Vivek Subbiah1, Ulrik Lassen2, Elena Élez3, Antoine Italiano4, Giuseppe Curigliano5, Milind Javle6, Filippo de Braud7, Gerald W Prager8, Richard Greil9, Alexander Stein10, Angelica Fasolo11, Jan H M Schellens12, Patrick Y Wen13, Kert Viele14, Aislyn D Boran15, Eduard Gasal16, Paul Burgess17, Palanichamy Ilankumaran16, Zev A Wainberg18. 1. Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: vsubbiah@mdanderson.org. 2. Department of Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 3. Medical Oncology Department, Vall d'Hebron Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain. 4. Early Phase Trials and Sarcoma Units, Institut Bergonié, Bordeaux, France. 5. Division of Early Drug Development, Istituto Europeo di Oncologia, IRCCS, and University of Milano, Milan, Italy. 6. Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA. 7. Dipartimento di Oncologia, Istituto Nazionale dei Tumori, Milan, Italy. 8. Department of Medicine I, Comprehensive Cancer Center Vienna, Medical University Vienna, Vienna, Austria. 9. Third Medical Department, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute, CCS Salzburg, Salzburg, Austria. 10. Department of Internal Medicine II (Oncology Center), University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 11. Department of Medical Oncology, IRCCS Ospedale San Raffaele, Milan, Italy. 12. Department of Clinical Pharmacology, Netherlands Cancer Institute, Antoni van Leeuwenhoek, Amsterdam, Netherlands. 13. Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. 14. Berry Consultants, Austin, TX, USA; Department of Biostatistics, University of Kentucky, Lexington, KY, USA. 15. Precision Medicine, Novartis Pharmaceuticals, East Hanover, NJ, USA. 16. Global Drug Development, Novartis Pharmaceuticals, East Hanover, NJ, USA. 17. Global Drug Development, Novartis Pharma, Basel, Switzerland. 18. Department of Medicine, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA, USA.
Abstract
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.
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.
Authors: James M Cleary; Srivatsan Raghavan; Qibiao Wu; Yvonne Y Li; Liam F Spurr; Hersh V Gupta; Douglas A Rubinson; Isobel J Fetter; Jason L Hornick; Jonathan A Nowak; Giulia Siravegna; Lipika Goyal; Lei Shi; Lauren K Brais; Maureen Loftus; Atul B Shinagare; Thomas A Abrams; Thomas E Clancy; Jiping Wang; Anuj K Patel; Franck Brichory; Anne Vaslin Chessex; Ryan J Sullivan; Rachel B Keller; Sarah Denning; Emma R Hill; Geoffrey I Shapiro; Anna Pokorska-Bocci; Claudio Zanna; Kimmie Ng; Deborah Schrag; Pasi A Jänne; William C Hahn; Andrew D Cherniack; Ryan B Corcoran; Matthew Meyerson; Antoine Daina; Vincent Zoete; Nabeel Bardeesy; Brian M Wolpin Journal: Cancer Discov Date: 2021-04-29 Impact factor: 39.397