Ponatinib efficacy maintained despite dose reductions

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.