Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial: The Lancet Oncology

V. Subbiah, U. Lassen, E. Élez, A. Italiano, G. Curigliano, M. Javle, F. de Braud, G.W. Prager, R. Greil, A. Stein, A. Fasolo, J.H.M. Schellens, P.Y. Wen, K. Viele, A.D. Boran, E. Gasal, P. Burgess, P. Ilankumaran, Z.A. Wainberg

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Background: Effective treatments for patients with cholangiocarcinoma after progression on gemcitabine-based chemotherapy are urgently needed. Mutations in the BRAF gene have been found in 5% of biliary tract tumours. The combination of dabrafenib and trametinib has shown activity in several BRAFV600E-mutated cancers. We aimed to assess the activity and safety of dabrafenib and trametinib combination therapy in patients with BRAFV600E-mutated biliary tract cancer. Methods: This study is part of an ongoing, phase 2, open-label, single-arm, multicentre, Rare Oncology Agnostic Research (ROAR) basket trial in patients with BRAFV600E-mutated rare cancers. Patients were eligible for the biliary tract cancer cohort if they were aged 18 years or older, had BRAFV600E-mutated, unresectable, metastatic, locally advanced, or recurrent biliary tract cancer, an Eastern Cooperative Oncology Group performance status of 0–2, and had received previous systemic treatment. All patients were treated with oral dabrafenib 150 mg twice daily and oral trametinib 2 mg once daily until disease progression or intolerance of treatment. The primary endpoint was the overall response rate, which was determined by Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat evaluable population, which comprised all enrolled patients regardless of receiving treatment who were evaluable (ie, had progression, began a new anticancer treatment, withdrew consent, died, had stable disease for 6 weeks or longer, or had two or more post-baseline assessments). The ROAR trial is registered with ClinicalTrials.gov, NCT02034110. These results are based on an interim analysis; the study is active but not recruiting. Findings: Between March 12, 2014, and July 18, 2018, 43 patients with BRAFV600E-mutated biliary tract cancer were enrolled to the study and were evaluable. Median follow-up was 10 months (IQR 6–15). An investigator-assessed overall response was achieved by 22 (51%, 95% CI 36–67) of 43 patients. An independent reviewer-assessed overall response was achieved by 20 (47%, 95% CI 31–62) of 43 patients. The most common grade 3 or worse adverse event was increased γ-glutamyltransferase in five (12%) patients. 17 (40%) patients had serious adverse events and nine (21%) had treatment-related serious adverse events, the most frequent of which was pyrexia (eight [19%]). No treatment-related deaths were reported. Interpretation: Dabrafenib plus trametinib combination treatment showed promising activity in patients with BRAFV600E-mutated biliary tract cancer, with a manageable safety profile. Routine testing for BRAFV600E mutations should be considered in patients with biliary tract cancer. Funding: GlaxoSmithKline and Novartis. © 2020 Elsevier Ltd
Original languageEnglish
Pages (from-to)1234-1243
Number of pages10
JournalLancet Oncol.
Issue number9
Publication statusPublished - 2020


  • B Raf kinase
  • dabrafenib
  • gamma glutamyltransferase
  • trametinib
  • antineoplastic agent
  • BRAF protein, human
  • imidazole derivative
  • oxime
  • pyridone derivative
  • pyrimidinone derivative
  • acute kidney failure
  • adult
  • advanced cancer
  • aged
  • anemia
  • arthralgia
  • Article
  • asthenia
  • biliary tract cancer
  • cancer combination chemotherapy
  • cancer growth
  • cancer localization
  • cancer recurrence
  • cancer survival
  • chill
  • cholangitis
  • clinical article
  • clinical evaluation
  • cohort analysis
  • constipation
  • coughing
  • decreased appetite
  • dehydration
  • diarrhea
  • dose response
  • drug dose reduction
  • drug effect
  • drug safety
  • dyspnea
  • eczema
  • epilepsy
  • erythema
  • fatigue
  • febrile neutropenia
  • female
  • femoral neck fracture
  • fever
  • follow up
  • headache
  • human
  • hyperglycemia
  • hypertension
  • hypokalemia
  • hypomagnesemia
  • hyponatremia
  • hypophosphatemia
  • insomnia
  • male
  • multicenter study
  • myalgia
  • nausea
  • neutropenia
  • outcome assessment
  • overall response rate
  • overall survival
  • panniculitis
  • phase 2 clinical trial
  • pneumonia
  • priority journal
  • progression free survival
  • pruritus
  • rash
  • rectum hemorrhage
  • respiratory tract infection
  • sciatica
  • sepsis
  • spinal pain
  • survival time
  • thrombocytopenia
  • thrombophlebitis
  • treatment planning
  • upper abdominal pain
  • vomiting
  • xerostomia
  • adolescent
  • biliary tract tumor
  • clinical trial
  • disease free survival
  • genetics
  • middle aged
  • mutation
  • pathology
  • treatment outcome
  • tumor recurrence
  • Adolescent
  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols
  • Biliary Tract Neoplasms
  • Disease-Free Survival
  • Female
  • Humans
  • Imidazoles
  • Male
  • Middle Aged
  • Mutation
  • Neoplasm Recurrence, Local
  • Oximes
  • Proto-Oncogene Proteins B-raf
  • Pyridones
  • Pyrimidinones
  • Treatment Outcome


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