Skip to main content
Premium Trial:

Request an Annual Quote

Patients With BRAF-Mutated Bile Duct Cancer See Benefit from Targeted Treatment Combination


NEW YORK – Interim results from an ongoing Phase II basket trial have demonstrated that the combination of dabrafenib and trametinib (Novartis' Tafinlar and Mekinist) may benefit patients with BRAF V600E mutated cholangiocarcinoma, or bile duct cancer.

Based on the encouraging activity and safety profile of the dabrafenib-trametinib regimen to date, some oncologists believe cholangiocarcinoma patients should be evaluated for these mutations and given the chance to receive the combination.

The basket trial, dubbed Rare Oncology Agnostic Research, or ROAR, is evaluating the combination of BRAF-inhibiting dabrafenib and MEK-inhibiting trametinib in patients with a variety of rare cancers harboring BRAF V600E mutations. The combination has previously garnered regulatory approvals for the treatment of BRAF V600E-mutated melanoma, non-small cell lung cancer, and anaplastic thyroid cancer. The US Food and Drug Administration's approval of the combination for BRAF-mutated thyroid cancer was based on the same rare cancer basket trial that is now reporting positive results in cholangiocarcinoma.

The results, published Monday in The Lancet Oncology, demonstrated that, among 43 patients with previously treated BRAF V600E-positive cholangiocarcinoma, the combination of dabrafenib and trametinib achieved an overall response rate of 51 percent. The median duration of response was 8.7 months, and seven patients continued to respond to the combination beyond the 12-month mark. Over 56 percent and 35 percent of patients were still alive after one and two years of treatment, respectively. The combination's safety profile was consistent with those seen in other cancer types.

"This is the first prospective study of patients with BRAF-mutated cholangiocarcinoma," said Vivek Subbiah of the MD Anderson Cancer Center, the first author of the Lancet Oncology paper. "It's new territory for cholangiocarcinoma."

There have been recent precision oncology advances for the treatment of cholangiocarcinoma. Earlier this year, the FDA approved pemigatinib (Incyte's Pemazyre) for advanced or metastatic cholangiocarcinoma patients with FGFR2 fusions or rearrangements, and the IDH1-targeting ivosidenib (Agios' Tibsovo) has shown efficacy against cholangiocarcinoma in clinical trials. However, the ROAR trial represents the emergence of BRAF V600E mutations as a treatment target for the rare disease.

Cholangiocarcinoma is a rare cancer of the bile ducts that occurs in approximately 8,000 patients in the US annually. Roughly 5 to 7 percent of patients with cholangiocarcinoma harbor BRAF V600E mutations, and these patients historically have experienced poorer outcomes. Single-agent BRAF-inhibitors have been tested in cholangiocarcinoma patients, but caused severe toxicities that were not seen with the addition of the MEK inhibitor.

Moreover, the activity seen with the dabrafenib-trametinib combination in BRAF-mutated cholangiocarcinoma patients in the ROAR cohort appears promising in light of the demonstrated activity of pemigatinib, Subbiah reflected. The FDA granted approval to pemigatinib for FGFR2 fusion-positive cholangiocarcinoma based on an overall response rate of 36 percent. Though the sample size was smaller for the dabrafenib-trametinib trial than it was with pemigatinib cohort, the 56 percent of patients who saw their tumors shrink on the combination does represent an encouraging magnitude of response in comparison.

"We will really need to discuss what will be the regulatory implications," Subbiah said of the dabrafenib-trametinib results, adding that, in his view, these data are sufficient grounds for physicians to begin prescribing the combination to previously-treated cholangiocarcinoma patients with BRAF V600E mutations, even if they must do so off-label.

"The safety of this combination is now well-established in multiple cancers, and this is a study that shows it is effective in biliary tract cancers," Subbiah said. "Based on this study, offering testing of BRAF V600E mutations should be considered in all patients with biliary tract cancer."

