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Ref Type Journal Article
PMID (32818466)
Authors Subbiah V, Lassen U, Élez E, Italiano A, Curigliano G, Javle M, de Braud F, Prager GW, Greil R, Stein A, Fasolo A, Schellens JHM, Wen PY, Viele K, Boran AD, Gasal E, Burgess P, Ilankumaran P, Wainberg ZA
Title Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial.
Journal Vol Issue Date Pages Journal Short Title
The Lancet. Oncology 21 9 2020 09 1234-1243 Lancet Oncol
URL
Abstract Text 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.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.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.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.GlaxoSmithKline and Novartis.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E biliary tract cancer sensitive Dabrafenib + Trametinib Phase II Actionable In a Phase II trial (ROAR), Tafinlar (dabrafenib) in combination with Mekinist (trametinib) demonstrated a manageable safety profile and resulted in an overall response rate of 51% (22/43, all partial responses) in patients with biliary tract cancer harboring BRAF V600E, with a median duration of response of 9 months, a median progression-free survival of 9 months, and a median overall survival of 14 months (PMID: 32818466; NCT02034110). 32818466
BRAF V600E Advanced Solid Tumor sensitive Dabrafenib + Trametinib FDA approved Actionable In 3 Phase II trials (ROAR, NCI-MATCH, X2101) that supported FDA approval, Tafinlar (dabrafenib) and Mekinist (trametinib) combination therapy demonstrated safety and efficacy in adult and pediatric (6 years or older) patients with advanced solid tumors harboring BRAF V600E (PMID: 34838156, PMID: 32818466, J Clin Oncol 37, no. 15_suppl (May 20, 2019) 3002, J Clin Oncol 38, no. 15_suppl (May 20, 2020) 10506; NCT02034110, NCT02465060, NCT02124772). 32818466 detail... detail... 34838156 detail... detail...