Ponatinib Is Safe and Effective in Pivotal Phase 2 Trial for Patients with Chronic Myeloid Leukemia

San Diego—Patients with chronic myeloid leukemia (CML) or Philadelphia-positive chromosome acute lymphoblastic leukemia (Ph+ALL) who are resistant or intolerant to popular tyrosine kinase inhibitors (TKIs) may soon have another option to treat their disease. Ponatinib, an experimental oral TKI under development by Ariad Pharmaceuticals, was effective and safe in early results of a pivotal, ongoing, open-label, phase 2 study presented at the ASH meeting. Jorge E. Cortes, MD, the study’s lead author and director of the leukemia fellowship program at the University of Texas MD Anderson Cancer Center, Houston, discussed the findings in an oral abstract session. The PACE (Ponatinib Ph+ALL and CML Evaluation) trial included patients ≥18 years of age with any phase of CML or Ph+ALL who were previously treated with or were intolerant to dasatinib or nilotinib. They were also included if they had developed the T315I mutation after taking any TKI. Study participants were not able to have had TKI therapy within 7 days of enrolling or any other anticancer therapy within 28 days of enrolling. Between September 2010 and September 2011, the authors enrolled 449 patients who received 45 mg of ponatinib daily: 271 had chronic-phase CML, 79 had advanced-phase CML, and 94 had blast-phase CML or Ph+ALL. Five of the patients did not meet eligibility criteria, but they received treatment. Before entering the trial, 94% of patients had taken ≥2 prior TKIs and 59% had taken ≥3 prior TKIs. The primary end point was major cytogenetic response (MCyR) in the chronic-phase CML group and major hematologic response (MaHR) in the other groups. Dr. Cortes said 47% of patients in the chronic-phase CML group had an MCyR, including 65% of patients with a T315I mutation. In addition, 67% of patients with advanced-phase CML had an MaHR and 37% of patients with blast-phase CML or Ph+ALL had an MaHR. Dr. Cortes said the authors observed similar responses in each cohort regardless of mutation or disease stage. The results also indicated the drug had a favorable safety profile. The majority of adverse events were grade 1 or 2, according to Dr. Cortes. The following treatment-related adverse events were found in ≥10% of patients: rash, dry skin, abdominal pain, headache, fatigue, myalgia, arthralgia, increased lipase, constipation, nausea, asthenia, and thrombocytopenia. No patient discontinued the study because of pancreatitis, which was a dose-limiting toxicity in the drug’s phase 1 trial. In addition, Dr. Cortes said 4 deaths observed were possibly related to ponatinib, including in 3 patients who had advanced-phase CML or Ph+ALL. The deaths were attributable to pneumonia, fungal pneumonia, gastric hemorrhage, and cardiac arrest. Of the 449 patients initially enrolled, 301 remain in the study, including 81% of the chronic-phase CML group, 71% of the advanced-phase CML group, and 22% of the blast-phase CML/Ph+ALL group. Of the 94 patients originally in the latter group, 37 discontinued because of disease progression, 5 because of lack of efficacy, 11 because of an adverse event, 11 because of death, and 11 due to another reason.