Pivotal Trial Shows Robust Activity of Ponatinib in Some Heavily Pretreated Leukemias

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Ponatinib is generally well tolerated, and more studies in CML and [Philadelphia chromosome–positive] ALL will be forthcoming

—Jorge E. Cortes, MD

The pivotal phase II Ponatinib Ph+ ALL and CML Evaluation (PACE trial) found that 1 year of treatment with the novel investigational drug ponatinib achieved robust activity in heavily pretreated patients with chronic myeloid leukemia (CML) and Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL). Responses occurred early, were generally deep and durable, and were seen regardless of mutation status or disease stage. This is promising news for patients who don’t respond or lose their response to initial treatment with the approved tyrosine kinase inhibitors imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna).

Durable Responses

“These results show that ponatinib has outstanding activity regardless of the stage or presence or absence of mutations associated with resistance, and responses are durable. Ponatinib is generally well tolerated, and more studies in CML and [Philadelphia chromosome–positive] ALL will be forthcoming,” stated lead author Jorge E. Cortes, MD, Professor of Medicine, Deputy Chair of the Department of Leukemia, and Chief of the CML and AML Sections at The University of Texas MD Anderson Cancer Center in Houston. He presented the findings of the PACE study at the 54th Annual Meeting of the American Society of Hematology in Atlanta.1

Ponatinib was engineered to overcome mutations associated with resistance to tyrosine kinase inhibitor therapy. The drug is the only tyrosine kinase inhibitor currently in use known to be effective against the T315I mutation.

PACE enrolled 449 patients: 270 with chronic-phase CML, 85 with accelerated-phase CML, and 94 with blast-phase CML or Philadelphia chromosome–positive ALL. At baseline, between 84% and 95% were resistant to dasatinib or nilotinib; about 92% were treated with two or more prior lines of tyrosine kinase inhibitor therapy, and 53% to 60% received three or more prior tyrosine kinase inhibitors.

Key Findings

Regarding primary endpoints, 56% of those in chronic-phase CML achieved a major cytogenetic response, 57% of those in accelerated-phase CML achieved a major hematologic response, and 34% of those in blast-phase CML or with Philadelphia chromosome–positive ALL achieved a major hematologic response.

Dr. Cortes focused his presentation on 267 evaluable patients in chronic-phase CML, 84% whom were resistant to other tyrosine kinase inhibitors. Detailed results in advanced-phase patients were presented separately.

Among chronic-phase patients, 67% had any cytogenetic response, 56% had a major cytogenetic response, and 46% had a complete cytogenetic response. A major molecular response (BCR-ABL–to–standardized control gene ratio ≤ 0.1) was achieved in 34% of this group.

“Molecular responses are deep and durable,” Dr. Cortes said. “At 12 months, 91% of all chronic-phase patients with [major cytogenetic response] maintained their response,” he stated.

Responses were maintained regardless of mutational status. A major cytogenetic response was achieved in 49% of patients with no mutations, 57% of those with any non-T315I mutation, and 70% of those with the T315I mutation.

Ponatinib was well tolerated, with skin rash, abdominal pain, headache, dry skin, and constipation of any grade occurring in more than one-third of patients. Grade 3/4 adverse events were rare. Grade 3 pancreatitis was reported in 6% of patients, and only one patient had to come off study because of pancreatitis.

Looking Ahead

Dr. Cortes said that other studies of ponatinib are planned, both as front-line therapy and in patients for whom one previous tyrosine kinase inhibitor has failed.

“This study shows that we have a drug that works in patients with mutations that cause resistance. These patients no longer respond to other drugs. This study, as well as others presented at the meeting, show that what we have learned about genetic abnormalities is paying off in terms of therapy,” stated Aaron D. Schimmer, MD, FRCPC, PhD, a medical oncologist at Princess Margaret Cancer Center, University Health Network, Toronto, Canada. ■

Disclosure:Dr. Cortes receives research support from Ariad, Pfizer, Chemgenex, Bristol-Myers Squibb, and Novartis; and is a consultant for Ariad, Pfizer, and Teva. Dr. Schimmer reported no potential conflicts of interest.


1. Cortes J, Kim D-W, Pinella-Ibarz J, et al: 12-month follow-up of the PACE trial. 2012 ASH Annual Meeting. Abstract 163. Presented December 9, 2012.

Editor’s Note: Ponatinib (Iclusig) was recently approved by the FDA for treatment of adult patients with CML or AML.