In this study, ponatinib showed significant clinical activity in a heavily pretreated population of patients with Ph-positive leukemias that were resistant to, or had relapsed during receipt of, currently available tyrosine kinase inhibitors. The most common treatment-related adverse events were skin disorders and constitutional symptoms, which were generally low-grade in severity and were manageable. Dose-limiting toxic effects included pancreatic events, with pancreatitis observed in 14% of patients. Myelosuppression, an expected adverse event in this heavily pretreated population, was also common. Among patients with chronic-phase CML, 93% had been treated with two or more approved tyrosine kinase inhibitors, and 49% had received all three approved tyrosine kinase inhibitors. The observed rate of major cytogenetic response in this group was 72%, the rate of complete cytogenetic response was 63%, and the rate of major molecular response was 44%. Clinically meaningful responses were also observed in patients with advanced disease. These findings identify ponatinib as a highly active agent for patients with CML who have shown resistance to multiple tyrosine kinase inhibitors.
Mutations in the BCR-ABL kinase domain that confer resistance to tyrosine kinase inhibitors have been shown to be responsible for 30 to 40% of resistance to imatinib.35
Such mutations have been found to increase in frequency with the duration of exposure to tyrosine kinase inhibitors13
and have been associated with an adverse prognosis.11,36
Dasatinib and nilotinib are active against a number of imatinib-resistant mutants but are ineffective against subsets of mutants.19,37
Imatinib, dasatinib, and nilotinib are all ineffective against the T315I mutant, a common mutation.19,37
In addition, therapy with tyrosine kinase inhibitors fails in some patients who carry mutants that are sensitive to these drugs.38
Moreover, mutations are undetectable in a substantial proportion of patients with imatinib failure.39
In many of these patients, mechanisms of resistance that are not associated with BCR-ABL may be operative,35,37
although this is poorly understood.
In our study, we found that ponatinib had activity in all of the following situations: against a spectrum of mutants in patients in whom previous therapy had failed, against the T315I mutant, and against disease that had been refractory to therapy with multiple tyrosine kinase inhibitors in the absence of detectable BCR-ABL mutations. The majority of patients with chronic-phase CML with non-T315I mutations had a complete cytogenetic response and a major molecular response. Similarly high rates of cytogenetic response were observed in patients with chronic-phase CML with the T315I mutation and in those with no detectable kinase domain mutations. Responses have been durable, with the median duration of response in patients with chronic-phase CML yet to be reached at the time of this analysis but exceeding 1 year. These data compare favorably with data regarding second-generation tyrosine kinase inhibitors that were used after imatinib failure (rate of major cytogenetic response, 35 to 63%)7-10,40
or after the failure of two drugs (rate of major cytogenetic response, 32 to 50%).41-44
Ponatinib was rationally developed to address the limitations of currently available CML-directed tyrosine kinase inhibitors. It was designed for high-affinity, optimized binding to the active site of BCR-ABL, with an emphasis on very high potency and the ability to overcome BCR-ABL mutation-based resistance. Blood levels that occurred at the recommended dose in this study were above the threshold defined in preclinical cell-based mutagenesis assays as uniformly preventing the development of resistant clones (40 nM)20
and were associated with high rates of cytogenetic and molecular responses. The high potency and relatively long half-life of ponatinib may contribute to its activity in this patient population. Ponatinib has also been shown to inhibit the activity of other clinically relevant kinases with 50% inhibitory concentrations of less than 20 nM and has shown cellular activity against RET, FLT3, KIT, and members of the FGFR and PDGFR families of kinases.32,45,46
In conclusion, once-daily ponatinib is a pan– BCR-ABL inhibitor with substantial and durable clinical activity in patients with Ph-positive leukemias with resistance to tyrosine kinase inhibitors.