Interim Results of Randomized Comparison of Ponatinib Starting Doses in Chronic-Phase CML

Response-based ponatinib dosing demonstrated clinical benefit in patients with resistant chronic-phase chronic myeloid leukemia (CML) with rate of arterial occlusive (AO) events that did not differ based on starting dose, according to an interim analysis of the phase II OPTIC study presented as part of the ASCO20 Virtual Scientific Program.1

Results from the PACE trial, published in 2013, showed a high rate of major molecular remission (MMR) and durable hematologic and cytogenetic responses to ponatinib in heavily pretreated patients with chronic-phase CML, including those with the T315I ABL kinase mutation that confers resistance to other approved tyrosine kinase inhibitors.2 However, longer-term follow-up of the PACE study and analysis of other ponatinib-treated patients revealed a high rate of AO events, which led to a temporary removal of ponatinib from the market in late 2013. (The FDA re-authorized sale of ponatinib in February 2014.)  When these results became available, investigators wondered if the approved starting dose of ponatinib (45 mg/day) was too high for optimal safety and efficacy.

The OPTIC trial was designed to gain a better understanding of the benefit-risk profile of three different starting doses of ponatinib. In this trial, 283 patients with chronic-phase CML were randomly assigned to ponatinib at a starting dose of:

  • 45 mg/day (cohort A)
  • 30 mg/day (cohort B)
  • 15 mg/day (cohort C)

In cohorts A and B, doses were reduced to 15 mg per day when patients achieved  ≤1% BCR-ABL1IS or experienced an adverse effect (AE). The primary endpoint of the study was achievement of ≤1% BCR-ABL1IS or lower by month 12 of therapy. At the time of the data cutoff, 77% of patients were evaluable for this primary endpoint.

At the interim analysis, 57% of patients remained on study. The median duration of exposure for the safety population was about 1 year: 14 months, 12 months, and 12 months for cohorts A, B, and C, respectively. Median dose intensity was 30 mg, 24.3 mg, and 15 mg for cohorts A, B, and C, respectively.

The primary endpoint was achieved in 38.7%, 27.4%, and 26.5% of patients in cohorts A, B, and C respectively. In contrast, MMR was achieved in a higher proportion of patients at the lowest starting dose (cohort C), although this difference was not statistically significant: 14.7% of cohort A, 17.8% of cohort B, and 19.1% of cohort C.

Dose reductions occurred in 75% and 88% of patients in cohort A and B, respectively. “The benefit seemed to be greater for patients who started at 45 mg daily, but responses were maintained in the majority of patients after a dose reduction to 15 mg daily,” said Jorge E. Cortes, MD, of Georgia Cancer Center in Augusta, who presented the data. He also noted that patients who lost response after dose reduction did so within 90 days, and some regained response with dose escalation.

The most common grade 3 or higher treatment-emergent AEs were thrombocytopenia (31.9%) and neutropenia (17%). Treatment-emergent AEs were slightly higher in cohort A (66.0%) than in cohort B (56.4%) or cohort C (57.4%). Discontinuation, dose reductions, or dose interruptions as a result of treatment-emergent AEs occurred in 69.1%, 57.4%, and 55.3% of cohorts A, B, and C, respectively. Between the three cohorts, discontinuations were reported at 18.1%, 14.9%, and 13.8%, respectively. There were four on-study deaths.

Across all cohorts, 5% of patients had investigator-AO events and 3.5% were adjudicated as genuine events by independent evaluators (a lower rate than previously reported in ponatinib trials). The rate did not differ by dose level. There were no deaths related to AO events.

Progression-free survival (PFS) and overall survival (OS) were very good for all 3 doses considering how heavily pretreated the population was, Dr. Cortes said. At 24 months, PFS was 80.6%, 79.8%, 84.0% and OS was 92.7%, 95.1%, and 93.9% in cohorts A, B, and C, respectively. “Data from longer follow-up may support an alternate dosing regimen for ponatinib [from the current label] in patients with chronic-phase CML,” Dr. Cortes said.


  1. Cortes JE, Lomaia E, Turkina A, et al. Interim analysis (IA) of OPTIC: a dose-ranging study of three ponatinib (PON) starting doses. Abstract #7502. Presented as part of the ASCO20 Virtual Scientific Program. May 29-31, 2020.
  2. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase II trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013; 369:1783-1796.