Phase II Trial of Ponatinib Shows Activity in Heavily Pretreated CML and Philadelphia Chromosome–Positive ALL
On October 31, 2013, Ariad Pharmaceuticals, the manufacturer of ponatinib, agreed to an FDA request to suspend marketing and sales of the drug due to the risk of life-threatening blood clots and severe narrowing of blood vessels. The FDA states that it will continue to evaluate ponatinib to further understand its risks and to identify potential patient populations in which the benefits of the drug may outweigh the risks. For more information on this subject and to view the FDA’s recommendations, please see this article.
Ponatinib (Iclusig) is active against unmutated and mutated BCR-ABL, including the T315I mutation present in up to 20% of patients with tyrosine kinase inhibitor–resistant disease that confers resistance to all other approved BCR-ABL tyrosine kinase inhibitors. In a phase II trial (PACE trial) reported in The New England Journal of Medicine, Jorge E. Cortes, MD, of The University of Texas MD Anderson Cancer Center, and colleagues evaluated ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL) who were heavily pretreated or harbored the T315I mutation. Ponatinib exhibited marked activity in both resistant/refractory disease and in patients with the T315I mutation.
Study Details
In the trial, 449 heavily pretreated patients with CML or Philadelphia chromosome–positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who harbored the BCR-ABL T315I mutation received ponatinib at an initial dose of 45 mg/d. The patients included 203 patients with chronic-phase CML with resistance to or unacceptable side effects from dasatinib (Sprycel) or nilotinib (Tasigna) and 64 with the T315I mutation, 65 patients with accelerated-phase CML refractory/resistant to dasatinib or nilotinib and 18 with the T315I mutation, and 48 patients with blast-phase CML or Philadelphia chromosome–positive ALL refractory/resistant to dasatinib or nilotinib and 46 with the T315I mutation.
Overall, patients had a median age of 59 years, 93% had previously received at least two tyrosine kinase inhibitors, median duration of prior tyrosine kinase inhibitor therapy was 4.6 years, 88% had resistance to dasatinib or nilotinib, and 12% had unacceptable side effects from either.
Response Rates
Median follow-up was 15 months. Among 267 patients with chronic-phase CML, 56% had a major cytogenetic response (including 51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (including 40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (including 27% and 56% in the two subgroups, respectively). Median duration of major cytogenetic response was not reached; major cytogenetic response was sustained for at least 1 year in 91% of responders.
Among 83 patients with accelerated-phase CML, 55% had a major hematologic response (including 57% and 50% in the two subgroups, respectively) and 39% had a major cytogenetic response (including 34% and 56% in the two subgroups, respectively). Median duration of major hematologic response was 12 months. Among 62 patients with blast-phase CML, 31% had a major hematologic response (including 32% and 39% in the two subgroups, respectively) and 23% had a major cytogenetic response (including 18% and 29% in the two subgroups, respectively). Median duration of major hematologic response was 5 months.
Among 32 patients with Philadelphia chromosome–positive ALL, 41% had a major hematologic response (including 50% and 36% in the two subgroups, respectively) and 47% had a major cytogenetic response (including 60% and 41% in the two subgroups, respectively). Median duration of major hematologic response was 3 months.
No single BCR-ABL mutation conferring resistance to ponatinib was detected. However, the acquisition of compound mutations in the same BCR-ABL allele was sometimes observed in patients with blast-phase CML or Philadelphia chromosome–positive ALL who had an unsustained major hematologic response, with all of these patients harboring one of the mutations at the start of the study.
Adverse Events
The most common nonhematologic adverse events of any grade considered at least possibly related to treatment were rash (34%), dry skin (32%), and abdominal pain (22%), and the most common hematologic adverse events were thrombocytopenia (37%), neutropenia (19%), and anemia (13%).
The most common nonhematologic serious adverse events considered related to treatment were pancreatitis (5%), abdominal pain (2%), increased lipase (2%), diarrhea (1%), pyrexia (1%), and myocardial infarction (1%), and the most common hematologic serious adverse events were thrombocytopenia (2%), anemia (1%), neutropenia (1%), febrile neutropenia (1%), and pancytopenia (1%). Treatment was discontinued due to an adverse event in 12% of patients.
Overall, 7.1% of patients had cardiovascular events, 3.6% had cerebrovascular events, and 4.9% had peripheral vascular events.
The investigators concluded, “Ponatinib had significant antileukemic activity across categories of disease stage and mutation status.”
The study was supported by Ariad Pharmaceuticals and by grants from the National Institutes of Health and the National Institute for Health Research Biomedical Research Centre.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
