FDA Grants Ponatinib Full Approval for Rare Leukemias

Jorge Cortes, MD

The FDA has granted a full approval and label update to ponatinib (Iclusig) for patients with chronic phase (CP), accelerated phase, or blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated, as well as for patients with T315I-positive CML or T315I-positive Ph+ ALL.

The full approval is based on 4-year follow-up data from the phase II PACE trial, which evaluated ponatinib in patients with CML or Ph+ ALL who were refractory to dasatinib (Sprycel) or nilotinib (Tasigna), or who harbored a T315I mutation. Among patients with CP-CML in the study, the major cytogenetic response (MCyR) rate was 55% and the major molecular response (MMR) rate was 39%

“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 four-year follow-up and updated safety profile demonstrate durability of responses in this heavily pretreated population,” lead study investigator Jorge Cortes, MD, professor and deputy chair, Department of Leukemia, The University of Texas MD Anderson Cancer Center, said in a statement.

“These results solidify ponatinib as an important and valuable treatment option for refractory patients with CML where no other TKI therapy is appropriate, including those who have the T315I mutation,” added Cortes.

The PACE trial included 449 patients who received ponatinib at a starting dose of 45 mg daily. Patients were heavily pretreated, with an estimated 93% and 56% of patients having previously received ≥2 TKIs and ≥3 TKIs, respectively.

At a minimum of 48 months’ follow-up (data cutoff: August 3, 2015), 110 of 270 CP-CML patients continued to receive ponatinib. The median durations of MCyR (range 2.7 to >50 months) and MMR (range 1.7 to >50 months) had not yet been reached.

In the overall 449-patient population, 150 patients had experienced arterial occlusive events (AOE) at 4 years. Some patients had more than 1 type of AOE, with cardiac vascular, peripheral vascular, and cerebrovascular arterial occlusive events occurring in 21%, 12%, and 9% of patients, respectively. Arterial occlusive serious adverse reactions were reported for 22% of patients, including 12% cardiac vascular, 8% peripheral vascular, and 7% cerebrovascular. Venous thromboembolic events were reported in 6% of patients.

In the CP-CML cohort, the most common all-grade adverse events 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%). Additionally, since ponatinib’s approval, there have been reported cases of reversible posterior leukoencephalopathy syndrome.

“The data on Iclusig 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,” Timothy P. Clackson, PhD, president of Research and Development and chief scientific officer at Ariad, the developer of ponatinib, said in a statement.

“We are pleased to have received full approval of this medicine that was discovered and developed by Ariad scientists to address rare cancers for patients who may have no other targeted treatment option. With this label update we are also now able to communicate to physicians that patients have experienced deep responses on Iclusig, measured by MMR. We are continuing our efforts to understand the optimal Iclusig dose for patients with the OPTIC (Optimizing Ponatinib Treatment In CML) post-marketing study,” added Clackson.

In a statement, Ariad noted that initial findings from the OPTIC study will likely be available for presentation next year at the 2017 ASH Annual Meeting.

Ponatinib initially received an accelerated approval from the FDA in 2012 based on earlier findings from the PACE trial.

Cortes JE, Pinilla-Ibarz J, Le Coutre PD, et al. 4-year results of the ponatinib phase II PACE trial in patients (pts) with heavily pretreated leukemia. J Clin Oncol 34, 2016 (suppl; abstr 7013).