FDA Grants Accelerated Approval to Ponatinib Plus Chemo for Newly Diagnosed Ph+ ALL

FDA

The FDA has granted accelerated approval to ponatinib (Iclusig) in combination with chemotherapy for the treatment of adult patients with newly diagnosed, Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL).

The regulatory decision is supported by findings from the phase 3 PhALLCON study (NCT03589326) in which the addition of ponatinib to chemotherapy (n = 164) led to a minimal residual disease (MRD)–negative complete remission (CR) rate of 30% at the end of induction vs 12% with imatinib (Gleevec) plus chemotherapy (n = 81), translating to a risk difference of 0.18 (95% CI, 0.08-0.28; P = .0004).

About PhALLCON: Treatment, Objectives, Demographic and Disease Characteristics

The randomized, active-controlled, multicenter, open-label study enrolled patients with newly diagnosed Ph-positive ALL (n = 245) who randomly assigned 2:1 to 30 mg of oral ponatinib once daily or 600 mg of oral imatinib plus chemotherapy.

In the induction phase, which represented cycles 1 to 3, ponatinib or imatinib were paired with vincristine at 1.4 mg/m² on days 1 and 14 (capped at 2 mg) and dexamethasone at 40 mg on days 1 to 4 and days 11 to 14 for those younger than 60 years and at 20 mg on days 1 to 4 and days 11 to 14 for those 60 years and older.

Only patients who achieved CR or CR with incomplete hematologic recovery and MRD negativity at the end of induction could continue study treatment per investigator's discretion.

For consolidation treatment, given for cycles 4 to 9, patients received a reduced dose of ponatinib at 15 mg if they achieved an MRD-negative CR or imatinib at 600 mg once daily plus alternating methotrexate and cytarabine. Specifically, methotrexate was given for cycles 4, 6, and 8, at doses of 1000 mg/m² or 250 mg/m² on day 1 for those under 60 years or 60 years or older, respectively. If a patient lost MRD negativity at any time following the dose reduction of ponatinib, re-escalation to a dose of 30 mg once daily was permitted.

In the maintenance phase, cycles 10 to 20, ponatinib was given at 30 mg, or reduced to 15 mg if patients achieved an MRD-negative CR, or imatinib at 600 mg once daily plus vincristine at 1.4 mg/m2 on day 1 of each cycle (again capped at 2 mg) plus prednisone at 200 mg, 100 mg, or 50 mg on days 1 to 5 if patients were younger than 60 years, 60 years of age or older, or at least 70 years, respectively.

After combination treatment was completed, participants continued to receive monotherapy treatment with ponatinib or imatinib until relapse from CR, disease progression, hematopoietic stem cell transplantation, initiation of alternative treatment, or intolerable toxicity.

Investigators evaluated efficacy based on MRD-negative CR at the end of induction treatment. The analysis population included 232 patients who had a BCR:ABL1 dominant variant of p190 or p210 at baseline.

The median patient age in the ponatinib vs imatinib arms was 54 years (range, 19-82) and 52 years (range, 19-75), respectively, with the highest percentage of patients falling in an age category of 18 years to younger than 45 years (35% vs 36%). Thirty-seven percent of patients in both arms were 60 years of age or older. Slightly more than half of the patients in both arms were female (55% vs 53%) and most patients were White (63% vs 77%).

Patients in the ponatinib and imatinib arms had an ECOG performance status of 0 (44% vs 41%), 1 (52% vs 53%), or 2 (4% vs 6%). Per trial protocol, patients were permitted to receive 1 cycle of optional prephase therapy, excluding TKIs, before undergoing randomization; 45% of those in the ponatinib arm and 51% of those in the imatinib arm did so.

Moreover, 70% and 24% of patients in the ponatinib arm had a baseline BCR::ABL1 dominant variant of p190 or p210; these rates were 65% and 31%, respectively, in the imatinib arm. In the ponatinib and imatinib arms, patients had comorbidities in the form of hypertension (35% vs 37%), diabetes (24% vs 30%), and dyslipidemia (18% vs 28%).

