EPIC: A Phase 3 Trial of Ponatinib Compared With Imatinib in CP-CML Patients

403 EPIC: A Phase 3 Trial of Ponatinib Compared With Imatinib in CP-CML Patients Jeffrey H. Lipton, PhD, MD1, Charles Chuah2, Agnes Guerci-Bresler3, Gianantonio Rosti4, David Simpson5, Stephanie Lustgarten6, Victor M. Rivera6, Tim Clackson6, Frank G. Haluska6, Michele Baccarani7, Jorge E. Cortes8, Francois Guilhot9, Andreas Hochhaus10, Timothy P. Hughes11, Hagop Kantarjian8, Neil P. Shah12, Moshe Talpaz13, Michael W. Deininger14 1Prince Margaret Cancer Centre, University of Toronto; 2Singapore General Hospital/Duke-NUS Graduate Medical School; 3Hopitaux de Brabois, Allee du Morvan; 4S’Orsola-Malpighi University Hospital; 5North Shore Hospital; 6ARIAD Pharmaceuticals, Inc.; 7S’Orsola-Malpighi University Hospital; 8The University of Texas MD Anderson Cancer Center; 9University Hospital; 10Jena University Hospital; 11Institute of Medicine and Veterinary Science; 12University of California San Francisco; 13Comprehensive Cancer Center, University of Michigan; 14Huntsman Cancer Institute, University of Utah Introduction: Ponatinib is an approved potent oral BCR-ABL TKI with activity in heavily-pretreated Ph+ leukemia. EPIC was an international, randomized, phase 3 trial of ponatinib (45mg qd) compared with imatinib (400mg qd) in newly-diagnosed CP-CML patients stratified by Sokal risk score. On 18-Oct-2013, EPIC was terminated due to arterial thrombotic events (ATEs) in the ponatinib clinical program. Consequently, prospectively-defined endpoints could not be analyzed. Data as of 1-Apr2014 are presented for analyzable endpoints: BCR-ABLIS<10% at 3 months; MMR, MR4, and MR4.5 at and after at least 3, 6, 9 and 12 months and at any time; time to response; CCyR at 6, 12 months and anytime; safety. Results: At study termination, data were available for 306 treated patients (154 ponatinib, 152 imatinib); median follow-up: 5.1 months. Fourteen ponatinib and 2 imatinib patients discontinued due to adverse events (AEs). Molecular response rates for ponatinib were uniformly higher than imatinib, for all response measures and at all timepoints (Table). Most common (≥25%) all-grade treatment-emergent AEs with ponatinib: rash (38%), abdominal pain (36%), headache (33%), constipation (27%), increased lipase (27%), myalgia (26%), thrombocytopenia (25%); with imatinib: nausea (34%), muscle spasms (34%), diarrhea (27%). 12% ponatinib and 7% imatinib patients had grade 3/4 thrombocytopenia; 3% ponatinib and 8% imatinib patients had grade 3/4 neutropenia. Treatment-emergent serious AEs (SAEs) in ≥3 ponatinib patients: pancreatitis (n=5), atrial fibrillation (n=3), and thrombocytopenia (n=3); no SAEs occurred in ≥3 imatinib patients. 11(7%) ponat inib and 3 (2%) imatinib patients experienced ATEs (designated serious for 10 (7%) ponatinib, 1 (0.7%) imatinib). Conclusions: Preliminary evidence suggests that ponatinib has improved efficacy over imatinib in newly-diagnosed CPCML, but has more AEs at the dose studied. To improve benefit/risk, future frontline ponatinib trials will likely use lower doses and account for relevant risk factors.