Triple-drug approach sets new standard for BRAF-mutant metastatic CRC : Study

July 10, 2019 0 By FM

A triplet of second-line targeted therapies showed significant improvement in survival for patients with BRAF-mutated metastatic colorectal cancer (mCRC), reported a recent study presented at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer in Barcelona.

According to the study, patients had a median overall survival of 9 months with the combination of encorafenib (Braftovi), binimetinib (Mektovi), and cetuximab (Erbitux) as compared with 5.4 months for patients treated with standard therapy.

About 15% of CRCs arise in association with a mutation in the BRAF gene. For years, standard chemotherapy plus the EGFR inhibitor cetuximab has represented standard of care for mCRC that has progressed beyond initial therapy.

“This study builds on a decade of research into the tumour biology of BRAF-mutated colorectal cancer and reflects a rational combination to address the vulnerabilities unique to this tumour,” said Scott Kopetz, MD, of the University of Texas MD Anderson Cancer Center in Houston in a statement.

The BRAF inhibitor encorafenib has already been approval for treatment of BRAF-mutated melanoma in combination with the MEK inhibitor binimetinib. Monotherapy with a BRAF inhibitor represented a significant advance in the treatment of melanoma as compared with previous options, but the benefits were short lived. The addition of a MEK inhibitor significantly improved outcomes as compared with a BRAF inhibitor alone, providing a rationale for evaluating the combination in other BRAF-mutated cancers.

The phase III BEACON CRC trial randomized 665 patients with BRAF-mutated mCRC to three treatment arms: encorafenib plus cetuximab, with or without binimetinib, or investigator’s choice of chemotherapy plus cetuximab.

The findings showed that the three-drug targeted combination reduced the survival hazard by 48% as compared with physician’s choice of standard therapy. A subgroup analysis showed a consistent advantage for the targeted triplet. Patients randomized to encorafenib and cetuximab had a median OS of 8.4 months, representing a 40% reduction in the survival hazard versus standard therapy.

One-fourth of patients responded to the triple-drug combination versus 2% of those randomized to the current standard of care.

A third treatment arm consisting of encorafenib and cetuximab also improved survival and response rate versus standard therapy.The findings also showed that vast majority of patients treated with the encorafenib triplet or doublet had some reduction in tumour size, somewhat greater with the three-drug regimen.

The primary endpoints were mean overall survival and objective response rate for the comparison of the triplet therapy to standard therapy.

“Colorectal cancer does not respond to BRAF therapy alone because tumour cells adapt through other mechanisms after initial treatment. With this triple targeted therapy, we are using a very scientifically logical combination to inhibit BRAF and these other mechanisms.”said Kopetz.