In a phase II trial reported by Vivek Subbiah, MD, and colleagues in The Lancet Oncology, the combination of dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor, achieved a 51% overall response rate in patients with BRAF V600E­–mutated cholangiocarcinoma.

This trial represents the first prospective study for patients with BRAF-mutated cholangiocarcinoma, or bile duct cancer, and suggests this targeted therapy combination could serve as a much-needed treatment option for patients with treatment-resistant advanced disease.

Vivek Subbiah, MD

“In this study, we saw that the dabrafenib and trametinib combination demonstrates clinical benefit and should be considered as a therapeutic option for these patients,” said Dr. Subbiah, Associate Professor of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center. “These findings also reinforce the need for routine testing of BRAF mutations in patients with biliary tract cancers. As we move forward with precision oncology, we’re seeing that alterations present in these rare cancers are actionable and the patients do benefit from targeted therapies.”

Background

Most cases of cholangiocarcinoma are diagnosed at advanced stages, and thus clinical outcomes are generally poor, with a 5-year survival rate below 20%. Standard of care includes surgery (when possible) and chemotherapy. In patients with advanced disease, median overall survival with chemotherapy treatment is less than 1 year, so there is a significant unmet need for effective new treatment approaches, explained Dr. Subbiah.

Mutations in the BRAF gene are found in 5% to 7% of those diagnosed with bile duct cancer, and patients with the BRAF V600E mutation are more likely to have poor outcomes. Trials with single-agent therapies targeting BRAF have been effective for treating these patients, but have shown significant toxicities, including secondary malignancies. However, combining these agents with MEK inhibitors, which act downstream in the same signaling pathway, have proven effective and are approved for use in other cancer types, including melanoma, lung cancer and anaplastic thyroid cancer.

Study Findings

This study is part of the ongoing, open-label, multicenter phase II ROAR trial, which is testing the efficacy and safety of the combination therapy in patients with a variety of BRAF V600E–mutated rare cancers. The bile duct cohort enrolled 43 patients, all of whom had received at least one prior line of therapy. Trial participants were 91% White (European heritage), 5% Asian (Japanese heritage), 2% Asian (East Asian heritage) and 2% White (Arabic/North African heritage). The median age was 57; 56% of participants were women and 44% were men.

In the current trial, the combination therapy achieved an overall response rate of 51% (22 patients) according to investigator assessments. The median duration of response was 8.7 months, with seven patients seeing an ongoing response beyond 12 months.

Median progression-free survival was 9.1 months and median overall survival was 13.5 months, with 56.4% and 35.8% of patients still alive at 12 months and 24 months, respectively.

All patients experienced at least one adverse event, with the most common being fever, nausea, vomiting, diarrhea and fatigue. Twenty-four patients (56%) experienced a grade 3 or 4 adverse event, the most common of which was an increase in gamma-glutamyltransferase, an enzyme found in the liver and bile ducts. According to the authors, these side effects were consistent with those seen previously from this combination in other cancer types.

The study authors concluded, “Dabrafenib plus trametinib combination treatment showed promising activity in patients with BRAF V600E–mutated biliary tract cancer, with a manageable safety profile. Routine testing for BRAF V600E mutations should be considered in patients with biliary tract cancer.”

Disclosure: This research was supported by GlaxoSmithKline and Novartis. For full disclosures of the study authors, visit thelancet.com.