Two-Drug Combination Could Provide Benefits for Cholangiocarcinoma Subset

The combination of Tafinlar (dabrafenib) plus Mekinist (trametinib) could offer patients with BRAF V600E-mutated biliary tract cancer another much-needed treatment option, according to results from a phase 2 study published in The Lancet Oncology.

The targeted duo was also found to have a manageable safety profile in patients with treatment-resistant advanced disease, making it a welcome possible addition to the typically limited cholangiocarcinoma treatment landscape.

Forty-three patients were enrolled in the biliary tract cancer cohort of this study, which is part of the ongoing open-label, single-arm, multicenter Rare Oncology Agnostic Research (ROAR) basket trial in patients with BRAF V600E-mutated rare cancers. All patients had to be 18 years or older, had BRAF V600E-mutated, unresectable, metastatic, locally advanced, or recurrent biliary tract cancer, and had to have received at least one prior line of treatment.

All 43 patients were treated with 150 mg of oral Tafinlar twice daily and 2 mg of oral Mekinist once daily, until their disease progressed, or treatment became intolerable. Measuring the overall response rate was the main goal of the study.

At a median follow-up of 10 months, all patients who received the two-drug combination had an ORR of 51%. Seven patients had an ongoing response beyond 12 months, while the median duration of response was 8.7 months. Additionally, median progression-free survival (PFS) was 9.1 months.

Median overall survival (OS) was 13.5 months, with 56.4% and 35.8% of patients still alive at 12 months and 24 months, respectively.

While the combination was found to have a manageable safety profile, all patients experienced at least one side effect. The most common side effects included fever, nausea, vomiting, diarrhea and fatigue. The most common serious or severe side effect was increased gamma-glutamyltransferase, an enzyme found in the liver and bile ducts, which occurred in five patients (12%).

Seventeen patients (40%) experienced serious side effects and nine (21%) experienced serious side effects that were related to treatment, the most frequent being pyrexia, which occurred in eight patients (19%). No treatment-related deaths were reported.

In a press release about the findings, lead author Dr. Vivek Subbiah, associate professor of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center explained how these results prove the importance of genetic testing when it comes to determining the appropriate treatment for this disease.

“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,” said Subbiah.

The researchers note that further study is needed to validate these exploratory biomarker findings to expand the use of targeted therapy in this patient population.

“The trajectory of cholangiocarcinoma is changing rapidly,” said co-author Dr. Milind Javle, professor of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center, in the release. “Targeted therapy has made meaningful inroads, and this study is an excellent example of that. This is an important development for patients with cholangiocarcinoma and BRAF V600E mutations, who often have limited treatment options.”