Response-Based Ponatinib Dose Reduction a Win-Win in Chronic-Phase CML?

For patients with chronic-phase chronic myeloid leukemia (CML), a response-based dose-reduction strategy for ponatinib (Iclusig) may limit its toxicity while maintaining or improving efficacy, a retrospective study suggested.

In a propensity score analysis of two phase II ponatinib trials (OPTIC and PACE), the risk for arterial occlusive events (AOEs) was roughly 60% lower with the response-based dose-reduction strategy (RR 0.41, 95% CI 0.21-0.80), Hagop Kantarjian, MD, of the University of Texas MD Anderson Cancer Center in Houston, reported here.

“This is in [line] with the general idea with targeted therapy that we need to use an optimal biologic dose,” Kantarjian said during a presentation at the Society of Hematologic Oncology annual meeting. “By reducing the dose in the OPTIC trial, once we achieved a complete cytogenetic response, we were able to have quicker dose reductions, reduce incidence of adverse events, maintain the patients for longer durations on the treatment, and, in fact, maintained the response or improved it.”

Kantarjian focused on what he called the “true problem” — incidence of serious AOEs. Here, an analysis of exposure-adjusted AOEs showed that incidence of serious AOEs fell from 15% to 4% with the OPTIC dose-reduction strategy.

Progression-free survival rates at 2 years were 66.7% in PACE and 80% in OPTIC, while overall survival (OS) rates at this time point were 87.5% and 91.3%, respectively.

Kantarjian, an investigator in the PACE trial, called these OS results “amazing” for this kind of a population, considering they were largely resistant to two prior tyrosine kinase inhibitors (TKIs).

“This is why we need to try to get those third-generation TKIs earlier in the treatment of these patients,” he said.

OPTIC and PACE

Ponatinib is a third-generation TKI that inhibits BCR-ABL1 with or without kinase domain mutations, including T315I.

The phase II PACE trial was a single-arm study that tested the efficacy and safety of ponatinib 45 mg once daily in patients with CML and Philadelphia chromosome-positive acute lymphoblastic leukemia that is resistant to or intolerant of dasatinib (Sprycel) or nilotinib (Tasigna), or that has the T315I mutation. Ponatinib demonstrated robust clinical activity regardless of BCR-ABL1 mutation status, with rapid, deep, and durable responses, and with favorable survival. However, AOEs occurred in about 31% of patients.

PACE had no prospective plan to reduce the dose of ponatinib, with dose reductions only for toxicity.

That was in contrast to OPTIC, a multicenter phase II study characterizing the efficacy and safety of ponatinib, in which patients were randomized 1:1:1 to ponatinib 15 mg, 30 mg, or 45 mg per day, and which required dose reductions once patients achieved the primary endpoint of complete cytogenetic response.

In both trials, patients were eligible if they had failed at least two previous TKIs and/or had a T315I mutation.

This current analysis included the entire cohort of 270 patients in the PACE trial (median follow-up of 57 months), and the 94 patients in OPTIC’s 45 mg cohort (follow-up of 32 months).

At 2 years, the median dose intensity was 30 mg/day in the PACE trial and 15 mg/day in OPTIC. Median time to dose reduction for efficacy was 2.6 months in the OPTIC trial, and the preemptive dose adjustment resulted in a longer time on therapy, at 19.5 months versus 12.6 months.

Adverse events (AEs) of any grade were reported in every patient in the two studies, with grade 3/4 AEs reported in 84% of patients in the PACE trial, and 68% of the patients in the OPTIC study. Dose reductions for AEs occurred in 46% and 65%.

Jane Apperley, MD, of Imperial College London, an investigator on both studies, said in a video presentation of the current analysis that its results “provide both physicians and their patients with more reassurance that ponatinib can be used with high efficacy and rather safely, when it is actually necessary to use it.”

Kantarjian said the results suggest that a response-based dose-reduction strategy should be used for other TKIs as well.

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