New combination therapy for colorectal cancer, with University of Pittsburgh Medical Center involvement, lengthens survival

Many cancer types — breast, prostate, skin cancer — have 5-year survival rates and ample treatment options if caught early.

Colorectal cancer is not one of them.

With a 5-year survival rate of 15% once it's spread, colorectal cancer kills around 2,600 Pennsylvania each year. In Allegheny County, around 160 people died from the disease between 2019 and 2023, per state data.

A new cancer combination therapy could provide a path forward. In a phase 3 clinical trial, the therapy showed success in reducing the risk of death by 20%. With UPMC Hillman Cancer Center involvement, it's the first phase 3 trial to show clinically meaningful improvements in survival for patients with metastatic colorectal cancer.

Experts say the findings are a beacon of hope for cancer patients — especially those seeking an alternative to chemotherapy — who have been waiting for advancements in the field and a wider treatment array.

"This patient population right now, in the current paradigm of therapy, we don't have a lot of really good options that would provide significant outcomes," said Anwaar Saeed, section chief of gastrointestinal oncology at the University of Pittsburgh, director of the Gastrointestinal Disease Center at UPMC Hillman Cancer Center, and senior author on a paper about the trial's results, published last month in The Lancet.

The study built on previous research, said Saeed — both from animal models and phase 1 trial results — that showed the combination therapy worked better than either of the drugs alone.

Recruiting 900-some participants with metastatic colorectal cancers who had tried multiple kinds of treatment, patients for the trial, known as STELLAR-303, came from around the world, representing 16 countries and 121 health centers. Patients were randomly assigned either the drug combination of zanzalintinib — atezolizumab or regorafenib and tracked over an 18-month period.

Regorafenib is considered a gold-standard treatment for colorectal cancer, making it the ideal "control" group for the study and ensuring cancer patients received treatment during the length of the trial. The drug works by stopping signaling of kinases, a type of protein in the body that helps cancer cells survive and grow.

In previous research, scientists found that patients had better outcomes if these kinase inhibitors were paired with cancer immunotherapy drugs. For the STELLAR-303 trial, they paired a new kinase-blocking drug, zanzalintinib, with the immunotherapy drug atezolizumab, which helps the immune system recognize and target cancer. These patients lived a little more than a month longer than patients taking regorafenib.

John Marshall, director of the Ruesch Center for the Cure of GI Cancers and chief medical officer of the Lombardi Comprehensive Cancer Center at Georgetown University Medical Center, said those in the cancer space have been waiting for the results of this study for a while.

"This is significant," he said. "It will likely result in approval and shifting our approach to using immune therapies" in this cancer type — which has not, in the past, responded well to immunotherapy. Marshall, who is the chief medical consultant for the Colorectal Cancer Alliance, was not involved in the study.

Exelixis, the California-based and cancer-focused biotech company that created zanzalintinib and sponsored the clinical trial, said in an Oct. 20 news release that the results signify progress toward increasing the scope and scale of the types of tumors zanzalintinib can effectively target.

"Before the end of this year, we intend to complete the submission of our first new drug application for zanzalintinib as we work toward bringing this combination regimen to a patient community seeking a new and chemotherapy-free option," said Dana T. Aftab, executive vice president of research and development at Exelixis, in the release.

The drug combination was deemed as having manageable toxicity in the trial results. According to the study, 1 in 5 patients taking the combination therapy reported experiencing a serious adverse event associated with the drug, compared to 1 in 10 in the regorafenib group. The most common side effects were diarrhea, high blood pressure, fatigue, nausea and decreased appetite.

Five patients were listed as having died due to treatment-related causes.

Marshall said that's not uncommon for patients with this advanced cancer type, who typically are very sick.

The trial's results were in line with what Saeed expected to see, she said, as she was validated by successes in earlier phases of the trial — something that does not always happen in cancer research.

"It was very gratifying," she said.

Marshall hopes more details can be drawn out with additional research so clinicians can learn why certain patients benefit from the treatment more than others and which patients will be the best candidates.

As a whole, he said any forward movement for colorectal cancer survival is positive.

"I think we are going to see an increased interest in immunotherapy for colon cancer as a result of this study," he said.

The next step, said Saeed, is to submit an application for drug approval with the Food and Drug Administration, and, ultimately, make the drug available to patients outside the clinical trial setting.

"We are thinking about developing the next generation of clinical trials and exploring this treatment in earlier stages of disease," she said. They also plan to look at patients with liver metastasis: This trial was restricted to patients who did not have cancer that spread to the liver, because of the potential side effects of zanzalintinib on the organ.

"Metastatic colorectal cancer is considered a major global health challenge," said Saeed. "The success of this is telling us there is a potential that we can change that trajectory."

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