Promising Activity Seen With Dabrafenib Doublet in BRAF V600E+ Biliary Tract Cancer

The combination of dabrafenib and trametinib in patients with biliary tract cancer and BRAF V600E mutations demonstrated clinical activity and a manageable safety profile, according to results from the phase 2 ROAR study.

The combination of dabrafenib (Tafinlar) and trametinib (Mekinist) in patients with biliary tract cancer and BRAF V600E mutations demonstrated clinical activity and a manageable safety profile, leading investigators to suggest routine testing for BRAF V600E mutations should be considered in this setting, according to results from the phase 2 ROAR study.

In this patient population, there is an unmet need for effective treatments following gemcitabine-based chemotherapy after patients have progressed. To find a beneficial treatment, investigators started the study of dabrafenib and trametinib combination which has shown activity and safety in multiple BRAF V600E-mutated cancers. Five percent of tumors have been shown to have mutations in the BRAF gene for patients with biliary tract cancer. In addition, the combination of a GRAF inhibitor and a MEK inhibitor historically decreased the number of cutaneous adverse events (AEs) and improved progression-free survival (PFS) and overall survival (OS). The effective combination is FDA approved for the treatment of multiple BRAF-mutated cancers, but its potential in biliary tract cancer is an area of investigation.

“To our knowledge, our study represents the first prospective analysis of a cohort of patients with BRAF V600E-mutated biliary tract cancer treated with a combination of BRAF and MEK inhibitors,” the investigators wrote in their discussion. “Dabrafenib plus trametinib combination treatment showed promising activity in this patient population and had a manageable safety profile. Our findings compare favorably with those of previous trials using targeted treatments in biliary tract cancer.”

The ongoing, open-label, single-arm, multicenter, Rare Oncology Agnostic Research (ROAR) basket trial (NCT02034110) showed an investigator-assessed overall response in 22 patients (51%; 95% CI, 36%-67%) out of 43 in the cohort at a median follow-up of 10 months. The independent reviewer-assessed response was achieved in 20 patients (47%; 95% CI, 31%-62%).

The overall response rate was estimated to be 42% (95% CI, 22%-63%) according to the Bayesian hierarchical model. There were 67% of patients with ongoing response at 6 months, 36% at 12 months, and 13% at 24 months out of the 22 patients with investigator-assessed response. There were only partial responses seen in this group of patients.

At 6, 12, and 24 months, the overall survival rate was 84% (95% CI, 69%-92%), 56% (95% CI, 38%-71%), and 36% (95% CI, 19%-53%) by investigator assessment, respectively. The median survival was 14 months (95% CI, 10-33 months). The progression-free survival rate was 63% (95% CI, 47%-76%) at 6 months, 30% (95% CI, 16%-45%) at 12 months, and 8% (95% CI, 2%-22%) at 24 months, and the median was 9 months (95% CI, 5-10 months).

Serious AEs were observed in 17 patients (40%), and treatment-related AEs were seen in 9 patients (21%). The most frequent of these was pyrexia in 8 (19%). Increased γ-glutamyltransferase in 5 patients (12%) was the most common grade 3 or worse AE, followed by pyrexia, a decrease in white blood cell count, hypertension, and hyponatraemia all at 7%.

With this combination, there were dose reductions for 15 patients (35%) due to AEs and 24 patients (56%) had AEs that warranted dose interruptions. There was 1 patient (2%) who experienced sepsis, which led to permeant discontinuation. No treatment-related deaths were reported.

For the patients in this cohort, dabrafenib was given orally at 150 mg twice a day and trametinib was given orally at 2 mg once a day until disease progression or intolerance of treatment. Patients had a median duration of exposure to the combination of 8 months (range, 2-34 months).

Most patients in the study had stage IVB disease (93%), adenocarcinoma histology (74%), and the intrahepatic bile duct at the site of the primary tumor (91%). The average age was 57 years and 56% of the participants were women. Sixty percent of patients had an ECOG performance status of 1.

The primary end point was overall response rate and secondary end points included OS, PFS, duration of response, and safety. There was also an exploratory biomarker analysis included in this study. Twenty-six patients had available baseline tissue samples; 16 were analyzed with targeted DNA sequencing and 19 were analyzed with a custom gene expression panel.

In patients who had their samples go through DNA sequencing, there was a heterogenous genetic landscape observed where most alterations in specific genes were not shared across patients. There were 11 patients with gene copy number variations, and 6 of those patients showed homozygous loss of CDKN2A and CDKN2B. There were also 6 patients with homozygous loss of MTAP. In all patients who had samples for DNA sequencing, there was low tumor mutational burden, or less than 6 mutations per Mb.

This combination “could be considered as a therapeutic option in this patient population. Routine testing for BRAF V600E mutations should be considered in all patients with biliary tract cancer. Our exploratory biomarker findings need to be validated in a larger study,” the investigators concluded.


Subbiah V, Lassen U, Elez E, et al. Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial. Lancet Oncol. 2020;21(9):1234-1243. doi:10.1016/S1470-2045(20)30321-1