Date: 2014-05-31
Type of information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at the 50th American Society of Clinical Oncology (ASCO) Annual Meeting, May 30 to June 3, 2014, in Chicago
Company: Ariad Pharmaceuticals (USA - MA)
Product: Iclusig® (ponatinib)
Action
mechanism: Ponatinib (Iclusig®) is a multitargeted oral tyrosine kinase inhibitor. Its primary target is BCR-ABL, an abnormal tyrosine kinase that is expressed in chronic myeloid leukemia (CML) and Philadelphia -chromosome positive acute lymphoblastic leukemia (Ph+ ALL). It was designed using ARIAD\'s computational and structure-based drug design platform specifically to inhibit the activity of BCR-ABL. Iclusig targets not only native BCR-ABL but also its isoforms that carry mutations that confer resistance to treatment, including the T315I mutation, which is the most common mutation among resistant patients.
Iclusig® is indicated for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant or intolerant to prior TKI therapy. This indication is based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig. The recommended dose of Iclusig is a 45 mg tablet taken once-daily with or without food.
Disease: newly diagnosed chronic-phase chronic myeloid leukemia
Therapeutic area: Cancer - Oncology
Country:
Trial
details: The EPIC trial (Evaluation of Ponatinib vs. Imatinib in CML) was a Phase 3, multicenter, international, two-arm, open-label trial of ponatinib (administered at a starting dose of 45 mg once daily) vs. imatinib (administered at a starting dose of 400 mg once daily) in patients with newly diagnosed chronic-phase CML. Patients were randomized (1:1) to ponatinib or imatinib and stratified by Sokal risk score determined at time of diagnosis. On October 18, 2013 , in consultation with the U.S. Food and Drug Administration ( FDA ), ARIAD terminated the EPIC trial due to the observation of the accumulation of arterial thrombotic events in the ponatinib clinical program. From August 2012 to October 2013 , 307 patients were randomized (58% of planned enrollment). None of the prospectively defined endpoints could be analyzed due to the early termination of the trial.
Latest
news: * On May 31, 2014, Ariad Pharmaceuticals announced preliminary safety and efficacy data from the discontinued Phase 3 EPIC trial of Iclusig® (ponatinib) vs. imatinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML). On October 18, 2013 , in consultation with the FDA, Ariad terminated the EPIC trial due to the observation of the accumulation of arterial thrombotic events in the ponatinib clinical program. From August 2012 to October 2013 , 307 patients were randomized (58% of planned enrollment). None of the prospectively defined endpoints could be analyzed due to the early termination of the trial. However, several endpoints were available for analysis. Despite the fact the primary endpoint could not be analyzed due to the early termination of the trial, analysis of key secondary endpoints provides preliminary evidence of efficacy of ponatinib compared to imatinib in newly diagnosed patients with chronic-phase CML at the doses studied and at the time points reached. The median follow-up for both arms was 5 months at the time of termination of the trial, and the following observations were made:
• A higher proportion of evaluable ponatinib (94%, n=109) vs. imatinib (68%, n=114) patients achieved <10% BCR-ABL transcript level at 3 months (P<0.001). This measure of efficacy has been shown in other trials to correlate with overall survival.
• While the primary end-point of the trial could not be assessed, the MMR rate at 12 months was higher for ponatinib patients (80% of n=10) than for imatinib patients (39% of n=13; P=0.074).
• MMR rates were higher for ponatinib vs. imatinib at 3, 6, and 9 months (P=0.001):
• At 3 months, ponatinib MMR was 31% of n=109 vs. imatinib MMR of 3% of n=114
• At 6 months, ponatinib MMR was 62% of n=69 vs. imatinib MMR of 22% of n=73
• At 9 months, ponatinib MMR was 86% of n=22 vs. imatinib MMR of 33% of n=27
• MR4 and MR4.5 rates were higher for ponatinib vs. imatinib at all time points through 12 months (P<0.02).
• Median time to MMR was shorter for ponatinib (100 days) vs. imatinib (169 days).
• CCyR rates were higher for ponatinib (74% of n=54) vs. imatinib (53% of n=64) at any time (P=0.019). CCyR for ponatinib at 6 months was 86% of n=36 vs. imatinib CCyR of 60% of n=50, P=0.012.
While no new safety signals were identified, there were more adverse events (AEs) in the ponatinib arm compared with imatinib:
• More ponatinib patients experienced vascular occlusive events (8%, n=12) vs. imatinib patients (2%, n=3).
• There was a higher incidence of treatment-emergent grade 3 or 4 AEs for ponatinib vs. imatinib. The most common AEs were lipase increase (14%, n=22) vs. (2%, n=3), thrombocytopenia (12%, n=19) vs. (7%, n=10), rash (7%, n=10) vs. (1%, n=2).
• There also was a higher incidence of serious AEs for ponatinib vs. imatinib. The most common SAE was pancreatitis (3%, n=5) on the ponatinib arm; none reported with imatinib.
• More ponatinib patients vs. imatinib patients had dose reductions (36%, n= 55 vs. 7%, n=10) and discontinuations due to AEs (9%, n=14) vs. (1%, n=2).
The starting dose of ponatinib used in the EPIC trial was the same as the dose used in refractory CML patients. Going forward, further evaluation in patients with newly diagnosed chronic-phase CML will require evaluation of lower doses of ponatinib.