Additional Efficacy Data

In the ponatinib arm, 79% of patients achieved a CR at the end of induction treatment vs 63% of those in the imatinib arm.

In the subset of patients who were not given prephase therapy, MRD-negative CR was achieved by 31% and 16% of those in the ponatinib and imatinib arms, respectively; 84% and 61% of patients, respectively, achieved a CR at the end of induction.

The median duration of follow-up in the ponatinib and imatinib arms was 20.4 months (95% CI, 18.4-23.9) and 18.1 months (95% CI, 13.9-24.3), respectively.

Safety

The median duration of exposure to ponatinib was 9.0 months (range, <1 month-4.2 years) vs 5.2 months (range, <1 month-4.4 years) in the imatinib arm.

Seventy-one percent of patients who received ponatinib required dose interruptions or reductions due to adverse effects (AEs). Moreover, 63% of patients experienced serious AEs and AEs led to permanent discontinuation of the agent for 13% of patients.

The most common AEs reported in more than 10% of patients who received ponatinib plus chemotherapy included hepatotoxicity (all grade, 66%; grade 3/4, 30%), arthralgia (47%; 4.3%), myalgia (13%; 1.2%), headache (45%; 1.8%), peripheral neuropathy (33%; 1.2%), paresthesia (22%; 0%), peripheral sensory neuropathy (12%; 0%), rash and related conditions (47%; 1.2%), abdominal pain (43%; 4.9%), constipation (41%; 0.6%), nausea (37%; 3.1%), oral mucositis (35%; 4.9%), pancreatitis/lipase elevation (34%; 15%), vomiting (24%; 1.2%), diarrhea (20%; 0%), pyrexia (44%; 4.3%), fatigue or asthenia (40%; 2.5%), fluid retention and edema (24%; 0.6%), hypertension (34%; 14%), hemorrhage (31%; 1.8%), venous thromboembolic events (12%; 3.1%), febrile neutropenia (28%; 25%), impaired glucose tolerance (20%; 4.9%), hyperlipidemia (16%; 1.2%), reduced appetite (10%; 0%), cardiac arrhythmias (22%; 2.5%), sepsis (17%; 12%), pneumonia (11%; 7%), cough (17%; 0%), and dyspnea (13%; 1.2%).

Clinically relevant AEs that occurred in 10% or fewer patients who received ponatinib plus chemotherapy included urinary tract infection (10%), arterial occlusive events (6%), cardiac failure (6%), and acute kidney injury (4.3%).

The most frequently experienced laboratory abnormalities that worsened from baseline and occurred in 20% or more of patients who received ponatinib plus chemotherapy included decreases in white blood cells (all grade, 79%; grade 3/4, 71%), lymphocyte cell count (77%; 61%), neutrophil cell count (66%; 63%), platelet count (65%; 62%), hemoglobin (53%; 38%), calcium (67%; 3.1%), phosphate (58%; 16%), potassium (44%; 10%), albumin (42%; 1.8%), sodium (32%; 3.1%), and magnesium (15%; 0.6%).

Additional laboratory abnormalities that worsened from baseline and occurred in at least 20% of patients in the ponatinib arm were increases in alanine aminotransferase (all grade, 69%; grade 3/4, 21%), aspartate aminotransferase (53%; 7%), alkaline phosphatase (44%; 1.2%), total bilirubin (25%; 0.6%), direct bilirubin (24%; 4.3%), lipase (60%; 24%), amylase (25%; 6%), glucose (34%; 2.5%), creatinine (34%; 3.7%), and potassium (31%; 3.7%).

References

1. FDA grants accelerated approval to ponatinib with chemotherapy for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. FDA. March 19, 2024. Accessed March 19, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-ponatinib-chemotherapy-newly-diagnosed-philadelphia-chromosome
2. Iclusig. Prescribing information. Takeda Pharmaceuticals USA, Inc.; 2024. Accessed March 19, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/203469s037lbl.pdf