UNC Lineberger Comprehensive Cancer Center researchers have demonstrated that combining two immunotherapy drugs with a targeted therapy drug proved effective in treating the most common form of metastatic colorectal cancer. In some cases, it produced a durable response, even in patients whose cancer had spread to the liver.
The study’s findings are published in JCO Oncology Advances.
Hanna Sanoff, MD, MPH, professor of medicine and gastrointestinal cancer section chief at UNC School of Medicine and UNC Lineberger, is the study’s corresponding author. Ashwin Somasundaram, MD, assistant professor at the UNC School of Medicine and UNC Lineberger, is the first author.
“Our research provides the rationale for better combination trials in the future for our many patients with colorectal cancer,” Sanoff said. “We hope some of these studies can keep their disease at bay for many years.”
The researchers enrolled 56 patients in a phase 2 clinical trial to evaluate whether a three-drug combination—ipilimumab, nivolumab, and panitumumab—would be effective against microsatellite stable metastatic colorectal cancer. The study’s primary objective was the overall response to treatment after 12 weeks.
The combination therapy shrank the tumors in 18 of 56 (32.1%) patients and produced a median survival of 17.4 months. Four patients, including two with liver metastases, experienced no cancer progression nearly 44 months after starting the trial. Seven withdrew from the study after their cancer progressed.
“Even patients with liver metastatic disease, which traditionally have not had durable responses, responded well to the intervention,” Somasundaram said. “This is a really promising sign that this combination might be more effective than immunotherapy combinations alone.”
Panitumumab, a monoclonal antibody that targets and blocks EGFR, a cellular growth protein, has been the standard therapy for microsatellite stable metastatic colorectal cancer. Unfortunately, it has been only modestly effective when used alone. However, tumors responding to EGFR inhibitors have increased T-cell infiltration and higher levels of CTLA-4 and PD-L1, immune checkpoint proteins.
Prior studies have shown that CTLA-4 and PD-L1 prevent the immune system from overreacting and targeting healthy tissues. These proteins can also disrupt immune T-cells from attacking cancer cells. Ipilimumab and nivolumab block CTLA-4 and PD-L1, respectively, releasing the immune system’s “brakes” and enabling T-cells to target cancer cells.
Somasundaram and his colleagues hypothesized that combining panitumumab with ipilimumab and nivolumab would be an effective treatment regimen. Findings from their trial support the hypothesis.
“Most patients with this disease do not have durable responses that last for years, but our study demonstrated that this combination did have that effect in a small number of patients,” Somasundaram said. “While few in number, without this study, they would not have had that benefit.
“These findings certainly support similar combinations in the future, and groups across the country are looking into similar studies.”
The research was supported by funding from the National Cancer Institute, Amgen and Bristol Meyers-Squibb.
Authors and disclosures
A complete listing of authors and disclosures is available in the published paper.