J. Lipton, C. Chuah, A. Guerci-Bresler
Dec 6, 2014
Citations
1
Influential Citations
56
Citations
Quality indicators
Journal
Blood
Abstract
Background : Ponatinib is an approved potent oral tyrosine kinase inhibitor active against native and mutated forms of BCR-ABL, including T315I. The phase 2 PACE study demonstrated that ponatinib is highly active in heavily pretreated Philadelphia chromosome‒positive leukemia patients. Ponatinib efficacy and safety were evaluated in newly diagnosed CP-CML patients in the EPIC trial. Methods : EPIC was a multicenter, international, phase 3, randomized, 2-arm, open-label trial of ponatinib (45 mg once daily) compared with imatinib (400 mg once daily) in newly diagnosed CP-CML; patients were stratified by Sokal risk score (low [ 1.2]). On 18 October 2013,EPIC was terminated due to the observation of arterial thrombotic events in the ponatinib development program. Consequently, none of the prospectively defined endpoints could be analyzed. Data as of 1 April 2014 are presented for endpoints that could be analyzed: BCR-ABLIS <10% rate at 3 months; major molecular response (MMR), molecular response (MR)4, and MR4.5 rates at and after at least 3, 6, 9, and 12 months and at any time; time to response; complete cytogenetic response rates at 6 and 12 months and any time; and safety. Results : At the time of study termination, 307 patients had been randomized; median follow-up was 5.1 (0.03-17.6) months. Groups were well-balanced with respect to sex, age, pretreatment, and Sokal score; however, the proportion of patients with 1 or more cardiovascular risk factors (hypertension, hypercholesterolaemia, diabetes, obesity and smoking) was higher in the ponatinib arm (n=97, 63%) compared to the imatinib arm (n=79, 52%). Data were available on 306 treated patients (154 ponatinib, 152 imatinib). Fourteen ponatinib and 2 imatinib patients discontinued due to adverse events (AEs). Molecular response rates for ponatinib were uniformly higher compared with imatinib for all response measures and at all time points ( Table ). The percentage of patients who achieved <10% BCR-ABL at 3 months was significantly higher in the ponatinib compared with imatinib arm overall (Table), and when patients were stratified by high-risk, intermediate-risk, and low-risk Sokal score (Figure). The percentage of patients who achieved MMR, MR4, and MR4.5 at any time in all Sokal risk groups was higher for ponatinib than imatinib ( Figure ). The most common (≥25%) all-grade treatment-emergent AEs with ponatinib were rash (38%), abdominal pain (36%), headache (33%), constipation (27%), increased lipase (27%), myalgia (26%), and thrombocytopenia (25%); with imatinib, they were nausea (34%), muscle spasms (34%), and diarrhea (27%). Twelve percent of ponatinib and 7% of imatinib patients had grade 3/4 thrombocytopenia; 3% of ponatinib and 8% of imatinib patients had grade 3/4 neutropenia. Serious treatment-emergent AEs (SAEs) occurring in ≥3 ponatinib patients were pancreatitis (n=5), atrial fibrillation (n=3), and thrombocytopenia (n=3); no individual SAEs occurred in ≥3 imatinib patients. Eleven (7%) ponatinib and 3 (2%) imatinib patients experienced arterial thrombotic events, designated serious for 10 [7%] ponatinib and 1 [0.7%] imatinib patient(s). One patient in the ponatinib arm experienced a serious venous thromboembolic event: there were none in the imatinib arm. Ten of 11 ponatinib patients, and 2 of 3 imatinib patients with arterial thrombotic events had 1 or more cardiovascular risk factors. Conclusions : Despite early termination, at a median follow-up of 5 months, preliminary evidence suggests that ponatinib has improved efficacy over imatinib in newly diagnosed CP-CML patients, but has a higher AE rate, including ATEs at the dose studied. Future investigations of ponatinib in the frontline setting will likely use lower doses and account for relevant risk factors. | Table: Molecular Response Rates | || | | At 3 months | At 6 months | At 9 months | At 12 months | At any time | | Ponatinib N=109 | Imatinib N=114 | Ponatinib N=69 | Imatinib N=73 | Ponatinib N=22 | Imatinib N=27 | Ponatinib N=10 | Imatinib N=13 | Ponatinib N=149 | Imatinib N=142 | | MMR, n (%) | 34 (31) | 3 (3) | 43 (62) | 16 (22) | 19 (86) | 9 (33) | 8 (80) | 5 (39) | 61 (41) | 25 (18) | | MR4, n (%) | 8 (7) | | 22 (32) | 1 (1) | 14 (64) | 1 (4) | 6 (60) | | 31 (21) | 2 (1) | | MR4.5, n (%) | 5 (5) | | 11 (16) | | 7 (32) | | 6 (60) | | 22 (15) | | | ≤10% BCR-ABL transcripts, n (%) | 103 (94) | 77 (68) | | | | | | | | | Abstract 519. Table ![Figure:][1] Figure: Patients Achieving <10% BCR-ABL Transcript Levels at 3 Months and Molecular Response (MMR, MR4, MR4.5) at Any Time, by Sokal Risk Score Disclosures Lipton: Novartis, BMS, Pfizer: Honoraria, Research Funding, Speakers Bureau; Novartis, BMS, Pfizer, Teva: Consultancy. Off Label Use: Ponatinib is a BCR-ABL kinase inhibitor that has been approved by the US FDA for the treatment of adult patients with CML (all phases) or Ph+ ALL that is T315I-positive or for whom no other TKI therapy is indicated.. Chuah: Novartis, BMS: Honoraria. Assouline: Pfizer, Novartis: Honoraria, Research Funding. Etienne: Novartis, BMS,Pfizer, ARIAD Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nicolini: Novartis, BMS, ARIAD Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Le Coutre: ARIAD Pharmaceuticals, Inc., Novartis, BMS, Pfizer: Honoraria. Clark: Novartis, Sanofi Aventis: Speakers Bureau; Novartis, Pfizer, Sanofi Aventis: Honoraria; Novartis, BMS, Pfizer, Sanofi Aventis: Research Funding. Stenke: ARIAD Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Oehler: ARIAD Pharmaceuticals, Inc.: Advisory board Other. Lustgarten: ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera: ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Clackson: ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Haluska: ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Baccarani: ARIAD, Novartis, BMS, Pfizer, Teva: Honoraria, Speakers Bureau; ARIAD, Novartis, BMS: Consultancy. Cortes: ARIAD, BMS, Novartis, Pfizer, Teva: Consultancy, Research Funding. Guilhot: ARIAD Pharmaceuticals, Inc.: Honoraria. Hochhaus: ARIAD Pharmaceuticals, Inc.: Research Funding. Hughes: Novartis, BMS, ARIAD: Honoraria, Research Funding. Kantarjian: ARIAD, Pfizer, Amgen: Research Funding. Shah: ARIAD Pharmaceuticals, Inc., BMS: Research Funding. Talpaz: ARIAD Pharmaceuticals, Inc., BMS, Sanofi, Incyte, Pfizer: Research Funding. Deininger: BMS, ARIAD, Novartis, Incyte, Pfizer: Consultancy; BMA, ARIAD, Novartis, Incyte, Pfizer: Advisory Board, Advisory Board Other; BMS, Novartis, Celgene, Genzyme, Gilead: Research Funding. [1]: pending:yes