In a group of heavily pretreated patients with Philadelphia (Ph)-chromosome-positive leukemia resistant to currently available tyrosine kinase inhibitors (TKIs), including patients with the BCR-ABL T315I mutation, ponatinib showed significant clinical activity in a phase 1 study published in the November 29 issue of the New England Journal of Medicine.
Ponatinib could be the "best of the bunch" of next-generation TKIs for managing chronic myeloid leukemia (CML), says John M. Goldman, DM, FRCP, from Imperial College London, United Kingdom, in an accompanying editorial. He calls the study results "very encouraging."
Ponatinib is a novel third-generation TKI that blocks native and mutated BCR-ABL, including the gatekeeper mutant T3151, which is uniformly resistant to existing TKIs.
The study involved 65 patients with Ph-positive leukemia: 43 with chronic-phase CML, 9 with accelerated-phase CML, 8 with blast-phase CML, and 5 with acute lymphoblastic leukemia (ALL). Patients received once-daily ponatinib at doses ranging from 2 to 60 mg. Follow-up ranged from 2 to 140 weeks (median, 56 weeks).
Of the patients with chronic-phase CML, 98% had a complete hematologic response, 72% had a major cytogenetic response, and 44% had a major molecular response, the authors, led by Jorge E. Cortes, MD, from the University of Texas M.D. Anderson Cancer Center in Houston, report.
Of the chronic-phase CML patients with the T315I mutation, 100% had a complete hematologic response and 92% had a major cytogenetic response. Of the chronic-phase CML patients without detectable mutations, 100% had a complete hematologic response and 62% had a major cytogenetic response.
Responses to ponatinib have been "durable," the authors note, "with the median duration of response in patients with chronic-phase CML yet to be reached at the time of this analysis but exceeding 1 year."
Of the patients with accelerated-phase or blast-phase CML or Ph-positive ALL, 36% had a major hematologic response and 32% had a major cytogenetic response.
Responses "Very Impressive"
"This is a very effective drug and a very welcome addition for the treatment of CML," Dr. Cortes told Medscape Medical News. "The responses are very impressive considering the nature of the patients, who have received so many previous therapies. The toxicity profile is very good also," he added.
The most common treatment-related adverse events were skin disorders and constitutional symptoms, "which were generally low-grade in severity and were manageable," the authors say. Dose-limiting toxic effects included pancreatic events, with pancreatitis occurring in 14% of patients.
Myelosuppression, an expected adverse event in this heavily pretreated population, was also common. The vast majority of study patients had been previously treated with at least 2 approved TKIs, and often 3 or more.
This phase 1 study led to a recommended clinical dose of 45 mg daily in a subsequent phase 2 study in which patients with CML who had resistance to imatinib and second-generation TKIs received ponatinib. "Preliminary results suggest that the drug has considerable activity in this patient population," Dr. Goldman notes in his editorial.
The phase 2 study will be discussed at the upcoming annual meeting of the American Society of Hematology. Ponatinib is also being tested in "2 ongoing front-line studies," Dr. Cortes said.
It is worth mentioning that ponatinib also functions as a multikinase inhibitor, with activity against other clinically relevant kinases, including KIT, PDFGRA, FGFR1, and FLT3, "and could therefore be useful in treating patients whose tumors harbor these gene mutations," Dr. Goldman writes.
"Ponatinib may turn out to be another step forward in the march toward real success with molecularly targeted therapy for cancer," he notes.
Ariad Pharmaceuticals has filed for regulatory approval of ponatinib in the United States.
The study was supported by Ariad Pharmaceuticals and by a grant to the University of Texas M.D. Anderson Caner Center from the National Institutes of Health. Dr. Cortes and Dr. Goldman report receiving consulting fees from Ariad Pharmaceuticals and other pharmaceutical companies, as detailed in the paper.
N Engl J Med. 2012;367:2075-2088, 2148-2149. Abstract, Editorial
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ALSO see home page for link to an article about the research collaboration as published on OHSU's website.
Snip:
'Druker said the Phase I trial results for ponatinib are similar to how patients responded during clinical trials of Gleevec, which had one of the fastest FDA approvals in history after proving it could successfully stop the rogue tyrosine kinase enzyme.
Gleevec was the first of what is now a growing class of targeted cancer therapies that work by manipulating specific molecules inside a cell. Druker and his colleagues revolutionized cancer treatment and research by proving with Gleevec that it was possible for a compound to zero in on only the molecules that are malfunctioning inside a patient’s cells without harming healthy cells. This work ushered in the era of truly personalized cancer medicine.'