Promising Secondary Endpoints for Ponatinib in CML Despite Early EPIC Trial Termination

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The EPIC trial of ponatinib vs imatinib for chronic myeloid leukemia terminated early due to a high risk of arterial events.
The EPIC trial of ponatinib vs imatinib for chronic myeloid leukemia terminated early due to a high risk of arterial events.

The head-to-head EPIC trial of ponatinib vs imatinib in previously untreated chronic myeloid leukemia (CML) was terminated early due to risk of arterial events, which resulted in insufficient data for full analysis of the primary outcome, but all secondary endpoints favored ponatinib.1

“Ponatinib outperformed imatinib in all aspects except disease-free survival, which could not be measured because of early termination of the study,” Jeffrey H. Lipton, MD, PhD, of the Cancer Clinical Research Unit at the Princess Margaret Cancer Centre in Toronto, Canada, told Cancer Therapy Advisor. Dr Lipton and colleagues published the results from the EPIC trial in the Lancet Oncology.1

The EPIC trial aimed to determine if ponatinib provided deeper molecular remissions without development of drug resistance, with an acceptable safety profile, compared with imatinib. Ponatinib is approved for the treatment of all phases of CML and Philadelphia chromosome–positive acute lymphoblastic leukemia that are resistant or intolerant to other tyrosine kinase inhibitors (TKIs).

First-line treatment of CML may include imatinib, a first-generation TKI, but about 25% of patients will develop resistance or intolerance to the drug. Alternatively, patients with chronic phase disease may receive the second-generation TKIs dasatinib or nilotinib, but can develop resistance to these agents as well.1

Ponatinib, a pan-TKI, has demonstrated efficacy in patients with CML who harbor the T315I mutation in the BCR-ABL1 protein.2 This mutation prevents binding of most TKIs, enabling drug evasion and resurgence of disease.

In patients with CML who were resistant to all other TKIs, treatment with ponatinib in a previous study resulted in a 56% major cytogenetic response (MCR) rate and a 39% major molecular response (MMR) rate.3 However, the researchers observed that about 11% of patients who received ponatinib for a median of 11 months developed arterial occlusive events, raising the question of ponatinib's benefit-to-risk ratio.4

In an effort to further study ponatinib's molecular remissions, investigators conducted the EPIC trial, in which 307 patients with CML were randomly assigned to receive 45 mg of ponatinib or 400 mg of imatinib once daily until progression, unacceptable toxicity, or other withdrawal criteria.

The primary endpoint was MMR at 12 months. Secondary endpoints included a proportion of patients with BCR-ABL1 transcripts less than 10% at 3 months, as well as MMR; molecular response (MR) 4.0; and MR 4.5 at 1, 2, 3, and 6 months and every 3 months thereafter; complete cytogenetic response (CCR) at 6 and 12 months; progression-free survival; and overall survival.

Adult patients were eligible for inclusion in EPIC if they had been diagnosed with CML within the prior 6 months and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Exclusion criteria included prior TKI or other anticancer therapy for CML (except anagrelide or hydroxyurea), uncontrolled hypertriglyceridemia, and significant and uncontrolled cardiovascular disease.

Patient characteristics were similar between arms at baseline, with a median age of 53 and 62% of patients were male. At baseline, 76.5% and 22.5% of patients had an ECOG performance status of 0 or 1, respectively. The Sokal risk score was low in 41% of patients, intermediate in 42.5%, and high in 16%.

The number of cardiovascular risk factors (hypertension, hypercholesterolemia, diabetes, obesity, and smoking) and history of cardiovascular disease (ischemic disease, nonischemic cardiac disease, and venous thromboembolism) was 0 in 30% of patients, 1 in 26% of patients, and 2 in 16.5% of patients. In the ponatinib arm, 32% of patients had 3 or more risk factors or a history of cardiovascular disease, whereas 21% did in the imatinib arm.

RELATED: Researchers Identify Risk Factors for Bosutinib-related Cardiac, Vascular Toxicities

Although EPIC did not meet the data monitoring committee's criterion for risk assessment, concerns of arterial occlusion from other ponatinib trials resulted in early termination in October 2013. Therefore, the median follow-up of the trial was 5.1 months, and the primary endpoint was evaluable in only 23 patients.

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