Dabrafenib and Trametinib Combination Successful in BRAF-Positive Biliary Tract Cancer

Metastatic biliary tract cancer has seen a notable success in personalized treatment. Biliary tract cancers are a mixed group of epithelial cancers originating in different biliary tree regions (intrahepatic, perihilar, extrahepatic ducts, or gallbladder). They are generally subclassified as intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder carcinoma.

Although surgery is the only curative option, 5-year survival remains low because of advanced diagnosis and aggressive biology (approximately %15). The dual chemotherapy regimen cisplatin + gemcitabine is standard for inoperable biliary tract cancers.

An increasing number of genetic studies have sought molecular foundations and potential treatments in recent years. However, because these cancers are relatively rare , only one genetic-targeted treatment is currently approved: for dMMR or MSI-high tumors, pembrolizumab immunotherapy. Another genetic change that can be tested in advanced biliary tract cancer is NTRK, but positivity is very rare. A new trial presented at ASCO 2019 Gastrointestinal Cancers Symposium is a phase-2 clinical study, detailed below, concerning an effectively targetable alteration: BRAF V600E mutations!

The ROAR Study

For BRAF mutations, FDA -approved dabrafenib (Tafinlar) and trametinib (mekinist) combined showed promising efficacy in the phase II ROAR trial involving biliary tract cancer patients. These results may support routine testing for these mutations in advanced disease.

Note: Dabrafenib plus trametinib previously received FDA approval for BRAF-positive lung cancer, anaplastic thyroid cancer, and malignant melanoma.

ROAR is a nine-cohort basket trial representing different rare cancers, all with BRAF V600E mutations.

Median age was 57, and % 43 were men. Most had adenocarcinoma (% 74), with % 17 hepatocholangiocarcinoma and % 9 cholangiocarcinoma. Most (% 74) had stage 4. cancer at enrollment, and all 35 had prior chemotherapy (% 80 at least 2 previous lines).

Study results:

• Median treatment duration was 6 months; % 86 remained on study treatment for more than 3 months.
• No complete responses occurred, but % 42 had partial responses. Another 15 (%45) achieved stable disease, and only 4 (% 12) had progressive disease.
• Median progression-free survival was 9,2 months, and median overall survival 11,7 months.
• All patients had at least one adverse effect of any grade; % 57 had serious (grade 3. or 4.) effects. Common treatment-related effects included pyrexia/fever (% 40), rash (% 29), nausea (% 23), and others.

These results represent the first cohort of BRAF V600-positive biliary tract cancer treated with combined BRAF and MEK inhibitors. Dabrafenib plus trametinib showed clinical benefit and should be considered a meaningful option. BRAF V600 is a cancer-driving mutation targetable in several ways; routine testing should be considered.

Though small, the trial clearly demonstrated this dual regimen’s efficacy in BRAF-mutant disease, with impressive results. Genomic targets will increase for biliary tract and many other cancers. Whole-genome sequencing and other molecular profiling methods should be incorporated into clinical practice. Most cancers arise through multiple mutations rather than one driver. Better identification of important mutations and their relationships may allow new combinations to offer the best treatment options.