(ChemotherapyAdvisor) – Once-daily ponatinib (AP24534), a pan-BCR-ABL inhibitor, was “highly active” in heavily pretreated patients with Philadelphia chromosome-positive leukemias resistant to tyrosine kinase inhibitors (TKIs), investigators concluded in the November 29 issue of The New England Journal of Medicine.
“In our study, we found that ponatinib had activity in all of the following situations: against a spectrum of mutants in patients in whom previous therapy had failed, against the T315I mutant, and against disease that had been refractory to therapy with multiple TKIs in the absence of detectable BCR-ABL mutations,” noted Jorge E. Cortes, MD, of the MD Anderson Cancer Center, Houston, TX, and colleagues.
A total of 81 patients were enrolled in the phase 1 dose-excalation study, 60 with CML and 5 with Ph-positive acute lymphoblastic leukemia (ALL). Ponatinib, which was rationally designed to address limitations of currently available TKIs, was administered at doses ranging from 2mg/day to 60mg/day.
Median follow-up was 56 weeks (range, 2 to 140 weeks). Among patients with chronic phase (CP) CML, 93% had received two or more approved TKIs and 49% had received all three approved agents; among Ph-positive patients, 91% and 51% had received two and three TKIs, respectively.
The most common treatment-related adverse events were generally low-grade rash, myelosuppression, and constitutional symptoms, which were manageable.
Dose-limiting toxic effects included elevated lipase or amylase levels and pancreatitis, the latter of which was observed in 14% of patients.
Of 43 patients with CP-CML, 98% had a complete hematologic response, 72% a major cytogenetic response, and 44% a major molecular response. Of 12 patients with CP-CML and the T315I mutation, 100% had a complete hematologic response and 92%, a major cytogenetic response. Of 13 patients with CP-CML without detectable mutations, 100% had a complete hematologic response and 62%, a major cytogenetic response. Responses among patients with CP-CML were durable. Of 22 patients with accelerated-phase or blast-phase CML or Ph-positive ALL, 36% had a major hematologic response and 32%, a major cytogenetic response.
An accompanying editorial noted: “Ponatinib, now termed a third-generation tyrosine kinase inhibitor, could prove to be the best of the bunch for managing CML. It could also be valuable for treating advanced-phase disease, an area in which the other tyrosine kinase inhibitors have not been conspicuously successful.”
This study was funded by Ariad Pharmaceuticals and others.