ARIAD has announced preliminary safety and efficacy data of ponatinib in patients with newly diagnosed chronic myeloid leukaemia (CML) from the discontinued phase III Evaluation of Ponatinib vs. Imatinib in CML (EPIC) trial.
ARIAD has announced preliminary safety and efficacy data of ponatinib in patients with newly diagnosed chronic myeloid leukaemia (CML) from the discontinued phase III Evaluation of Ponatinib vs. Imatinib in CML (EPIC) trial.
EPIC trial design
The EPIC trial was a phase III, multicentre, international, two-arm, open-label trial of ponatinib (administered at a starting dose of 45 mg once daily) versus 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 US 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 programme.
From August 2012 to October 2013, 307 patients were randomized (58% of planned enrolment). None of the prospectively defined endpoints could be analysed due to the early termination of the trial. However, the following endpoints were available for analysis:
• <10% BCR-ABL transcript level by the international scale at 3 months;
• major molecular response (MMR), MR4 and MR4.5 rates at 3, 6, 9 and 12 months;
• MMR, MR4 and MR4.5 rates at least 3, 6, 9 and 12 months;
• MMR, MR4 and MR4.5 rates at any time (best response);
• time to MMR, MR4 and MR4.5;
• complete cytogenetic response (CCyR) at any time and at 6 and 12 months; and
• safety.
MMR at 12 months was the primary end-point of the trial. MMR is defined as a less than or equal to 0.1% ratio of BCR-ABL to ABL transcripts on the International Scale measured in peripheral blood. MR4 and MR4.5 are 4 log and 4.5 log reductions in BCR transcript levels, respectively.
EPIC trial findings
Despite the fact the primary end-point could not be analysed due to the early termination of the trial, analysis of the main secondary end-points provides preliminary evidence of efficacy of ponatinib compared with 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) versus 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 versus imatinib at 3, 6 and 9 months (p =0.001):
• at 3 months, ponatinib MMR was 31% of n=109 versus imatinib MMR of 3% of n=114;
• at 6 months, ponatinib MMR was 62% of n=69 versus imatinib MMR of 22% of n=73;
• at 9 months, ponatinib MMR was 86% of n=22 versus imatinib MMR of 33% of n=27;
• MR4 and MR4.5 rates were higher for ponatinib versus imatinib at all time points through 12 months (p<0.02);
• Median time to MMR was shorter for ponatinib (100 days) versus imatinib (169 days); and
• CCyR rates were higher for ponatinib (74% of n=54) versus imatinib (53% of n=64) at any time (p=0.019). CCyR for ponatinib at 6 months was 86% of n=36 versus 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) versus imatinib patients (2%, n=3).
• There was a higher incidence of treatment-emergent grade 3 or 4 AEs for ponatinib versus imatinib. The most common AEs were lipase increase (14%, n=22) versus (2%, n=3), thrombocytopenia (12%, n=19) versus (7%, n=10), and rash (7%, n=10) versus (1%, n=2).
• There also was a higher incidence of serious AEs for ponatinib versus imatinib. The most common SAE was pancreatitis (3%, n=5) on the ponatinib arm; none reported with imatinib.
• More ponatinib patients versus imatinib patients had dose reductions (36%, n=55 versus 7%, n=10) and discontinuations due to AEs (9%, n=14) versus (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.
“The data from the EPIC trial have helped inform a planned dose-ranging trial of ponatinib in patients with refractory CML and will help guide potential future studies in earlier lines of CML therapy, including in front-line patients,” stated Frank G. Haluska, MD, PhD, senior vice president of clinical research and development and chief medical officer at ARIAD. “Our continued goal is to optimize the benefit/risk of ponatinib in each of these patient populations.”
