Ponatinib (PON) in patients (pts) with chronic-phase chronic myeloid leukemia (CPCML) and the T315I mutation (mut): 4-year results from OPTIC

Abstract

Background: PON, an approved BCR::ABL1 TKI, potently inhibits native BCR::ABL1 and all reported single-resistance muts, including T315I. In the primary analysis of the phase 2 OPTIC study (NCT02467270) at 12 mo, pts with CP-CML and the T315I mut had robust responses to PON. We present 4-year results from the OPTIC trial in pts with the T315I mut. Methods: Pts with CP-CML resistant to ≥2 TKIs or with the BCR::ABL1T315I mut were randomized 1:1:1 to PON starting doses of 45, 30, or 15 mg QD, with dose reduction to 15 mg upon achievement of ≤1% BCR::ABL1IS in the 45-mg and 30-mg cohorts. This subgroup analysis evaluated 48-mo ≤1% BCR::ABL1IS, PFS and OS rates and safety outcomes in pts with the T315I mut. Results: Overall, 283 pts received PON (45 mg/30 mg/15 mg: n=94/95/94); 23.8% had the T315I mut (n=25/21/21). At the data cutoff for the 4-year analysis (May 8, 2023), median follow-up in the 45-, 30-, and 15-mg cohorts was 60.6, 63.5, and 60.7 mo, respectively. The proportion of pts with the T315I mut achieving ≤1% BCR::ABL1IS by 48 mo was highest in the 45-mg cohort (64%; Table). Median time to response (mo) and estimated median duration of response (mo) were 6.0 and 16.7 in the 45-mg cohort, 3.1 and 12.0 in the 30-mg cohort, and 6.0 and not reached (NR) in the 15-mg cohort. In the 45- and 30-mg cohorts, 15 and 5 pts had dose reduction to 15 mg after achieving ≤1% BCR::ABL1IS, of which 7 and 2 maintained response; of pts not maintaining response, 6 and 1 regained response after dose re-escalation. Median PFS was NR, 28.4 mo, and 45.6 mo in the 45-, 30-, and 15-mg cohorts, respectively, and median OS was NR in all groups. The 45-mg cohort had the highest 4-year survival rates (OS: T315I 86%; overall 88%; Table). Grade ≥3 TEAE rates in the 45-, 30-, and 15-mg cohorts were 60%, 38%, and 38%, with TEAEs leading to discontinuation in 8%, 14%, and 5%, respectively. Arterial occlusive events (AOEs) occurred in 8%, 14%, and 5% of pts in the 45-, 30-, and 15-mg cohorts; exposure-adjusted AOE rates were 2.4%, 7.3%, and 2.8%, respectively. Conclusions: PON demonstrated robust long-term efficacy and manageable safety in this 4-year update in pts with the T315I mut. A PON starting dose of 45 mg with reduction to 15 mg upon achievement of ≤1% BCR::ABL1IS provided the optimal benefit:ratio