By Lynda Williams, Senior medwireNews Reporter
The primary endpoint of major molecular response (MMR) at 12 months for ponatinib versus imatinib in patients with newly diagnosed chronic phase-chronic myeloid leukaemia (CML) remains undetermined, report the EPIC trial investigators.
EPIC was terminated early due to concerns over an increased risk of vascular adverse events reported in other ponatinib studies, giving a median follow-up of just 5.1 months, the researchers explain in The Lancet Oncology.
Just 10 of the 155 patients randomly assigned to receive open-label ponatinib 45 mg/day and 13 of the 152 patients given imatinib 400 mg/day were assessed for MMR (BCR-ABL1 transcript ≤0.1%) at 12 months. The endpoint was reached by 80% and 38% of these patients, respectively, and this difference did not reach significance.
However, the secondary endpoint results indicate that ponatinib might be more effective than imatinib in this patient population, say Jeffrey Lipton, from the Princess Margaret Cancer Centre in Toronto, Ontario, Canada, and co-authors.
Patients given ponatinib were significantly more likely than imatinib-treated participants to achieve MMR at 3 months (31% of 109 patients vs 3% of 114 patients), 6 months (62% of 69 patients vs 22% of 73 patients) and 9 months (86% of 22 patients vs 33% of 27 patients).
Ponatinib-treated patients were also significantly more likely to achieve MR4 (BCR-ABL1 transcript ≤0.01%) and MR4.5 (BCR-ABL1 transcript ≤0.0032%) at all times points than the imatinib group, "although patient numbers were small", the team notes.
And the median time to MMR and MR4 was shorter with ponatinib than imatinib, at 3.3 vs 5.6 months, and 5.6 versus 7.1 months, respectively. Median time to MR4.5 with ponatinib was 5.6 months while none of the imatinib-treated patients had this level of response.
"Achieving MR4.5 is a prerequisite for sustained responses in the absence of continued tyrosine kinase inhibitor therapy", the investigators write. "[T]he EPIC trial results provide a rationale to further explore the potential of ponatinib in this setting."
But they caution that arterial occlusive events occurred in 7% of 154 ponatinib-treated patients and 2% of 152 imatinib-treated patients, with serious episodes in 6% and 1%, respectively. There was a comparable rate of grade 3 and 4 ischaemic events, at 3% versus 1%.
Ponatinib was also associated with an increased risk of grade 3 or 4 lipase elevation (14 vs 2%), thrombocytopenia (12 vs 6%) and rash (6 vs 1%), compared with imatinib, but a reduced risk of neutropenia (4 vs 8%).
The authors of an accompanying comment agree that the EPIC results show the "potential of ponatinib to induce early molecular response, early MR4, and early MR4.5" but suggest that the 45 mg dose used "might not outweigh the risk of developing arterial occlusive events."
Carmen Fava and Giuseppe Saglio, from the University of Turin in Italy, therefore advise: "For this reason, the potential of ponatinib should be evaluated at lower doses even in the first-line setting, with more stringent inclusion criteria to avoid patients with high cardiovascular risk scores."
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