Ponatinib Achieves Primary Endpoints in CML Subtypes

Anita T. Shaffer @Shaffer1
Published: Wednesday, Aug 08, 2012
Dr. Jorge E. Cortes

Jorge E. Cortes, MD

Ponatinib, an oral multikinase inhibitor, generated significant responses in more than 50% of patients with certain chronic myeloid leukemia (CML) subtypes, in a phase II trial intended to pave the way for a regulatory submission. The benefit reached 70% for some patients with CML who also harbored a T315I gene mutation.

The drug is under investigation as a treatment for patients with CML who are resistant or intolerant (R/I) to dasatinib (Sprycel) or nilotinib (Tasigna), or for those with the T315I mutation, said lead investigator Jorge E. Cortes, MD, chair of the CML Section in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston. Those two drugs have joined imatinib (Gleevec) as front-line treatment for CML.

“These results are outstanding,” Cortes said in an interview after presenting the findings at an oral session at ASCO 2012. “Two-thirds of patients had failed three tyrosine kinase inhibitors, so this was a very, very heavily treated population.”

Ponatinib is a third-generation tyrosine kinase inhibitor that has demonstrated potent activity against native and mutated bcr-abl and other kinases, as well as in subtypes with a T315I gene mutation.

The PACE trial enrolled 449 patients in cohorts based on whether they were diagnosed with refractory CML in chronic phase (CP), acute phase (AP), or blast phase (BP) CML, and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). Each group was further categorized according to whether the participants were R/I to prior treatment, or whether they exhibited a T315I mutation.

The primary endpoint for the patients with CP-CML was a major cytogenic response (MCyR), while the outcome was a major hematologic response (MaHR) in the other subtypes. All patients received 45 mg of ponatinib once daily.

In the CP-CML group, 54% of patients (144 of 267) achieved MCyR, which included 70% of patients with the T315I mutation (45 of 64).

For the AP-CML group, 58% of patients (48 of 83) reached MaHR; patients in the R/I group achieved a higher response of 60% (39 of 65) than those with the mutation.

In the BP-CML and Ph+ALL groups, 34% of patients achieved MaHR (32 of 94), with a slight advantage for those without the T315I mutation (35% vs 33%, respectively).

In a further breakdown for patients in the chronic CP-CML phase, Cortes said 44% of patients overall (118 of 267) exhibited a complete cytogenic response (CCyR), a figure that includes a 66% CCyR for those with the T315I mutation (42 of 64).

Overall, Cortes said that responses in patients with CML were observed regardless of mutation status or disease stage, and that the responses occur early and improve over time. He also said that responses tend to be durable, with 93.3% of those in the CP-CML group projected to remain in MCyR at one year.

Although enrollment in the study is closed, the data are continuing to mature. The results Cortes reported at ASCO were for median follow-up periods of approximately 10 months for the CML patients and 6.2 for the BP-CML/Ph+ALL group.

Cortes said ponatinib was well tolerated, with most adverse events consisting of “transient and manageable” grade I or II effects; the most frequently reported problems being rash, dry skin, and abdominal pain. Lipase elevation was the most frequently reported ≥grade III adverse event (10% of patients overall).

Eighteen patients died during the study, with five of those deaths potentially attributed to the study, said Cortes. He said the number of deaths is relatively small considering the trial’s total enrollment, and is similar to mortality experienced with other trials.

Cortes said ponatinib may be an important new treatment for patients with CML and Ph+ALL who are R/I to dasatinib or nilotinib, or who have the T3151 mutation.

Michael J. Mauro, MD, the discussant for the ASCO session, agreed about ponatanib’s potential. “Ponatinib is seemingly re-revolutionalizing CML and providing remarkable ability to salvage resistant disease, especially in T315I patients,” said Mauro, who specializes in blood cancers at the Knight Cancer Institute at the Oregon Health & Science University in Portland. He said earlier use may provide even better results.

Ariad Pharmaceuticals, Inc, which is developing the drug, plans to file for regulatory approvals for ponatinib in the United States and the European Union during the third quarter of 2012, the company said in mid-June.


Cortes JE, Kim D-W, Pinilla-Ibarz J, et al. PACE: a pivotal phase II trial of ponatinib in patients with CML and Ph+ALL resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation. J Clin Oncol. 2012;30(suppl; abstr 6503).



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