On 19 March 2024, the US Food and Drug Administration (FDA) granted accelerated approval to ponatinib (Iclusig, Takeda Pharmaceuticals U.S.A., Inc.) with chemotherapy for adult patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL).
Efficacy was evaluated in PhALLCON (NCT03589326), a randomised, active-controlled, multicentre, open-label study of 245 adult patients with newly diagnosed Ph+ ALL. Patients were randomised (2:1) to receive either ponatinib 30 mg orally once daily or imatinib 600 mg orally once daily with chemotherapy (imatinib with chemotherapy is an unapproved regimen). Chemotherapy consisted of 3 cycles of induction with vincristine and dexamethasone, 6 cycles of consolidation alternating between methotrexate and cytarabine, and 11 cycles of maintenance with vincristine and prednisone. The ponatinib dose was reduced to 15 mg once daily after completion of the induction phase and achievement of minimal residual disease (MRD)-negative complete remission (CR).
Efficacy was based on the MRD-negative CR rate at the end of induction. The MRD-negative CR rate at the end of induction was 30% in the ponatinib arm and 12% in the imatinib arm (risk difference 0.18; 95% confidence interval 0.08, 0.28, p-value = 0.0004).
The most common adverse reactions were hepatic dysfunction, arthralgia, rash and related conditions, headache, pyrexia, abdominal pain, constipation, fatigue, nausea, oral mucositis, hypertension, pancreatitis/elevated lipase, peripheral neuropathy, haemorrhage, febrile neutropenia, fluid retention and oedema, vomiting, paresthesia, and cardiac arrhythmias.
The recommended ponatinib dose is 30 mg orally once daily with a reduction to 15 mg orally once daily upon achievement of MRD-negative CR at the end of induction. Continue ponatinib with chemotherapy for up to 20 cycles until loss of response or unacceptable toxicity. For a description of dosing agents administered with ponatinib, see the prescribing information.
This review used the Real-Time Oncology Review pilot programme, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
This application was granted priority review and orphan drug designation.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System.
For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact FDA’s Oncology Center of Excellence Project Facilitate.