A clinical trial, led by researchers at UPMC Hillman Cancer Center, is the first to show that an immunotherapy-based, chemotherapy-free treatment can extend the lives of people with metastatic colorectal cancer who have exhausted prior standard chemotherapy options.
The results of the phase 3 trial, presented Oct. 20, 2025 at the European Society for Medical Oncology annual meeting in Berlin and simultaneously published in The Lancet, represent a major advancement in therapy for a type of cancer that is fatal within five years for 85% of those with the diagnosis.
“Colorectal cancer is a common malignancy that is typically resistant to treatment when diagnosed in later stages and after previous therapies, so this is a great win,” said presenter and senior author Anwaar Saeed, associate professor of medicine, School of Medicine; chief of the Gastrointestinal Medical Oncology Program and director of the Gastrointestinal Disease Center at UPMC Hillman Cancer Center. “Previous immunotherapy trials with other targeted agents in this patient population have failed in phase 3 trials. Our trial results offer hope for our patients in a field filled with devastating losses.”
Saeed is a lead investigator of the STELLAR-303 clinical trial, which randomized patients whose metastatic colorectal cancer had progressed following previous treatment with at least two different standard chemotherapy regimens.
The participants received either standard-of-care treatment with an approved drug called regorafenib or an investigational immunotherapy-based regimen that combines atezolizumab, an established immune checkpoint inhibitor, with an experimental drug called zanzalintinib, which blocks key signals that tumors use to grow and form new blood vessels while also helping the immune system detect cancer cells. When used in combination, these drugs “take the brakes off” the immune system, enabling it to better recognize and attack cancer.
Patients at 121 sites in 16 countries enrolled in the STELLAR-303 trial. Between Sept. 7, 2022, and July 15, 2024, 901 patients were randomized to receive standard-of-care or the combination therapy.
Trial participants who received the combination therapy had a 20% reduction in risk of death compared to standard-of-care, with an overall survival of 10.9 months for the zanzalintinib-atezolizumab combination participants compared to 9.4 months in the standard-of-care group. The most common side effects were high blood pressure, high levels of protein in the urine, fatigue and diarrhea, and were consistent with those seen in similar cancer therapies.
Importantly, survival benefit—the improvement in survival rates of patients receiving an experimental treatment compared to the control group—appeared early in the patients receiving the combination therapy compared to the patients who received standard-of-care and remained consistent throughout the trial.
“That early and sustained benefit gives us confidence that this approach can make a real difference for patients,” added Saeed, whose prior work leading the CAMILLA and STELLAR-001 trials laid the groundwork for the pivotal STELLAR-303 study. “It’s incredibly gratifying to see years of bench-to-bedside research finally translating into clinical progress for patients.”
Looking ahead, Saeed noted that future studies will likely explore whether this immunotherapy-based combination could be used earlier in treatment—potentially offering a more convenient and effective option for patients newly diagnosed with advanced colorectal cancer.
Additional authors of this research and their disclosures are listed in The Lancet.
This study was sponsored by Exelixis, Inc., which develops zanzalintinib. Roche provided atezolizumab.
Media contact: HSNews@pitt.edu