, creating a critical need for new therapeutic strategies.
Researchers, led by Dr. J.Randolph Hecht of the David Geffen School of Medicine at UCLA, focused on overcoming this limitation. They investigated the potential of combining zanzalintinib, a targeted therapy designed to disrupt tumor growth and suppress immune responses, with atezolizumab, an immune checkpoint inhibitor. “This study represents an significant step forward for a group of patients who have historically had very few treatment options,” stated dr. Hecht.”We may finally be finding ways to make immunotherapy work for more patients with colorectal cancer.”
The team hypothesized that zanzalintinib could “prime” tumors, making them more susceptible to attack by the immune system.The drug targets key proteins – VEGFR,MET,and TAM kinases – that contribute to tumor advancement and immune suppression. By blocking these pathways, zanzalintinib aims to create a more favorable environment for immunotherapy to function effectively.
To test this hypothesis, the researchers launched the international Phase 3 STELLAR-303 trial, enrolling 901 patients from 121 sites across 16 countries. Participants, all with previously treated metastatic colorectal cancer, were randomly assigned to receive either the zanzalintinib and atezolizumab combination or the standard treatment, regorafenib.
After approximately 18 months of follow-up, the results were compelling. Patients receiving the combination therapy lived a median of 10.9 months, compared to 9.4 months for those on regorafenib – a roughly 20% reduction in the risk of death. Notably, 20% of patients on the combination were still alive after two years, double the rate observed in the regorafenib group.
“The survival benefit was seen across all major subgroups, including patients whose cancer had spread to the liver, a group that typically doesn’t respond well to immunotherapy,” explained Dr. hecht, who is also a member of the UCLA Health Jonsson Extensive Cancer Center and director of the UCLA Gastrointestinal Oncology Program.”We think that’s as zanzalintinib, which blocks multiple growth and immune-suppressing pathways, helps create a tumor environment that’s more receptive to immune attack.”
Beyond extending overall survival,the combination therapy also demonstrated improvements in disease control. Tumors took longer to grow or spread (median 3.7 months vs. 2.0 months), and a higher percentage of patients experienced tumor shrinkage (4% vs. 1%).
Importantly, the side effects associated with the combination were manageable and consistent with those expected from the individual drugs, including fatigue, high blood pressure, and diarrhea. “These results show that zanzalintinib plus atezolizumab is a promising new therapy option and could redefine how we approach care for patients whose disease no longer responds to standard therapies,” Dr.Hecht concluded.
The full study details are available in The Lancet: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)02025-2/abstract. This breakthrough offers renewed hope for individuals facing a challenging diagnosis and signals a potential paradigm shift in the treatment of metastatic colorectal cancer.
