Chemotherapy-Free, Immunotherapy-Based Treatment – First of its Kind – Improves Survival for Patients with Colorectal Cancer

PITTSBURGH – A clinical trial, led by 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 today 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, M.D., section chief of Gastrointestinal Oncology at the University of Pittsburgh and director of the Gastrointestinal Disease Center at UPMC Hillman Cancer Center. “Previous combination immunotherapy trials using 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 or a new immunotherapy-based combination that combines 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 with atezolizumab, an established immune checkpoint inhibitor, 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 trial. Between September 7, 2022 and July 15, 2024, 901 patients were randomized to receive standard-of-care – an approved drug called regorafenib that can inhibit tumor growth – or the new combination therapy. 

Trial participants who received the new 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 combination therapy compared to the standard-of-care patients and stayed 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.”

Next steps involve applying for approval of zanzalintinib-atezolizumab regimen by the U.S. Food and Drug Administration so that it can be prescribed to patients outside of a clinical trial, something that Exelixis, the company that makes zanzalintinib, has announced it plans to do. 

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, which makes zanzalintinib. Roche provided atezolizumab. 

PHOTO DETAILS: click image for high-res version

Caption: Anwaar Saeed, M.D., section chief of Gastrointestinal Oncology at the University of Pittsburgh and director of the Gastrointestinal Disease Center at UPMC Hillman Cancer Center

Credit: UPMC