Triple Chemo Combo Improves CRC Outcomes

Results of the SWOG study, led by Scott Kopetz, MD, PhD, of M.D. Anderson Cancer Center, are published in the Journal of Clinical Oncology. The findings are expected to change the standard of care for patients with colorectal cancer that is metastatic – when tumors spread to other parts of the body – and includes a mutation in the BRAF gene called V600E. This mutation is found in about 10 percent of metastatic colorectal cancers and tumors with the mutation rarely responds 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 variety of combination therapies to treat it, including leading the BEACON trial. This phase III trial found that two targeted drugs – cetuximab and encorafenib – significantly shrank tumors and helped patients live longer compared with those who received standard treatment. These results made a splash last year when simultaneously published in the New England Journal of Medicine and presented at the European Society of Medical Oncology annual meeting.

In his SWOG study, S1406, Kopetz and his team also pursued combination therapies to see what might work best. In this trial, they tested 106 patients whose metastatic colorectal cancer includes the deadly V600E mutation. All the patients had been previously treated with chemotherapy, and their cancer didn’t 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 patients who received the triple combination had better tumor response rates to the drugs – 17 percent compared to 4 percent – and stayed cancer-free longer. On a 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 cancer growth by blocking the action of a protein called epidermal growth factor receptor, or EGFR. Kopetz says vemurafenib, a BRAF inhibitor and another targeted therapy, attacks the BRAF protein directly, further slowing tumor growth.

“That 1-2-3 action, that triple threat, shuts off a powerful growth pathway in these cancers,” Kopetz said. “In this trial, unlike in BEACON, we added chemo and found that it makes for a more effective way to treat this aggressive form of colorectal cancer.”

Another intriguing finding: An 87 percent decline in circulating tumor DNA (ctDNA) of the BRAFV600E variant allele frequency in patients receiving all three drugs, compared with no ctDNA drop in patients receiving the two-drug combination. 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 SWOG study results will be accompanied by an editorial in JCO in January 2021.

Kopetz’ study was supported by the National Institutes of Health through National Cancer Institute awards CA180888, CA180819, CA180820, CA180821, CA180868, CA189821, CA187238, CA180834, CA180826, CA189858, CA180801, CA180835, CA180858, CA189954, CA189873, CA189822, CA189812, CA189972, CA189952, CA189953, CA189854,  CA189830, CA189809, CA180830; and in part by The Hope Foundation for Cancer Research, Guardant Health, and Genentech, a member of the Roche Group.

Kopetz’ SWOG team includes Katherine A. Guthrie, PhD, of the SWOG Statistics and Data Management Center at Fred Hutchinson Cancer Research Center; Van K. Morris, MD,  of M.D. Anderson Cancer Center; Heinz-Josef Lenz, MD, of the Keck School of Medicine of the University of Southern California; Anthony M. Magliocco, MD, formerly of Moffitt Cancer Center and now at Protean BioDiagnostics; Dipen Maru, MD, of M.D. Anderson Cancer Center; Yibing Yan, PhD, of Genentech, Richard Lanman, MD, of Guardant Health; Ganiraju Manyam, PhD, of M.D. Anderson Cancer Center; David Hong, MD, of M.D. Anderson Cancer Center; Alexey Sorokin, PhD, of M.D. Anderson Cancer Center; Chloe E. Atreya, MD, PhD, of the UCSF Helen Diller Comprehensive Cancer Center; Luis A. Diaz, MD, of Memorial Sloan Kettering Cancer Center; Carmen Allegra, MD, of the Cancer Evaluation Therapy Program in the National Cancer Institute; Kanwal P. Raghav, MBBS, MD, of M.D. Anderson Cancer Center; Stephen E. Wang, MD, of Kaiser Permanente South Sacramento Medical Center; Christopher H. Lieu, MD, of University of Colorado Denver; Shannon L. McDonough, MS, of the SWOG Statistics and Data Management Center at Fred Hutchinson Cancer Institute; Philip A. Philip, MD, PhD, of the Barbara Ann Karmanos Cancer Institute; and Howard S. Hochster, MD, of Rutgers Cancer Institute of New Jersey.