BRAF, MEK Inhibitors Offer Promise in Biliary Tract Cancer

The combination of dabrafenib and trametinib offered promising efficacy in a phase II trial of patients with biliary tract cancer and BRAF V600E mutations. Routine testing for these mutations may be warranted in biliary tract cancer patients.

“Biliary tract cancer is an aggressive disease with poor clinical outcomes,” said Zev A. Wainberg, MD, of the University of California, Los Angeles School of Medicine. He added that most patients present with advanced disease, and the 5-year survival rate is approximately 15%. “A number of genetic mutations have been identified in patients with biliary tract cancer that open the possibility of targeted treatment.”

The ROAR trial was a basket trial including nine different cohorts; these represented different rare malignancies, but all had BRAF V600E mutations. Wainberg presented results from the biliary tract cancer cohort, which included 35 patients, all treated with the combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib, at the American Society of Clinical Oncology (ASCO) 2019 Gastrointestinal Cancers Symposium, held January 17–19 in San Francisco (Abstract 187).

The median age in the trial was 57.0 years, and 43% of the cohort was male. Most patients had adenocarcinoma (74%), though 17% had hepatocholangiocarcinoma and 9% had cholangiocarcinoma. Most patients (74%) had stage IV disease at enrollment, and all 35 patients had received prior chemotherapy; 80% of the cohort had received at least 2 prior lines of therapy.

The median duration of treatment exposure was 6 months, and 86% of patients were on the study treatments for more than 3 months.

There were no complete responses seen, but 42% of the cohort had a partial response according to investigator assessment (36% by independent review). Another 15 patients (45%) had stable disease (39% by independent review), while only 4 patients (12%) had progressive disease. The median progression-free survival by investigator assessment was 9.2 months, and the median overall survival was 11.7 months.

All patients experienced at least one adverse event of any grade; 57% had a grade 3 or 4 event. The most common treatment-related adverse events included pyrexia (40%), rash (29%), nausea (23%), and others.

“These results represent the first prospectively analyzed cohort of patients with BRAF V600–mutant biliary tract cancer treated with a combination of BRAF and MEK inhibitors,” Wainberg said. “Dabrafenib plus trametinib demonstrated clinical benefit in patients with BRAF-mutant biliary tract cancer and should be considered a meaningful therapeutic option for these patients. BRAF V600 is one of several actionable driver mutations and should be considered for routine testing in patients with biliary tract cancer.”

Heinz-Josef Lenz, MD, of the University of Southern California Keck School of Medicine, was the discussant for the study, and he said the efficacy results were “incredibly impressive.” He said that in the future, it will become more and more important to incorporate whole-genome sequencing and other types of molecular profiling into practice. “I think in the future it will be not one mutation we’re looking for,” he said. “We’ll be looking for a combination of mutations in redundant pathways.” Once those combinations of mutations are better characterized, the best approaches may involve other combination therapies, Lenz said.