CML-114: Interim Analysis from the OPTIC Trial - A Dose-Ranging Study of 3 Starting Doses of Ponatinib

Abstract

Objectives In PACE ( NCT01207440 ), heavily pretreated patients with chronic-phase chronic myeloid leukemia (CP-CML) demonstrated deep, lasting ponatinib responses; long-term follow-up showed increasing rates of arterial occlusive events (AOEs). We present OPTIC ( NCT02467270 ) interim analysis (IA) results, evaluating the association between ponatinib exposure, efficacy, and safety. Methods This phase 2 trial randomized patients with CP-CML resistant/intolerant to ≥2 tyrosine kinase inhibitors (TKIs) or with a T315I mutation to ponatinib starting doses of 45 mg (cohort A), 30 mg (B), and 15 mg (C) qd. Doses were reduced to 15 mg qd on achievement of ≤1% BCR-ABL1IS in A/B. Primary endpoint: 12-month ≤1% BCR-ABL1IS; secondary endpoints include cytogenetic and molecular response, and AOE, venous thromboembolism (VTE), and treatment-emergent adverse event rates. IA results are descriptive and will be inferential by adjusting multiplicity across 3 cohorts at final analysis. Results 283 patients were randomized (A/B/C: n=94/95/94); median age 48 y (range, 18-81 y). 26% had hypertension history; 2/43/55% received 1/2/ ≥3 TKIs; 40% had ≥1 baseline mutations, with 23% T315I, all well balanced between cohorts. At IA data cutoff (20 Jul 2019), 162 patients (57%; n=57/51/54) remained on treatment. Within the safety population (N=282), median duration of exposure was ∼1 y (A/B/C, 14/12/12 mo). At 12 mo, 39% (95% CI, 27.6, 50.6), 27% (17.6, 39.1), and 26% (16.5, 38.6) in A, B, and C, respectively, achieved ≤1% BCR-ABL1IS. Dose reductions due to efficacy (A/B): 35/21%. Molecular responses were maintained in all patients who were on the reduced dose for at least 90 days (n=37). Most common TEAEs (any grade/≥3): thrombocytopenia 39/27%, neutropenia 25/17%. AOEs/serious AOEs were reported by (A, B, C) in 5%/2%, 4%/3%, and 1%/0%. Dose reductions for TEAEs: (A/B/C): 44/31/28%; discontinuations due to TEAEs: 18/15/14%. There were 4 (1.4%) on-study deaths; A, sudden death, n=2; C, pneumonia, n=2; no deaths were due to AOEs. Conclusions OPTIC IA shows a trend toward dose-dependent efficacy and safety, and may provide a refined understanding of the ponatinib benefit:risk profile and its relation to dose. Data from longer follow-up may support an alternate dosing regimen for patients with CP-CML.