Five-year follow-up of OPTIC: long-term efficacy, safety, and mutation analyses of ponatinib in chronic-phase chronic myeloid leukemia from a randomized phase 2 trial

Abstract The primary analysis of the phase 2 OPTIC trial (NCT02467270) demonstrated optimal benefit:risk with response-based ponatinib dosing (45 mg once daily (QD) reduced to 15 mg QD) upon achieving ≤1% BCR::ABL1 IS in patients with tyrosine kinase inhibitor-resistant or T315I-positive chronic-phase chronic myeloid leukemia (CP-CML). Here, we report 5-year long-term outcomes. Overall, 283 patients were randomized to 45-mg, 30-mg, or 15-mg QD starting doses ( n = 94, 95, and 94, respectively), with dose reduction to 15 mg QD upon response in the 45-mg and 30-mg cohorts. At data cutoff, 61 patients remained on trial. Median follow-up time was 75–78 months. By 5 years, 60%, 41%, and 40% of patients in the 45-mg, 30-mg, and 15-mg cohorts, respectively, achieved ≤1% BCR::ABL1 IS . Five-year progression-free survival rates were 63%, 57%, and 60%, respectively, by cohort; overall survival rates exceeded 80%. In patients with a T315I mutation, 5-year rates of ≤1% BCR::ABL1 IS , PFS, and OS were highest in the 45-mg cohort. Exposure-adjusted rates of adjudicated arterial occlusive events were 4.1, 3.8, and 2.0 patients per 100 patient-years, respectively, by cohort; results were comparable in T315I-positive patients. These findings support long-term clinical benefit of response-based ponatinib dosing in third-line CP-CML, especially in patients with the T315I mutation.