Researchers from the SWOG Cancer Research Network, a group of clinical trials funded by the National Cancer Institute (NCI), part of the National Institutes of Health, have shown that the triple combination of drugs – irinotecan, cetuximab and vemurafenib – is a more powerful tumor fighter with metastatic colon cancer free for a significantly longer period of time compared to patients treated with irinotecan and cetuximab.
Results of the SWOG study led by dr. Scott Kopetz, Ph.D. Med. Anderson Center for Cancer, were published in Journal of Clinical Oncology. The findings are expected to change the standard of care for patients with colon cancer that is metastatic – when tumors spread to other parts of the body – and involves a mutation in a BRAF gene called the V600E. This mutation is found in about 10 percent of metastatic colon and bowel cancers, and tumors with the mutation rarely respond to treatment, resulting in a poor prognosis for patients.
Kopetz is an expert in the science of BRAF-mutated colorectal cancer and has tested a number of combination therapies for its treatment, including conducting the BEACON trial. This phase III study showed that two targeted drugs – cetuximab and encoraphenib – significantly reduced tumors and helped patients live longer than those receiving standard treatment. These results came to prominence last year when they were simultaneously published in the New England Journal of Medicine and presented at the annual meeting of the European Society of Medical Oncology.
In their SWOG study, S1406, Kopetz and his team also looked at combination therapy to see what might work best. In this trial, 106 patients whose metastatic colon cancer included the fatal V600E mutation were tested. All patients were previously treated with chemotherapy and their cancer did not respond. The team randomly assigned study participants to one of two treatment groups – those who received irinotecan and cetuximab and those who received this combination with a third drug, vemurafenib.
The SWOG team found that patients who received the triple combination had a better rate of tumor response to the drug – 17 percent compared to 4 percent – and remained cancer-free for longer. At the molecular level, Kopetz said, here’s how the triplet works: Irinotecan, a traditional chemotherapy drug, kills cancer cells. Cetuximab, a monoclonal antibody, is a targeted drug that blocks the growth of cancer by blocking the action of a protein called the epidermal growth factor receptor, or EGFR. Kopetz says vemurafenib, a BRAF inhibitor and other targeted therapy, directly attacks the BRAF protein, further slowing tumor growth.
“That 1-2-3 action, that triple threat, precludes a powerful growth pathway in these cancers,” Kopetz said. “In this experiment, unlike BEACON, we added chemotherapy and found that it provided a more effective way to treat this aggressive form of colon cancer.”
Another intriguing finding: an 87 percent decrease in circulating tumor DNA (ctDNA) allele frequency of the BRAFV600E variant in patients receiving all three drugs, compared with a decrease in ctDNA in patients receiving a combination of the two drugs. Kopetz said this is strong evidence that measuring the presence of ctDNA can be an effective way to measure short-term response to treatment. And it could be as easy as drawing blood, using a test known as a liquid biopsy.
The results of the SWOG study will be accompanied by an editorial in the JCO in January 2021.
The Kopetz study was supported by the National Institutes of Health through the National Cancer Institute Awards CA180888, CA180819, CA180820, CA180821, CA180868, CA189821, CA187238, CA180834, CA180826, CA189858, CA180801, CA1808 , CA189830, CA189809, CA180830; and in part The Hope Cancer Research Foundation, Guardant Health, and Genentech, a member of the Roche Group.
Kopetz’s SWOG team includes Dr. Katherine A. Guthrie, of the SWOG Center for Statistics and Data Management at the Fred Hutchinson Cancer Research Center; Van K. Morris, Ph.D. Med., Dr. Anderson, Cancer Center; Heinz-Josef Lenz, Ph.D. Med., Of Keck University School of Medicine, Southern California; Anthony M. Magliocco, Ph.D. Med., Formerly of the Moffitt Cancer Center, and now of Protean BioDiagnostics; Dipen Maru, Ph.D. Med., With dr. Anderson, Cancer Center; Yibing Yan, Ph.D. From Genentech, dr. Richard Lanman of Guardant Health; Dr. They honor Manyam, dr. Med. Anderson, Cancer Center; David Hong, Ph.D. Med., Dr. Med. Anderson, Cancer Center; Dr. Alexei Sorokin, Ph.D. Med. Anderson, Cancer Center; Chloe E. Atreya, Ph.D. Med., From the UCSF Comprehensive Cancer Center Helen Diller; Luis A. Diaz, Ph.D. Med., From the Memorial Sloan Kettering Cancer Center; Carmen Allegra, Ph.D. Med., From the Cancer Assessment Therapy Program at the National Cancer Institute; Kanwal P. Raghav, MBBS, dr. Med., At MD Anderson Cancer Center; Stephen E. Wang, Ph.D. Med., From Kaiser Permanente South Sacramento Medical Center; Christopher H. Lieu, Ph.D. Med., Of the University of Colorado Denver; Shannon L. McDonough, MS, of the SWOG Center for Statistics and Data Management at the Fred Hutchinson Institute of Cancer; Philip A. Philip, Ph.D. Med., From the Barbara Ann Karmanos Cancer Institute; and Howard S. Hochster, Ph.D. med., from the Rutgers Cancer Institute in New Jersey.
The SWOG Cancer Research Network is part of the National Cancer Research Network of the National Cancer Institute and the NCI Community Oncology Research Program and is part of the oldest and largest state-funded cancer research network in the country. SWOG has nearly 12,000 members in 47 states and six foreign countries who design and conduct clinical trials to improve the lives of people with cancer. SWOG trials have led to the approval of 14 anti-cancer drugs, changed more than 100 cancer treatment standards and saved more than 3 million years of human life. Learn more at swog.org.