Ghassan K Abou-Alfa1, Teresa Macarulla2, Milind M Javle3, Robin K Kelley4, Sam J Lubner5, Jorge Adeva6, James M Cleary7, Daniel V Catenacci8, Mitesh J Borad9, John Bridgewater10, William P Harris11, Adrian G Murphy12, Do-Youn Oh13, Jonathan Whisenant14, Maeve A Lowery15, Lipika Goyal16, Rachna T Shroff17, Anthony B El-Khoueiry18, Bin Fan19, Bin Wu19, Christina X Chamberlain19, Liewen Jiang19, Camelia Gliser19, Shuchi S Pandya19, Juan W Valle20, Andrew X Zhu21. 1. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Medical College at Cornell University, New York, NY, USA. 2. Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. 3. Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA. 4. Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. 5. Department of Medicine, University of Wisconsin Carbone Cancer Center, Madison, WI, USA. 6. Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain. 7. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. 8. Department of Medicine, University of Chicago Medical Center, Chicago, IL, USA. 9. Department of Hematology-Oncology, Mayo Clinic Cancer Center, Phoenix, AZ, USA. 10. Department of Medical Oncology, UCL Cancer Institute, London, UK. 11. Department of Medicine, University of Washington, Seattle, WA, USA. 12. Department of Oncology-Gastrointestinal Cancer, Johns Hopkins University, Baltimore, MD, USA. 13. Department of Internal Medicine, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea. 14. Medical Oncology and Hematology, Utah Cancer Specialists, Salt Lake City, UT, USA. 15. Trinity St James Cancer Institute, Trinity College Dublin, Dublin, Ireland. 16. Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. 17. Department of Medicine, University of Arizona Cancer Center, Tucson, AZ, USA. 18. Department of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA. 19. Agios Pharmaceuticals, Cambridge, MA, USA. 20. Division of Cancer Sciences, University of Manchester, Manchester, UK; Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK. 21. Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA; Jiahui International Cancer Center, Jiahui Health, Shanghai, China. Electronic address: azhu@mgh.harvard.edu.
Abstract
BACKGROUND: Isocitrate dehydrogenase 1 (IDH1) mutations occur in approximately 13% of patients with intrahepatic cholangiocarcinoma, a relatively uncommon cancer with a poor clinical outcome. The aim of this international phase 3 study was to assess the efficacy and safety of ivosidenib (AG-120)-a small-molecule targeted inhibitor of mutated IDH1-in patients with previously treated IDH1-mutant cholangiocarcinoma. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 3 study included patients from 49 hospitals in six countries aged at least 18 years with histologically confirmed, advanced, IDH1-mutant cholangiocarcinoma who had progressed on previous therapy, and had up to two previous treatment regimens for advanced disease, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and a measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (2:1) with a block size of 6 and stratified by number of previous systemic treatment regimens for advanced disease to oral ivosidenib 500 mg or matched placebo once daily in continuous 28-day cycles, by means of an interactive web-based response system. Placebo to ivosidenib crossover was permitted on radiological progression per investigator assessment. The primary endpoint was progression-free survival by independent central review. The intention-to-treat population was used for the primary efficacy analyses. Safety was assessed in all patients who had received at least one dose of ivosidenib or placebo. Enrolment is complete; this study is registered with ClinicalTrials.gov, NCT02989857. FINDINGS:Between Feb 20, 2017, and Jan 31, 2019, 230 patients were assessed for eligibility, and as of the Jan 31, 2019 data cutoff date, 185 patients were randomly assigned to ivosidenib (n=124) or placebo (n=61). Median follow-up for progression-free survival was 6·9 months (IQR 2·8-10·9). Progression-free survival was significantly improved with ivosidenib compared with placebo (median 2·7 months [95% CI 1·6-4·2] vs 1·4 months [1·4-1·6]; hazard ratio 0·37; 95% CI 0·25-0·54; one-sided p<0·0001). The most common grade 3 or worse adverse event in both treatment groups was ascites (four [7%] of 59 patients receiving placebo and nine [7%] of 121 patients receiving ivosidenib). Serious adverse events were reported in 36 (30%) of 121 patients receiving ivosidenib and 13 (22%) of 59 patients receiving placebo. There were no treatment-related deaths. INTERPRETATION:Progression-free survival was significantly improved with ivosidenib compared with placebo, and ivosidenib was well tolerated. This study shows the clinical benefit of targeting IDH1 mutations in advanced, IDH1-mutant cholangiocarcinoma. FUNDING: Agios Pharmaceuticals.
RCT Entities:
BACKGROUND:Isocitrate dehydrogenase 1 (IDH1) mutations occur in approximately 13% of patients with intrahepatic cholangiocarcinoma, a relatively uncommon cancer with a poor clinical outcome. The aim of this international phase 3 study was to assess the efficacy and safety of ivosidenib (AG-120)-a small-molecule targeted inhibitor of mutated IDH1-in patients with previously treated IDH1-mutant cholangiocarcinoma. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 3 study included patients from 49 hospitals in six countries aged at least 18 years with histologically confirmed, advanced, IDH1-mutant cholangiocarcinoma who had progressed on previous therapy, and had up to two previous treatment regimens for advanced disease, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and a measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (2:1) with a block size of 6 and stratified by number of previous systemic treatment regimens for advanced disease to oral ivosidenib 500 mg or matched placebo once daily in continuous 28-day cycles, by means of an interactive web-based response system. Placebo to ivosidenib crossover was permitted on radiological progression per investigator assessment. The primary endpoint was progression-free survival by independent central review. The intention-to-treat population was used for the primary efficacy analyses. Safety was assessed in all patients who had received at least one dose of ivosidenib or placebo. Enrolment is complete; this study is registered with ClinicalTrials.gov, NCT02989857. FINDINGS: Between Feb 20, 2017, and Jan 31, 2019, 230 patients were assessed for eligibility, and as of the Jan 31, 2019 data cutoff date, 185 patients were randomly assigned to ivosidenib (n=124) or placebo (n=61). Median follow-up for progression-free survival was 6·9 months (IQR 2·8-10·9). Progression-free survival was significantly improved with ivosidenib compared with placebo (median 2·7 months [95% CI 1·6-4·2] vs 1·4 months [1·4-1·6]; hazard ratio 0·37; 95% CI 0·25-0·54; one-sided p<0·0001). The most common grade 3 or worse adverse event in both treatment groups was ascites (four [7%] of 59 patients receiving placebo and nine [7%] of 121 patients receiving ivosidenib). Serious adverse events were reported in 36 (30%) of 121 patients receiving ivosidenib and 13 (22%) of 59 patients receiving placebo. There were no treatment-related deaths. INTERPRETATION: Progression-free survival was significantly improved with ivosidenib compared with placebo, and ivosidenib was well tolerated. This study shows the clinical benefit of targeting IDH1 mutations in advanced, IDH1-mutant cholangiocarcinoma. FUNDING: Agios Pharmaceuticals.
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