BRAF/MEK Targeting May Yield Benefit in Treating Biliary Tract Cancer

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ROUTINE TESTING for BRAF V600E mutations in patients with biliary tract cancer may prove to be a good idea, based on the findings of a phase II study in which treatment with dabrafenib plus trametinib showed activity.1 The results suggest there may be a benefit to testing patients with biliary tract cancer for the presence of actionable driver mutations, one of which is BRAF V600E.

Zev Wainberg, MD

Zev Wainberg, MD

“Dabrafenib plus trametinib demonstrated a clinical benefit in patients with BRAF V600E-mutant biliary tract cancer and should be considered a meaningful therapeutic option for these patients,” said Zev Wainberg, MD, of the University of California, Los Angeles, School of Medicine, at the 2019 Gastrointestinal Cancers Symposium. He noted that this study represents the first prospectively analyzed cohort of patients with BRAF V600E–mutant biliary tract cancer treated with a combination of BRAF and MEK inhibitors.

As described by Dr. Wainberg, biliary tract cancer is an aggressive disease with poor clinical outcomes. Most patients present with advanced disease, and the 5-year survival rate is approximately 15%. The identification of a number of genetic mutations in this disease “opens the possibility of targeted treatment,” he said. Mutations in the BRAF gene have been found in 5% of biliary tumors, and they may be enriched in intrahepatic forms of the cancer.

ROAR Basket Trial

THE ROAR study is a basket trial involving 9 different cohorts of 178 patients with rare malignancies, all harboring BRAF V600E mutations. The biliary cancer cohort included 35 patients treated with the combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib.

The cohort included 74% with biliary tract adenocarcinoma, 17% with hepatocholangiocarcinoma, and 9% with 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. The median duration of treatment exposure was 6 months, and 86% of patients were treated for more than 3 months. The median follow-up was 8 months.

Partial responses were observed in 42% of the cohort by investigator assessment and in 36% by independent review. Stable disease was achieved by 45% and 39%, respectively, and 12% had progressive disease as best response (by either assessment). The median progression-free survival by investigator assessment was 9.2 months, and the median overall survival was 11.7 months, Dr. Wainberg reported.

“Dabrafenib plus trametinib demonstrated a clinical benefit in patients with <em>BRAF</em> V600E–mutant biliary tract cancer and should be considered a meaningful therapeutic option for these patients.”
— Zev Wainberg, MD

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“The efficacy in this population with advanced disease was comparable to that of first-line chemotherapy with gemcitabine and cisplatin,” he observed.

At 6 months, 66% of patients were still responding. Of 14 patients, 7 had a duration of response exceeding 6 months, and 5 patients had an ongoing response at the time of analysis.

Genetic analysis of 16 patients revealed heterogeneity and a low tumor mutational burden in all individuals, a finding consistent with previous observations about the genetic landscape of biliary tract cancer. Gene-expression levels of the MAP kinase pathway were observed to be higher in two patients with progressive disease as their best response, compared with patients who had stable disease. “Additional study is needed to confirm any association of this with clinical benefit,” Dr. Wainberg commented.

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 were pyrexia (40%), rash (29%), and nausea (23%).

DISCLOSURE: Dr. Wainberg is a consultant/advisor for Aduro Biotech, Array BioPharma, Bristol-Myers Squibb, Five Prime Therapeutics, Genentech, Lilly, Merck, Novartis, and Sirtex Medical; has received travel expenses from Genentech; and has received institutional research funding from Five Prime Therapeutics, Merck, Novartis, Pfizer, and Plexxikon.


1. Wainberg ZA, Lassen UN, Elez E, et al: Efficacy and safety of dabrafenib and trametinib in patients with BRAF V600E–mutated biliary tract cancer: A cohort of the ROAR basket trial. 2019 Gastrointestinal Cancers Symposium. Abstract 187. Presented January 18, 2019.