SWOG S1406 Study: Combo Therapy Attacks Metastatic Colorectal Cancer with V600E Mutation, Extending Life

SWOG S1406 Study: Combo Therapy Attacks Metastatic Colorectal Cancer with V600E Mutation, Extending Life

A triple-drug combination involving irinotecan, cetuximab, and vemurafenib may actually keep people with metastatic colon cancer disease-free for a significantly longer period time, compared with patients treated with irinotecan and cetuximab reports investigators from the SWOG Cancer Research Network, a cancer clinical trials group funded by the National Cancer Institute (NCI), part of the National Institutes of Health (NIH). Led by principal investigator Scott Kopetz, MD, Ph.D., of M.D. Anderson Cancer Center, the SWOG study results were published in the Journal of Clinical Oncology. These findings may very well change the standard of care for metastatic colorectal cancer patients—when tumors spread to other parts of the body—and includes a mutation in the BRAF gene known as V600E. This particular mutation is identified in about 10% of all metastatic colorectal cancers and tumors with the mutation rarely respond to treatment, resulting in poor patient outcomes. The study was funded in part by Genentech, part of the Roche Group, as it was their Vemurafenib that contributed to this new result.

BEACON Trial Establishes Combo Therapy Pathway

Dr. Kopetz out of M.D. Anderson is an expert in the science of BRAF-mutated colorectal cancer and has tested a variety of combination therapies to treat this condition, including the oversight of the BEACON trial.

This Phase 3 trial found that two targeted drugs—cetuximab and encorafenib—significantly reduced tumors and helped patients live longer compared to those who received standard treatment. These findings were a hit among the oncology research and care community when the results were published in the New England Journal of Medicine and simultaneously presented at the European Society of Medical Oncology annual meeting.

S1406: The SWOG Study

In this study, Kopetz and team pursue combination therapies to see what could 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.

S1406 Results: ‘A 1-2-3 Action’

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.

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

Interestingly, the study team also found that the triple combination therapy led to an 87% decline in circulating tumor DNA (ctDNA) of the BRAFV600E variant allele frequency in patients receiving the combination as compared with no ctNDA drop in patients receiving only the two-drug combination. This represents evidence, according to the principal investigator, that measuring the presence of ctDNA can be an effective way to measure the short-term response to treatment. This could be as easy as drawing blood, using a test known as a liquid biopsy.

What is Vemurafenib?

Marketed as Zelboraf, this drug is an inhibitor of the B-Raf enzyme developed by Plexxikon (now part of Daiichi-Sankyo) and Genentech (part of Roche) for the treatment of late-stage melanoma. The name actually is derived from V600E mutated BRAF inhibition.

The drug has been approved by the U.S. FDA for treatment of late-stage melanoma and as a monotherapy for the treatment of adult patients with BRAF V600 mutation positive unresectable or metastatic melanoma. By 2017 the drug was approved by the FDA for the treatment of some patients with Erdheim-Chester disease (ECD), a rare form of histiocytic neoplasm.


This study was financially supported by the National Institutes of Health via the National Cancer Institute (award numbers available at source) as well as the Hope Foundation for Cancer Research, Guardant Health and Genentech, a member of the Roche Group.

The Team

The study team included in addition to Dr. Kopetz a powerful SWOG team coming from prominent academic medical centers, and health systems. All of the study investigators can be seen at the source.

About SWOG

SWOG Cancer Research Network is part of the National Cancer Institute’s National Clinical Trials Network and the NCI Community Oncology Research Program and is part of the oldest and largest publicly-funded cancer research network in the nation. 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 life.

Lead Research/Investigator

Edmund Scott Kopetz, MD, PhD, FACP, M.D. Anderson Cancer Center

Call to Action: For those that may have a love one diagnosed with Braf mutated, metastatic colorectal cancer consider connecting with one of the investigators in this study. They represent global experts on the topic.