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Ponatinib (Iclusig)
Final results from the phase 2 PACE trial suggest dose reductions did not have an effect on the efficacy of ponatinib in patients with chronic phase (CP) chronic myeloid leukemia (CML).
Trial investigators began reducing ponatinib doses after the drug was linked to arterial occlusive events (AOEs).
Most patients who achieved a major molecular response (MMR) or major cytogenetic response (MCyR) on higher doses of ponatinib maintained those responses after dose reductions.
These results were published in Blood. The trial was sponsored by Ariad Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
Earlier results from the PACE trial indicated that ponatinib increased a patient’s risk of vascular occlusive events (VOEs), including AOEs.
Therefore, in October 2013, a phase 3 trial of ponatinib was discontinued, and all other ponatinib trials were put on partial clinical hold. Trial enrollment was halted temporarily, and investigators began reducing ponatinib doses.
Then, the US Food and Drug Administration suspended sales and marketing of ponatinib, pending results of a safety evaluation.
However, in December 2013, the agency decided ponatinib could return to the market if new safety measures were implemented. In January 2014, the drug was back on the market.
Patients
The PACE trial included 449 patients with CML or acute lymphoblastic leukemia, but the results published in Blood focused only on patients with CP-CML. All of these patients were resistant or intolerant to dasatinib or nilotinib, or they had the BCR-ABLT315I mutation.
There were 270 patients with CP-CML. They had a median age of 60 (range, 18-94), and 47% were female.
Ninety-three percent had received at least 2 prior approved tyrosine kinase inhibitors (TKIs), and 57% had received at least 3. The median duration of prior TKI treatment was 5.4 years (range, 0.4-13.3).
Eighty percent of patients were resistant to dasatinib or nilotinib, 14% were intolerant to either drug, and 19% were both resistant and intolerant. Twenty-four percent of patients had the T315I mutation.
Treatment
The starting dose of ponatinib was 45 mg once daily. Doses were reduced to 30 mg or 15 mg once daily to manage adverse events (AEs), or reductions were implemented proactively (starting on October 10, 2013) due to concerns about VOEs.
Unless a benefit-risk analysis justified use of a higher dose, the recommendation for CP-CML patients was a 15 mg daily dose for those with an MCyR and a 30 mg daily dose for those without an MCyR.
Patients received ponatinib until disease progression, intolerance, or the patient or investigator decided to stop treatment.
The median duration of treatment was 32.1 months (range, 0.1-73.0), and the median follow-up was 56.8 months (range, 0.1-73.1).
Efficacy
Of the 267 evaluable patients, 60% achieved an MCyR at any time, with 54% achieving a complete cytogenetic response. Forty-eight percent of patients were still in MCyR at the last response assessment, and 82% of patients who achieved an MCyR were estimated to remain in MCyR at 5 years.
There were 69 patients in MCyR as of October 10, 2013, when pre-emptive dose reduction began, who had their dose reduced. Ninety-six percent of these patients (n=66) maintained MCyR after dose reduction. Of the 34 patients in MCyR who did not have pre-emptive dose reductions, 94% (n=32) maintained MCyR.
Forty percent of patients attained a major molecular response (MMR) at any time during the study, with 30% achieving MR4 and 24% achieving MR4.5. Thirty percent of patients were in MMR at the last response assessment, and 59% of patients who achieved MMR were estimated to remain in MMR at 5 years.
There were 52 patients in MMR as of October 10, 2013, who had their dose reduced. Ninety percent (n=47) of these patients maintained MMR following dose reduction. Of the 19 patients in MMR who did not have pre-emptive dose reductions, 95% (n=18) maintained MMR.
“The PACE trial is among the longest and largest studies of patients with CP-CML who have received 2 or 3 prior TKIs, and the findings provide treating physicians with important updated information . . . ,” said study author Jorge Eduardo Cortes, MD, of MD Anderson Cancer Center in Houston, Texas.
“These final PACE results demonstrate that [ponatinib] provides lasting clinically meaningful responses, irrespective of dose reductions, in this population.”
At 5 years, the progression-free survival rate was 53%, and the overall survival rate was 73%.
AOEs
The incidence of AOEs was 31%, and the incidence of serious AOEs was 26%. This included cardiovascular AOEs (16%, 12% serious), cerebrovascular (13%, 10% serious), and peripheral vascular AOEs (14%, 11% serious). The exposure-adjusted incidence of AOEs was 14.1 per 100 patient-years.
Among patients without AOEs prior to October 2013 when pre-emptive dose reductions began, the incidence of AOEs was 19% in patients who had dose reductions and 18% in patients who did not.
The cumulative incidence of AOEs increased over time, but the exposure-adjusted incidence of new AOEs did not. It was 15.8 per 100 patient-years in year 1 and 4.9 per 100 patient-years in year 5.
The investigators said the lack of increase in exposure-adjusted AOE incidence could be due to the natural history or etiology of AOEs, dose reductions, or a change in the patient population (ie, an enrichment of patients who may have a lower risk of vascular events).
Therefore, it is unclear whether lower doses of ponatinib reduce the risk of AOEs in patients with risk factors. However, AOEs appear to be dose-related and modified by pre-existing cardiovascular disease and other risk factors.
Venous thromboembolism (VTE), on the other hand, does not seem to be dose-related. The investigators said the rate of VTE in this study was consistent with rates typically observed in cancer patients.
The incidence of VTE was 6%, and 5% of patients had serious VTEs. The exposure-adjusted incidence of VTEs was 2.1 per 100 patient-years.
Other AEs
The most common any-grade treatment-emergent AEs (≥40%) were rash (47%), abdominal pain (46%), thrombocytopenia (46%), headache (43%), dry skin (42%), and constipation (41%).
The most common grade 3/4 treatment-emergent AEs (≥10%) were thrombocytopenia (35%), neutropenia (17%), hypertension (14%), increased lipase (13%), abdominal pain (10%), and anemia (10%).
Serious AEs (≥5%) included pancreatitis (7%), atrial fibrillation (6%), pneumonia (6%), and angina pectoris (5%).
There were 12 deaths (4%) that occurred on study or within 30 days of the end of study treatment. Two deaths were considered possibly or probably related to ponatinib, 1 due to pneumonia and 1 due to acute myocardial infarction.