Abstract
The U.S. Food and Drug Administration has given expedited approval to ponatinib (Iclusig; ARIAD Pharmaceuticals) for patients with chronic myeloid leukemia or Philadelphia chromosome–positive acute lymphoblastic leukemia who have developed resistance to other tyrosine kinase inhibitors.
Ponatinib (Iclusig; ARIAD Pharmaceuticals) will become the fifth tyrosine kinase inhibitor (TKI) available to treat chronic myeloid leukemia (CML).
In December, the FDA gave expedited approval to the drug for patients with CML or Philadelphia chromosome–positive acute lymphoblastic leukemia. For both of the BCR–ABL mutation protein cancers, the drug is approved for patients who have developed resistance to other TKIs.
The FDA go-ahead came just 5 days after results from the 449-patient PACE phase II trial were presented at the annual meeting of the American Society of Hematology (ASH). Those results demonstrated that ponatinib was effective in patients after their cancers had become resistant to multiple TKIs or exhibited the T3151 mutation that resistant cancers acquire.
Ponatinib produced a major cytogenetic response (MCyR) in 56% (149 out of 267) of the chronic-phase CML patients in the trial and a complete cytogenetic response in 46%. Results for accelerated- and blast-phase patients were also favorable. Pancreatitis was the most common serious side effect, but only 1 patient dropped out of the trial because of it.
Ponatinib was designed to be an especially sticky molecule that could sneak under the bulky isoleucine residue of the “gatekeeper” T3151 mutation that keeps the other TKIs from binding to the BCR–ABL fusion protein, Cortes says.
The drug produced “very deep and very rapid” responses that were not isolated to just a few groups of patients, notes Jorge E. Cortes, MD, professor of medicine at the University of Texas MD Anderson Cancer Center in Houston, who reported on PACE. “These responses happen regardless of the stage of the disease and regardless of the presence or absence of mutations.”
The results presented at the ASH meeting extended findings presented at the American Society of Clinical Oncology annual meeting in June 2012 to include a full year of data from patients taking a 45-mg ponatinib pill daily.
PACE's latest results show that ponatinib has worked as planned, achieving MCyR in 70% (45 of 64) of the patients whose cancers have the T3151 mutation. Moreover, 57% (38 of 67) of those patients with other mutations and 49% (66 of 136) with no detectable mutations also achieved MCyR.
One important question to be answered is whether ponatinib will become a first-line therapy. ARIAD Pharmaceuticals in Cambridge, MA, started a multicenter phase III trial in June that will compare ponatinib and imatinib (Gleevec; Novartis) side by side as first-line CML drugs.
In addition to imatinib, the other TKIs previously approved for CML are bosutinib (Bosulif; Pfizer), dasatinib (Sprycel; BristolMyersSquibb), and nilotinib (Tasigna; Novartis). The growing selection of TKIs means doctors can tailor treatment to patients, Cortes says, drawing a comparison with the array of drugs for the treatment of hypertension from which doctors and patients can now choose.
In a phase II trial, ponatinib produced a major cytogenetic response in 56% of patients with chronic-phase chronic myeloid leukemia.
In a phase II trial, ponatinib produced a major cytogenetic response in 56% of patients with chronic-phase chronic myeloid leukemia.
For more news on cancer research, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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