Alessandro Rizzo , Angela Dalia Ricci,Giovanni Brandi

Division of Oncology, Azienda Ospedaliero-Universitaria di Bologna, via Albertoni 15, Bologna, Italy

TotheEditor:

In the last decade, next-generation sequencing (NGS)-based molecular profiling has shed light on the molecular landscape of biliary tract cancer (BTC), revealing the presence of several poten-tially actionable mutations [1] . According to ClinicalTrials.gov, there are at least 40 phase I to IV ongoing trials aimed at evaluating the role of targeted treatments in BTC, as monotherapy or in combi-nation with other anticancer agents [2] . Early encouraging results have been observed with therapies targetingIDHmutations,FGFRfusions,HERfamily and, more recently,BRAFmutations [3] .

The frequency ofBRAFmutations, both V600E and non-V600E, has ranged between 5% and 8% of BTCs among previous reports [4] . Interestingly,BRAFV600E-mutated BTC appears to be a unique clinical and molecular subtype of biliary malignancies, with this mutation being associated with higher TNM stage at diagno-sis, intrahepatic disease, chemotherapy resistance and worse over-all survival [5] . In this setting, early studies assessing the role of BRAF inhibitors monotherapy have shown disappointing responses, with short duration of disease control. In 2015, Hyman and col-leagues evaluated the efficacy of single agent vemurafenib in 8 metastatic intrahepatic cholangiocarcinomas (iCCAs), and only one patient (12%) demonstrated a partial response [6] . More recently, in view of enhanced efficacy of dual targeting with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) in other malignancies, this therapeutic strategy has been evaluated inBRAFV60 0E-mutated BTC. In fact, the dual inhibition of BRAF and MEK has its rational in reducing the paradoxical upregulation in MAPK signaling observed with BRAF inhibitor monotherapy [7] .

Subbiah and colleagues have recently reported the results of the BTC cohort of the phase II, open-label, non-randomized Rare On-cology Agnostic Research (ROAR) trial includingBRAFV60 0E-mutated cancer patients treated with oral dabrafenib 150 mg twice daily plus oral trametinib 2 mg once daily [8] . Dabrafenib and trametinib were evaluated in 43 patients with advanced or metastatic BTC who did not respond to at least one previous systemic treatment. Twenty-two of 43 patients achieving an overall response of 51% (95% CI: 36%-67%), a median progression-free survival of 9 months (95% CI: 5-10 months) and a median overall survival of 14 months (95% CI: 10-33 months) represent a clinically significant improve-ment. In fact, although caution is necessary in analyzing results from single-arm trials without comparator arms, these results are noteworthy –especially considering the pretreated patient popula-tion and the extremely unsatisfactory prognosis of metastatic BTC. In addition, the incidence of adverse events was similar to that ob-served in melanoma and non-small cell lung cancer, with 17 pa-tients (40%) presenting grade 3-4 adverse events and 9 (21%) seri-ous treatment-related adverse events.

Compared with previous trials testing BRAF or MEK inhibition inBRAFV600E-mutated BTC, the study by Subbiah and colleagues has shown robust and promising results, and dabrafenib plus trame-tinib combination is therefore likely to add to the range of avail-able treatments for metastatic BTC. However, although the re-sponses in ROAR trial are durable [median duration of response of 9 months (95% CI: 6-14 months)], several challenges remain.

First, acquired drug resistance represents a remarkable barrier to the use of targeted therapies in BTC, and addressing mecha-nisms of resistance is a timely topic. If heterogeneous resistance mechanisms have been observed in other malignancies such as melanoma (e.g.denovoNRASmutations,BRAFamplification,denovoMEK1/2mutations, etc.) -with this malignancy serving as guide in the use of BRAF and MEK inhibitors in other solid tumors -a further step forward in understanding the molecular landscape and resistance mechanisms to targeted therapies in BTC is manda-tory [9] . Second, combining dual inhibition of BRAF and MEK with other compounds is an approach which requires further investiga-tion, in the first-or later-line setting. Lastly, the difficulty in con-ducting timely trials in subgroups with these extremely rare mu-tations is an important obstacle. In fact, the authors locally pre-screened 626 BTC patients to enroll 43 subjects, which underlined the difficulties in completing such a trial [8] .

We are witnessing a new era in medical management of BTC and treatment paradigms that are rapidly changing. Nonetheless, the prognosis of metastatic disease has not changed in the last decade, with most of patients carrying a median survival of less than a year. In this scenario,BRAFV60 0Emutation has the potential to become an important therapeutic target in BTC in the near fu-ture followingFGFR2fusions andIDHmutations and further stud-ies are warranted in this direction.

Acknowledgments

None.

CRediT authorship contribution statement

Alessandro Rizzo:Resources, Validation, Writing -original draft, Writing -review & editing.Angela Dalia Ricci:Conceptu-alization, Data curation, Formal analysis, Investigation, Methodol-ogy, Resources.Giovanni Brandi:Project administration, Resources, Software, Supervision, Validation.

Funding

None.

Ethical approval

Not needed.

Competing interest

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the sub-ject of this article.