In the study, 56% of patients experienced a grade 3 or 4 adverse event, most commonly abnormally high levels of gamma-glutamyltransferase in the liver. But these toxicities seem to be in keeping with those seen when the combination is used in other cancer types, such as melanoma.

“I agree with the authors in saying that the side-effect profile overall is manageable. In this trial, 35% of the patients required a dose reduction and 36% required dose interruptions, but many oncologists have experience with these 2 drugs and while these drugs have toxicity, oftentimes it is manageable,” said Dr Li.

Given the impressive results for patients with advanced, pretreated cholangiocarcinoma, should this treatment combination now be used as a first-line option for newly diagnosed patients with BRAFV600E-mutated cholangiocarcinoma?


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“I think this should be a part of a trial. We see patients respond better before chemotherapy on targeted treatments typically, we don’t know the answer in this context yet,  but we need to run a clinical trial looking at the standard of care vs targeted therapy,” said Dr Subbiah.

“Despite the rarity of V600E mutation, with this data, I sure would now treat with the studied combination of dabrafenib plus trametinib as a first line approach. The response rate is positively intriguing at 47%. This compares favorably to other treatments that were done with the combination or variation of the combination in different cancer types,” said Dr Abou-Alfa.

Although genomic testing is undoubtedly now providing new treatment options for patients with a variety of cancers with specific genetic alterations, how common and accessible is this type of testing for patients with cholangiocarcinoma currently?

“All big centers definitely do this type of next generation sequencing screening, but a majority of the cancer patients in the community may not be getting this screening to recommend applicable treatment approaches based on such results. Access and cost could be an issue and sometimes there’s an issue with physician awareness,” said Dr Abou-Alfa.

There’s also often an issue of cost with DNA sequencing of tumor samples with tests frequently costing thousands of dollars6 and not all of them being covered by insurance companies or government programs like Medicare.

“In smaller centers, people are more likely to have standard therapy and then perhaps they get tested, but I would prefer for them to be tested at diagnosis. If there are approved therapeutic options, there’s more reason for testing patients for these alterations. I think cholangiocarcinoma in the future will get wider community testing as these drugs become more available,” said Dr Subbiah.

Despite these advances, cholangiocarcinoma still remains an incurable cancer for the majority of people who have it, with a 5-year survival rate of below 20%. But there may be promising treatment options on the horizon.

“What I would like to see in the years to come is a cure for this type of cancer. I’d like to move away from chemotherapy,  and enhance further the targeted therapies in first-line settings like we are doing with FGFR2 and figure out if immune checkpoint inhibition and immunotherapy is going to have a role in treating this type of cancer,” said Dr Abou-Alfa.

Editor’s note: This article was updated on 10/5/20.

References

  1. Subbiah V, Lassen U, Élez E, et al. Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trialLancet Oncol. 2020;21(9):1234-1243. doi:10.1016/S1470-2045(20)30321-1
  2. Lamarca A, Palmer DH, Wasan HS, et al. ABC-06 | A randomised phase III, multi-centre, open-label study of active symptom control (ASC) alone or ASC with oxaliplatin / 5-FU chemotherapy (ASC mFOLFOX) for patients (pts) with locally advanced / metastatic biliary tract cancers (ABC) previously-treated with cisplatin/gemcitabine (CisGem) chemotherapy. J Clin Oncol. 2019;37(15_suppl):4003-4003.
  3. Furlow B. Wider use of basket trials could hasten development of precision therapies. Cancer Therapy Advisor. Published April 23, 2019. Accessed September 25, 2020.
  4. US Food and Drug Administration. FDA approves dabrafenib plus trametinib for anaplastic thyroid cancer with BRAF V600E mutation. Published May 4, 2018. Accessed September 25, 2020.
  5. Subbiah V, Baik C, Kirkwood JM. Clinical development of BRAF plus MEK inhibitor combinations. Trends Cancer. 2020;6(9):797-810. doi:10.1016/j.trecan.2020.05.009
  6. Primeau ASB. Next-generation sequencing for patients: What test will I get? Cancer Therapy Advisor. Published June 14, 2019. Accessed September 25, 2020.