Acting 3 months ahead of schedule, the FDA approved ponatinib (Iclusig) for the treatment of patients with all phases of chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) that is resistant or intolerant (R/I) to prior TKIs. 

Ponatinib, a potent pan-BCR-ABL inhibitor, was reviewed under the FDA’s priority review program. The agent is active against native and mutated forms of the BCR-ABL gene fusion, including the T315I mutation. A mutation in T315I indicates that a patient will not respond to traditional BCR-ABL targeted agents, such as imatinib, dasatinib, and nilotinib.

“The availability of Iclusig will improve the outcome of many patients with CML and Philadelphia-positive ALL who are resistant or intolerant to prior TKI therapy. It is an effective therapy that meets an unmet medical need and has to date overcome all known resistant mutations in preclinical studies,” Jorge Cortes, MD, lead author and professor of Medicine, deputy chair of the Department of Leukemia, and chief of the CML and AML Sections at the University of Texas MD Anderson Cancer Center in Houston, said in a press release.

The approval was based on results from the phase II PACE trial, which were recently presented by Cortes during the 54th Annual Meeting and Exposition of the American Society of Hematology.

The PACE trial enrolled 449 patients who were R/I to dasatinib or nilotinib, or had the T315I mutation. Patients were stratified into three main cohorts based on disease stage. Each group was further categorized according to T315I mutation status. Five patients were included in the safety analysis but did not fall into the criteria to be assigned to a cohort.

In total, the first main cohort contained 267 patients with chronic phase CML. Of these patients, 203 were R/I and 64 harbored a mutation in T315I. A major cytogenic response was observed in 50% of R/I patients (95% CI, 0.43-0.57) and in 70% of those with a T315I mutation (95% CI, 0.58-0.81).

The second group included 83 patients with accelerated phase CML. A major hematologic response (MaHR) was observed in 58% of the 65 R/I patients (95% CI, 0.46-0.71) and in 50% of the 18 patients with mutations in T315I (95% CI, 0.26-0.74). 

The final cohort contained 94 patients with blast phase CML and Ph+ALL. Overall, 48 were R/I with 35% experiencing a MaHR (95% CI, 0.22-0.51). Additionally, 33% of the 46 patients who harbored a T315I mutation experienced a MaHR (95% CI, 0.20-0.48).

“Clinical responses to Iclusig have been observed in patients regardless of their mutation status or stage of disease. It is a valuable new treatment option for leukemia patients,” Cortes said.

Ponatinib was approved with a boxed warning from the FDA concerning blood clots and liver toxicity. The most common adverse events reported in the trial were thrombocytopenia (36%), rash (33%), and dry skin (31%). The most common serious adverse event was pancreatitis (occurring in 5% of patients), which led to one patient discontinuing the drug.

“The approval of Iclusig is important because it provides a treatment option to patients with CML who are not responding to other drugs, particularly those with the T315I mutation who have had few therapeutic options,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

Ponatinib is marketed by Ariad Pharmaceuticals, which is based in Cambridge, Massachusetts.