FDA Grants Full Approval and Label Update for Ponatinib in CML and ALL


The U.S. Food and Drug Administration (FDA) has granted ponatinib (Iclusig) full approval for the treatment of adult patients with chronic-phase, accelerated-phase, or blast-phase chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL) for whom no other tyrosine kinase inhibitor therapy is indicated; and for the treatment of adult patients with T315I­–positive CML (chronic phase, accelerated phase, or blast phase) or T315I­-positive, Philadelphia chromosome–positive ALL. Ponatinib was initially approved in December 2012 under the FDA’s accelerated approval program. The therapy was granted the FDA’s orphan drug designation because it is intended to treat a rare disease or condition.

Ponainib is a tyrosine kinase inhibitor targeting BCR-ABL, an abnormal tyrosine kinase that is expressed in CML and Philadelphia chromosome–positive ALL. Ponatinib targets not only native BCR-ABL but also its isoforms that carry mutations that confer resistance to treatment, including the T315I mutation, which has been associated with resistance to other approved tyrosine kinase inhibitors.

This full approval and label update is based on 48-month follow-up data (as of August 2015) from the phase II PACE clinical trial of ponatinib in heavily pretreated patients with resistant or intolerant CML or Philadelphia chromosome–positive ALL. These data were presented at the 2016 meetings of ASCO (Abstract 703) and the European Hematology Association (EHA) (Poster P228).

“The data on ponatinib continue to show that with a minimum follow-up of 48 months, many chronic-phase CML patients in the PACE trial have retained long-term cytogenetic and molecular responses,” stated Timothy P. Clackson, PhD, President of Research and Development and Chief Scientific Officer at Ariad. “With this label update we are also now able to communicate to physicians that patients have experienced deep responses on ponatinib, measured by major molecular response. We are continuing our efforts to understand the optimal ponatinib dose for patients with the OPTIC postmarketing study.”

“The longer follow-up of the PACE study confirms the clinical benefit of ponatinib in this setting. We had learned from the initial report of the high response rate with ponatinib among CML patients with resistance or intolerance to prior therapies. The 4-year follow-up and updated safety profile demonstrate durability of responses in this heavily pretreated population. These results solidify ponatinib as an important and valuable treatment option for refractory patients with CML where no other tyrosine kinase inhibitor therapy is appropriate, including those who have the T315I mutation,” stated Jorge Cortes, MD, Professor and Deputy Chair, Department of Leukemia, The University of Texas MD Anderson Cancer Center, and a leading investigator in the PACE trial.

Four-Year PACE Trial Data Included in Labeling Update

The efficacy and safety of ponatinib in CML and Philadelphia chromosome–positive ALL patients resistant or intolerant to dasatinib (Sprycel) or nilotinib (Tasigna), or with the T315I mutation, were evaluated in the PACE trial. A total of 449 patients were treated with ponatinib at a starting dose of 45 mg/d. An estimated 93% of patients previously received two or more approved tyrosine kinase inhibitors, and 56% of all patients had received three or more approved tyrosine kinase inhibitors. Enrollment in the PACE trial was completed in October 2011.

Updated data on chronic-phase CML patients (n = 270) from the ongoing trial indicate that with a minimum follow-up of 48 months (data as of August 3, 2015), 110 patients continued to receive ponatinib. Additional data for chronic-phase CML patients include:

  • 55% of patients with chronic-phase CML achieved major cytogenetic response, the primary endpoint, at any time.
  • The median duration of major cytogenetic response (range, 2.7 to 50+ months) has not been reached.
  • 39% of patients achieved a major molecular response at any time.
  • The median duration of major molecular response (range, 1.7 to 50+ months) has not been reached.
  • With 4 years of follow-up, 33% (150/449) of all patients experienced arterial occlusive events. Twenty-one percent of patients experienced cardiac vascular, 12% experienced peripheral vascular, and 9% experienced cerebrovascular arterial occlusive events, with some patients experiencing more than one type of arterial occlusive event. Twenty-two percent experienced arterial occlusive serious adverse reactions (12% cardiac vascular, 8% peripheral vascular, and 7% cerebrovascular).
  • 6% of all patients experienced a venous thromboembolic event.
  • The most common any-grade treatment-emergent adverse events occurring in ≥ 20% of chronic-phase CML patients included hypertension (69%), rash (63%), abdominal pain (48%), fatigue (47%), headache (43%), arterial ischemia (42%), dry skin (42%), constipation (41%), arthralgia (32%), nausea (28%), pyrexia (26%), peripheral neuropathy (24%), myalgia (24%), pain in extremity (23%), back pain (21%), and diarrhea (20%). Postmarketing cases of reversible posterior leukoencephalopathy syndrome have been reported.

OPTIC Postmarketing Trial

Ariad is currently enrolling patients in the OPTIC postmarketing trial of ponatinib, which is expected to inform optimal dosing. This randomized, dose-ranging trial is enrolling patients with chronic-phase CML who are resistant to at least two approved tyrosine kinase inhibitors. Patients are randomized equally to receive once-daily administration of 45 mg (cohort A), 30 mg (cohort B), or 15 mg (cohort C) of ponatinib. Patients in cohorts A and B will have their daily dose reduced to 15 mg upon achievement of major cytogenetic response. The primary endpoint of the trial is major cytogenetic response by 12 months for each cohort. Ariad expects initial data from the OPTIC trial to be submitted to the American Society of Hematology (ASH) Meeting in 2017.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.