FDA Approves the Supplemental New Drug Application (sNDA) for ICLUSIG in Combination with Chemothera

On March 19, Takeda announced that the U.S. Food and Drug Administration (FDA) has approved the supplemental New Drug Application (sNDA) for ponatinib, for use in combination with chemotherapy for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). This indication was granted under accelerated approval based on minimal residual disease (MRD)-negative complete remission (CR) at the end of induction therapy. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Notably, ponatinib has become the first and only targeted therapy approved in the United States for use in combination with chemotherapy for the first-line treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).

Ponatinib is a kinase inhibitor. The drug is also approved in the United States as a monotherapy for the treatment of the following conditions:

Ph+ALL or T315I-positive Ph+ALL for which no other kinase inhibitor indication exists;

Chronic-phase (CP) chronic myeloid leukemia (CML) in patients who are resistant or intolerant to at least two prior kinase inhibitors;

Accelerated-phase (AP) or blast-phase (BP) CML or T315I-positive CML (chronic, accelerated, or blast phase) for which no other kinase inhibitor indication exists.

It should be noted that ponatinib is not indicated for the treatment of patients with newly diagnosed chronic myeloid leukemia.

This approval was based on data from the randomized, active-controlled, open-label Phase 3 PhALLCON trial (ClinicalTrials.gov Identifier: NCT03589326), which evaluated the efficacy and safety of the kinase inhibitor ponatinib in combination with chemotherapy in 245 adult patients with newly diagnosed Ph+ALL. Study participants were randomized in a 2:1 ratio to receive either oral ponatinib 30 mg once daily (n=164) or oral imatinib 600 mg once daily (n=81), both in combination with 20 cycles of chemotherapy (imatinib plus chemotherapy is an unapproved regimen).

The chemotherapy regimen consisted of:

Induction phase (cycles 1–3): vincristine and dexamethasone;

Consolidation phase (cycles 4–9): alternating cycles of methotrexate and cytarabine;

Maintenance phase (cycles 10–20): vincristine and prednisone.

After 20 cycles, participants continued to receive ponatinib or imatinib monotherapy until disease recurrence. The primary endpoint was the proportion of participants achieving MRD-negative CR at the end of the induction phase.

Results showed that 30% of patients in the ponatinib group achieved MRD-negative CR at the end of induction, compared with 12% in the imatinib group (risk difference, 0.18 [95% CI, 0.08–0.28]; P=.0004). The median follow-up time for overall survival was 20.4 months (95% CI, 18.4–23.9) in the ponatinib group and 18.1 months (95% CI, 13.9–24.3) in the imatinib group.

The most common adverse reactions associated with ponatinib in combination with chemotherapy included hepatic dysfunction, arthralgia, rash and related conditions, headache, pyrexia, abdominal pain, constipation, fatigue, nausea, mucositis oral, hypertension, pancreatitis/elevated lipase, peripheral neuropathy, hemorrhage, febrile neutropenia, fluid retention and edema, vomiting, paresthesia, and arrhythmia.