CML-129: OPTIC Primary Analysis: A Dose-Optimization Study of 3 Starting Doses of Ponatinib (PON)

Context: PON, a third-generation tyrosine kinase inhibitor (TKI), demonstrated deep, long-lasting responses/survival in patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant/intolerant to second-generation TKI therapy (PACE; NCT01207440); post hoc analysis suggested a relationship between dose and adverse events/response. We present the primary analysis of OPTIC (NCT02467270), an ongoing, randomized, phase 2 trial in resistant/intolerant CP-CML to evaluate safety and efficacy of PON response–based dosing regimens. Methods: Patients with CP-CML resistant/intolerant to ≥2 TKIs or with the BCR-ABL1 T315I mutation were randomized to PON starting doses of 45 mg (cohort A), 30 mg (B), and 15 mg (C) once daily. Doses were reduced to 15 mg with achievement of ≤1% BCR-ABL1IS in cohorts A and B. Primary endpoint is Results: 283 patients were randomized (A/B/C: n=94/95/94) and had the following baseline characteristics: median age 48 y (18–81 y); 98% received ≥2 (55% ≥3) TKIs; 99% had resistant disease; 40% had ≥1 baseline mutations (23% T315I). At 32-mo median follow-up, 134 patients (47%; n=50/41/43) remained on treatment and 204 patients (72%) had PON exposure ≥12 mo. At 12 mo, 44% (41/93) in A, 29% (27/93) in B, and 23% (21/91) in C achieved ≤1% BCR-ABL1IS; cohort A met the primary endpoint. Progression-free survival/overall survival at 36 months was 73/89% (A), 66/89% (B), and 70/92% (C). Most common grade ≥3 treatment-emergent adverse events (TEAEs) were thrombocytopenia, 27%; neutropenia, 17%; and anemia, 7%. Arterial occlusive events (AOEs)/serious AOEs were reported in cohorts A (10%/4%), B (5%/4%), and C (3%/3%). Dose reductions or discontinuations for TEAEs (A/B/C) were 46/35/32% and 19/16/14%, respectively. Conclusions: The OPTIC primary analysis demonstrates the optimal benefit/risk profile for PON was achieved with a response-based dosing regimen starting with 45 mg/d, followed by dose reduction to 15 mg/d upon achieving ≤1% BCR-ABL1IS. Observed ≤1% BCR-ABL1IS responses are supported by robust survival outcomes in patients with and without BCR-ABL1 mutations. The OPTIC study is sponsored by ARIAD Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, with additional funding from Incyte Corporation (Wilmington, DE).