ORLANDO – The novel oral drug ponatinib may provide a much-needed therapeutic option for patients who develop resistance to at least two approved therapies for Philadelphia chromosome-positive chronic myeloid leukemia, a study has shown.
Results from an open-label phase I dose-escalation trial show major cytogenetic response rates as high as 66% in this heavily pretreated population.
Dr. Jorge Cortes
In addition, all 11 patients with the dreaded T315I mutation that responds to none of the approved therapies had complete hematologic responses with ponatinib (also known as AP24534), and 9 had had a major cytogenetic response (8 of which were complete). The T315I subgroup included patients with other Philadelphia-positive (Ph+) blood cancers.
The trial followed laboratory studies that demonstrated ponatinib, a multitargeted tyrosine kinase inhibitor, can eliminate cells with "this very tough mutation" in the test tube, the lead author, Dr. Jorge Cortes, noted at a press briefing in advance of a presentation Dec. 6 at the annual meeting of the American Society of Hematology. The preclinical work also showed the new agent could prevent the emergence of cells with mutations that make them resistant to the existing CML drugs.
"So that made us think it could be a very valuable drug for these patients," said Dr. Cortes, professor of medicine at the University of Texas M.D. Anderson Cancer Center in Houston.
Investigators enrolled 74 patients with refractory hematologic cancers in the trial, for which he reported data as of Oct. 15. The malignancies included acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), but the large majority of patients had Ph+ CML.
Nearly all (95%) of the Ph+ CML patients had experienced failures of more than two previous therapies, and 64%, more than three – these included imatinib (Gleevec, 96%); dasatinib (Sprycel, 89%); and nilotinib (Tasigna, 55%). All patients were assigned to daily doses of ponatinib in the trial, which identified the maximum tolerated dose as 45 mg/day. Men comprised just over half of the population, and the median age was 56 years (range, 26-85).
Among 55 evaluable patients, 38 had CML in the chronic phase. Of these, 36 (95%) had a complete hematologic response, and 25 (66%) had a major cytogenetic response; the latter included 20 (53%) patients with complete cytogenetic responses.
When 17 Ph+ patients were grouped together regardless of disease or stage of disease, 6 (35%) had a major hematologic response, and 4 (24%) had a major cytogenetic response, including 2 (12%) with a complete cytogenetic response.
The investigators projected that the sustained major cytogenetic response rate would be 78% at 1 year, with the median not yet reached.
Based on these results, Dr. Cortes announced that a phase II study called PACE has already been started to look at treating "all patients with Philadelphia-positive diseases in all stages of the disease."
At this point imatinib, dasatinib, and nilotinib have been approved as first- and second-line therapies for Ph+ CML, and at least two other drugs, bosutinib and omacetaxine mepesuccinate, are in development. Despite the success of the approved tyrosine kinase inhibitors, more drugs are needed, Dr. Cortes said, because they do not cure everyone.
"We need to recognize [that as good as] results so far are, we are not curing everybody," he said.
For physicians, the challenge will be to select the right drugs for each patient, he added in an interview. "We are going to have to be smart enough to learn how to integrate more of these options into treatment with algorithms to identify which patients are more likely to respond to one drug than another."
More drugs are needed, agreed Dr. Peter Emanuel, moderator of the press briefing, but the number and efficacy of drugs raises questions about which will continue to be used. "The burning question is whether imatinib will eventually become a historical drug," said Dr. Emanuel, director of the Winthrop P. Rockefeller Cancer Institute at the University of Arkansas for Medical Sciences in Little Rock.
Dr. Cortes disclosed receiving funding from Ariad Pharmaceuticals, which sponsored the trial. Seven coauthors disclosed relationships with the company. In addition, several coauthors disclosed relationships with Novartis and other companies.