The case for routine BRAF testing

According to Subbiah, most cholangiocarcinoma patients enrolled in the ROAR trial were known to harbor BRAF V600E mutations because they had undergone genomic testing, mostly on next-generation sequencing panel tests, such as Caris Life Sciences' Caris Molecular Intelligence, Foundation Medicine's FoundationOne CDx, or Tempus' Tempus xT. Patients recruited from major comprehensive cancer centers such as MD Anderson might have had their tumors profiled with Thermo Fisher Scientific's Oncomine assays. Regardless of the specific test used, all patients had their BRAF mutation status confirmed via centralized testing using BioMérieux's THxID-BRAF kit.

Though BRAF mutation testing is not yet part of the standard of care for cholangiocarcinoma, Subbiah believes that it should be in the wake of the ROAR study results. The ability to assess multiple targetable alterations, such as FGFR2 fusions and BRAF mutations, makes it all the more urgent to offer broad genomic profiling to cholangiocarcinoma patients. Pemigatinib, in fact, was approved with FoundationOne CDx, a large NGS panel, as its companion diagnostic.

"Right now, in cholangiocarcinoma, we're seeing more and more patients being tested [with broad-based tests]," Subbiah said. This is in part because of the recent pemigatinib approval, he explained, as well as multiple tumor-agnostic approvals for pembrolizumab (Merck's Keytruda), larotrectinib (Bayer's Vitrakvi) and entrectinib (Roche's Rozlytrek) — all of which could be options for patients with advanced or refractory cholangiocarcinoma should their tumors harbor the appropriate biomarkers. In the process of determining eligibility for these drugs, patients would also learn if their tumors harbor BRAF mutations.

"I am a personal believer that for rare disease, we need universal genomic testing," Subbiah said, adding that, going forward, "when patients are being tested for multiple genes, if they find a BRAF V600E mutation, dabrafenib and trametinib should be a therapeutic option that's open to them."

Exploratory endpoints, mechanism of action

Despite Subbiah's belief in the immediate actionability of the ROAR study results, researchers still have questions about the underlying biology of cholangiocarcinoma and mechanisms of resistance that might keep some patients from benefiting from dabrafenib and trametinib. The number of patients with cholangiocarcinoma assessed in the ROAR study was too small for the researchers to confidently complete some of the exploratory analyses they'd hoped for.

For instance, researchers conducted an exploratory analysis of DNA and RNA biomarkers, and tumor mutational burden using a combination of NGS, a custom NanoString nCounter Gene Expression panel, and Bioconductor Project's PureCN. However, while DNA sequencing was done on 16 baseline samples and RNA sequencing was performed on 19 baseline samples, only one sample was available for analysis after disease progression, rendering it impossible to identify molecular mechanisms of resistance.

The investigators had hoped to assess downstream MAPK pathway activity using two known gene expression signatures, but were limited in their ability to do so by the small portion of genes represented in the custom panel from NanoString Technologies. "Additional studies are needed to confirm any association between increased MAPK pathway member expression and progressive disease," wrote Subbiah and coauthors.

The rarity of cholangiocarcinoma in the population has historically made it difficult to enroll sufficient numbers of patients into clinical trials, let alone conduct exploratory analyses. According to Subbiah, for instance, ROAR study investigators had to test over 600 patients to identify the 43 BRAF-mutated patients who would be treated with dabrafenib and trametinib.

There are efforts underway, however, to expand access to precision medicine research for patients with rare diseases like cholangiocarcinoma across the country, including those treated in community settings. The TargetCancer Foundation's recently launched TRACK study, for instance, for which Subbiah is also a co-principal investigator, allows patients with cholangiocarcinoma and a number of other rare cancers to participate remotely, without having to travel to a central clinical trial location. Efforts like these, Subbiah hopes, will enable a more comprehensive understanding of the disease and treatment options.

"We need to gather every bit of intelligence [about cholangiocarcinoma], that we can," Subbiah said. "Because every patient deserves an accurate diagnosis, and genomics is the diagnosis."