IMAGE: Scott Kopetz, MD, of the SWOG Cancer Research Network perspective more
Credit: SWOG Cancer Research Network
Researchers from the SWOG Cancer Research Network, a cancer clinical trial group funded by the National Cancer Institute (NCI), part of the National Institutes of Health, have shown that a combination of three-component drugs – of irinotecan, cetuximab, and vemurafenib – more powerful. tumor suppression and keeping people with metastatic colon cancer free for a much longer time compared to patients treated with irinotecan and cetuximab.
The results of the SWOG study, led by Scott Kopetz, MD, PhD, of the Anderson Anderson Cancer Center, are published in the Journal of Clinical Oncology. The findings are expected to change the status of care for patients with metastatic colorectal cancer – when tumors spread to other parts of the body – and introduce a mutation in the BRAF gene called V600E. This mutation is found in approximately 10 percent of colorectal metastatic cancers and tumors with the rare mutation in treatment, leading to a poor prognosis for patients.
Kopetz is an expert in the science of BRAF-mutated colorectal cancer and has tested several combination therapies to treat it, including conducting a BEACON test. This phase III trial found that two targeted drugs – cetuximab and encorafenib – significantly suppressed tumors and helped patients live longer compared to those who received conventional treatment. These results sparked a shower last year when it was simultaneously published in the New England Journal of Medicine and presented at the annual meeting of the European Society of Medical Oncology.
In his SWOG study, S1406, Kopetz and his team went on a combination of remedies to see what might work best. In this trial, they tested 106 patients with colorectal metastatic cancer including lethal V600E. 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 that combination with a third drug, vemurafenib.
The SWOG team found that the drugs had better tumor response rates – 17 percent compared to 4 percent – and stayed cancer-free longer. On a molecular level, Kopetz said, this is how the triplet works: Irinotecan, a traditional chemotherapy drug, kills cancer cells. Cetuximab, a monoclonal antibody, is a targeted drug that inhibits cancer growth by inhibiting the action of a protein called epidermal growth factor receptor, or EGFR. Kopetz states that vemurafenib, a BRAF inhibitor and other targeted therapy, directly attacks BRAF proteins, slowing tumor growth further.
“That 1-2-3 action, that triple threat, shuts off a powerful growth path in these cancers,” Kopetz said. “In this trial, unlike BEACON, we added chemo and found that it provides a more effective way to treat this aggressive form of colorectal cancer.”
Another interesting finding: An 87 percent decrease in circulating tumor DNA (ctDNA) of the variable allele frequency of BRAFV600E in patients receiving all three drugs, compared with a drop in ctDNA in patients receiving a a two-drug mixture. 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 can be as easy as drawing blood, using a test called a liquid biopsy.
The results of the SWOG review will be accompanied by an editorial at JCO in January 2021.
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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, CA180835, CA180835, CA1808 CA189972, CA189952, CA189953, CA189854, CA189830, CA189809, CA180830; and in partnership with The Hope Foundation for Cancer Research, Protective Health, and Genentech, a member of the Roche Group.
Kopetz ’SWOG team includes Katherine A. Guthrie, PhD, of the SWOG Center for Statistics and Data Management at the Fred Hutchinson Cancer Research Center; Van K. Morris, MD, of Anderson Anderson Cancer Center; Heinz-Josef Lenz, MD, of the Keck School of Medicine at the University of Southern California; Anthony M. Magliocco, MD, formerly of the Moffitt Cancer Center and now at Protein BioDiagnostics; Dipen Maru, MD, of Anderson MD Cancer Center; Yibing Yan, PhD, of Genentech, Richard Lanman, MD, of Defensive Health; Ganiraju Manyam, PhD, of MD Anderson Cancer Center; David Hong, MD, of the Anderson Anderson Cancer Center; Alexey Sorokin, PhD, of MD Anderson Cancer Center; Chloe E. Atreya, MD, PhD, of UCSF Helen Diller Comprehensive Cancer Center; Luis A. Diaz, MD, of Sloan Kettering Cancer Center; Carmen Allegra, MD, of the Cancer Assessment Medicine Program at the National Cancer Institute; Kanwal P. Raghav, MBBS, MD, of Anderson MD Cancer Center; Stephen E. Wang, MD, of Kaiser Permanente South Sacramento Medical Center; Christopher H. Lieu, MD, of the University of Colorado Denver; Shannon L. McDonough, MS, of the SWOG Center for Statistics and Data Management at the Fred Hutchinson Cancer Institute; Philip A. Philip, MD, PhD, Barbara Ann Karmanos Cancer Institute; and Howard S. Hochster, MD, of the Rutgers Cancer Institute in New Jersey.
The SWOG Cancer Research Network is part of the National Cancer Institute’s National Clinical Trials Network and NCI’s Community Oncology Research Program, and is part of the nation’s oldest and most publicly funded cancer research network. 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 cancer drugs, changed more than 100 standards of cancer care, and saved more than 3 million years of human lives. Learn more at swog.org.