Triple chemotherapy combination improves metastatic colorectal cancer outcomes

December 23, 2020

Researchers from SWOG Cancer Research Network, a cancer clinical trials group funded by the National Cancer Institute (NCI), part of the National Institutes of Health, have shown that a triple drug combination - of irinotecan, cetuximab, and vemurafenib - is a more powerful tumor fighter and keeps people with metastatic colon cancer disease free for a significantly longer period of time compared with patients treated with irinotecan and cetuximab.

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.
-end-
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.

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. Learn more at swog.org.

SWOG

Related Colorectal Cancer Articles from Brightsurf:

Colorectal cancer treatment: the winning combinations
Chemotherapy has distressing side effects for patients and increases the risk of developing resistance to the treatment.

A new model to predict survival in colorectal cancer
This signature could be useful in clinical practice, especially for colorectal cancer diagnosis and therapy.

Roadmap to reducing colorectal cancer deaths
The American Gastroenterological Association has outlined a strategy to increase the number of people screened via tests that are more convenient, accurate and less expensive and tailored to people's individual cancer risks.

Study provides new insight on colorectal cancer growth
A new study by researchers at the University of Kentucky identifies a novel function of the enzyme spermine synthase to facilitate colorectal cancer growth.

Researchers ID target for colorectal cancer immunotherapy
Researchers at the Indiana University Melvin and Bren Simon Comprehensive Cancer Center have identified a target for colorectal cancer immunotherapy.

Colorectal cancer partner-in-crime identified
A protein that helps colorectal cancer cells spread to other parts of the body could be an effective treatment target.

Cancer cell reversion may offer a new approach to colorectal cancer treatment
A novel approach to reverse the progression of healthy cells to malignant ones may offer a more effective way to eradicate colorectal cancer cells with far fewer side effects, according to a KAIST research team based in South Korea.

A novel pathway to target colorectal cancer
Survival rates for patients with late-stage colorectal cancer are dismal, and new therapeutic strategies are needed to improve outcomes.

Colorectal cancer rates in Canada
The incidence of colorectal cancer among younger adults increased in recent years in this analysis of data from Canadian national cancer registries that included about 688,000 new colorectal cancers diagnosed over more than 40 years.

Cancer drugs promote stem cell properties of colorectal cancer
Scientists from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) and the Mannheim University Medical Center have now discovered that a certain group of cancer drugs (MEK Inhibitors) activates the cancer-promoting Wnt signalling pathway in colorectal cancer cells.

Read More: Colorectal Cancer News and Colorectal Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.