Richard D Kim1, Shannon McDonough2, Anthony B El-Khoueiry3, Tanios S Bekaii-Saab4, Stacey M Stein5, Vaibhav Sahai6, George P Keogh7, Edward J Kim8, Ari D Baron9, Abby B Siegel10, Afsaneh Barzi3, Katherine A Guthrie2, Milind Javle11, Howard Hochster5. 1. H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. Electronic address: Richard.Kim@moffitt.org. 2. SWOG Statistics and Data Management Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. 3. University of Southern California, Los Angeles, CA, USA. 4. Ohio State University, Columbus, OH, USA. 5. Rutgers Cancer Institute, New Brunswick, NJ, USA. 6. University of Michigan, Ann Arbor, MI, USA. 7. Charleston Hematology Oncology Associates, Southeast COR NCORP, Charleston, SC, USA. 8. University of California Davis Cancer Center, Sacramento, CA, USA. 9. California Pacific Medical Center/Sutter Cancer Research Consortium, San Francisco, CA, USA. 10. Columbia University, Columbia MU-NCORP, New York, NY, USA. 11. University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Abstract
BACKGROUND: The rationale for the evaluation of trametinib in advanced biliary cancer (BC) is based on the presence of mitogen-activated protein kinase alterations and on earlier promising results with MEK inhibitors in BC. METHODS:Patients with histologically proven BC who progressed ongemcitabine/platinum were randomised to trametinib daily (arm 1) versus fluoropyrimidine therapy (infusional 5-fluorouracil or oral capecitabine, arm 2). The primary end-point was overall survival (OS). Secondary end-points included progression free survival (PFS) and response rate. A planned interim futility analysis of objective response was performed on the first 14 patients registered to the trametinib arm. RESULTS: The study was stopped early based on the lack of measurable response in the trametinib arm. A total of 44 eligible patients were randomised (24 patients in arm 1 and 20 patients in arm 2). Median age was 62 years and the primary sites of tumour were cholangiocarcinoma (68%) and gallbladder (32%). The overall response rate was 8% (95% CI 0%-19%) in arm 1 versus 10% (95% CI 0%-23%) in arm 2 (p > .99) Median OS was 4.3 months for arm 1 and 6.6 months for arm 2. The median PFS was 1.4 months for arm 1 and 3.3 months for arm 2. CONCLUSIONS: This is the first prospective randomised study of a targeted agent versus chemotherapy for the second-line treatment of BC. In this unselected population, the interim analysis result of unlikely benefit with trametinib resulted in early closure.
RCT Entities:
BACKGROUND: The rationale for the evaluation of trametinib in advanced biliary cancer (BC) is based on the presence of mitogen-activated protein kinase alterations and on earlier promising results with MEK inhibitors in BC. METHODS:Patients with histologically proven BC who progressed on gemcitabine/platinum were randomised to trametinib daily (arm 1) versus fluoropyrimidine therapy (infusional 5-fluorouracil or oral capecitabine, arm 2). The primary end-point was overall survival (OS). Secondary end-points included progression free survival (PFS) and response rate. A planned interim futility analysis of objective response was performed on the first 14 patients registered to the trametinib arm. RESULTS: The study was stopped early based on the lack of measurable response in the trametinib arm. A total of 44 eligible patients were randomised (24 patients in arm 1 and 20 patients in arm 2). Median age was 62 years and the primary sites of tumour were cholangiocarcinoma (68%) and gallbladder (32%). The overall response rate was 8% (95% CI 0%-19%) in arm 1 versus 10% (95% CI 0%-23%) in arm 2 (p > .99) Median OS was 4.3 months for arm 1 and 6.6 months for arm 2. The median PFS was 1.4 months for arm 1 and 3.3 months for arm 2. CONCLUSIONS: This is the first prospective randomised study of a targeted agent versus chemotherapy for the second-line treatment of BC. In this unselected population, the interim analysis result of unlikely benefit with trametinib resulted in early closure.
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