Outcome By Mutation Status and Line of Treatment in Optic, a Dose-Ranging Study of 3 Starting Doses of Ponatinib in Patients with CP-CML

Introduction: In PACE (NCT01207440), patients with refractory chronic-phase chronic myeloid leukemia (CP-CML) with substantial prior second-generation tyrosine kinase inhibitor (TKI) treatment demonstrated deep, lasting responses to ponatinib. However, long-term follow-up identified rates of arterial occlusive events (AOEs) as a risk. OPTIC (NCT02467270) is a randomized Phase 2 trial evaluating ponatinib at 3 starting doses: 45 mg, 30 mg, and 15 mg daily in patients with CP-CML resistant/intolerant to ≥2 TKIs or with a T315I mutation. The interim analysis showed that the 45-mg (vs 30 mg or 15 mg) starting dose (with reduction to 15 mg upon response) provided the best clinical outcomes and responses were maintained in >75% of patients who dose reduced. Here, we present efficacy and safety outcomes by baseline mutation status and line of treatment for the 3 dose cohorts.

Methods: Patients with CP-CML resistant/intolerant to ≥2 TKIs or with T315I mutation were randomized to ponatinib starting doses of 45 mg (Cohort A; 45 mg → 15 mg), 30 mg (B; 30 mg → 15 mg), and 15 mg (C) once daily (qd). Doses were reduced to 15 mg on achievement of ≤1% BCR-ABL1^IS in Cohorts A and B. Doses also could be reduced for safety. The primary endpoint is ≤1% BCR-ABL1^IS at 12 months. In this analysis, the outcome was analyzed by baseline mutation status (none, any, T315I, and non-T315I) and number of prior TKIs (≤2 or ≥3) in the intent-to-treat (ITT) population. Treatment-emergent adverse events (TEAEs), serious TEAEs, and AOEs by adjudication were summarized by number of prior TKIs (≤2 or ≥3). Interim analysis results are descriptive.

Results: Patients (N=283) were randomized: A/B/C n=94/95/94; median age was 48 y (18‒81 y). Seven patients were excluded from the intent-to-treat population (N=276) because they had atypical transcripts. Mutation status was well balanced between cohorts; 59% had no mutation, 41% had ≥1 baseline mutation, 24% had T315I, and 17% had a non-T315I mutation. In all categories of mutation status, the rate of ≤1% BCR-ABL1^IS by 12 months was highest in Cohort A, with the most notable differences seen in patients with T315I (A: 60%, B: 25%, C: 6%) (Table 1). Patients with no mutations or other mutations had smaller differences but the outcomes all still favored 45 mg. Patients in all cohorts were treated with multiple TKIs, with 54% (A), 60% (B), and 53% (C) having 3 or more prior TKIs. The rate of ≤1% BCR-ABL1^IS by 12 months was highest in Cohort A, both in patients treated with ≤2 or ≥3 prior TKIs (43% and 49%, respectively) (Table 1). Table 2 shows rates of TEAEs and TE-AOEs by cohort and number or prior TKIs. There was a trend toward higher event rates in Cohort A and for patients treated with ≥3 TKIs. Rates of adjudicated AOEs were low (≤6%) in all 3 cohorts irrespective of the number of prior TKIs.

Conclusions: At this interim analysis with a median follow-up of ~21 months, the maximum benefit:risk, regardless of mutation status or number of prior TKIs, was observed in patients treated with a 45-mg starting dose, with a reduction to 15 mg upon achievement of response. Patients with the T315I mutation who initiated ponatinib at 45 mg experienced better response rates than those who initiated ponatinib at 30-mg or 15-mg starting doses. Primary analysis will provide a refined understanding of the benefit:risk profile of 3 different starting doses of ponatinib.