5-Year Follow-up of the Phase 2 Optic Study in Patients with Chronic-Phase Chronic Myeloid Leukemia: Efficacy, Safety, and First End-of-Treatment Mutational Results

Introduction: Ponatinib is a third-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) that potently inhibits native and mutant forms of BCR::ABL1, including T315I. The phase 2 OPTIC (NCT02467270) study evaluated a response-based ponatinib dosing strategy to optimize efficacy and improve safety of ponatinib in patients (pts) with chronic-phase chronic myeloid leukemia (CP-CML) whose disease was resistant to ≥2 TKIs or who had the T315I mutation. The 45-mg once-daily (QD) starting dose with dose reduction to 15 mg QD upon achievement of BCR::ABL1^IS ≤1% (MR2) was associated with optimal benefit:risk outcomes, resulting in FDA approval of this response-based dosing strategy for the treatment of pts with CP-CML with disease resistant to ≥2 TKIs or with T315I. We present results from the 5-year update of efficacy and safety outcomes from OPTIC.

Methods: Pts with CP-CML resistant to ≥2 TKIs or with the T315I mutation were randomized to ponatinib starting doses of 45 mg, 30 mg, and 15 mg QD. Upon achievement of ≤1% BCR::ABL1^IS, doses were reduced to 15 mg in the 45-mg and 30-mg cohorts. The primary endpoint was ≤1% BCR::ABL1^IS at 12 months; secondary endpoints included molecular response rates and safety outcomes, including arterial occlusive events (AOEs) adjudicated prospectively by an independent review committee. Progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier methods. Exploratory mutational analyses were conducted with baseline and end-of-treatment (EOT) blood samples.

Results: A total of 283 pts were randomized (45 mg/30 mg/15 mg: n=94/95/94; median age, 48 years [range: 18‒81 years]; male, 50%; race: White 79%, Asian 15%, Black 2%; ethnicity: 74% not Hispanic or Latino; T315I mutation, 24%). Median dose intensity was 27.7, 23.5, and 14.7 mg/day in the 45-mg, 30-mg, and 15-mg cohorts, respectively. As of the data cutoff (May 2, 2024), when the last pt still on study reached at least 5 years of treatment, 73 pts (26%) remained on ponatinib treatment; the most common reasons for treatment discontinuation were adverse event (45 mg/30 mg/15 mg: n=20/19/17), lack of efficacy (n=16/22/28), and progressive disease (n=8/10/7). By 60 months, 60% (56/93), 41% (38/93), and 40% (36/91) of pts in the 45-mg, 30-mg, and 15-mg cohorts, respectively, achieved ≤1% BCR::ABL1^IS. Pts with a T315I mutation at baseline also had a higher MR2 rate by 60 months at the 45-mg starting dose (64%; n=25), which was comparable to those with no mutations at baseline (60%; n=50). Median duration of ≤1% BCR::ABL1^IS was not reached in any cohort. By 60 months, the rates of ≤0.01% BCR::ABL1^IS were 24% (22/93), 18% (17/93), and 19% (17/91) in the 45-mg, 30-mg, and 15-mg starting dose cohorts, respectively, and rates of ≤0.0032% BCR::ABL^IS were 13% (12/93), 14% (13/93), and 15% (14/91), respectively. The estimated PFS rates at 60 months were 63%, 57%, and 60% in the 45-mg, 30-mg, and 15-mg cohorts. Estimated OS rates at 60 months were similar across starting dosing cohorts. Among pts who had dose reduction to 15 mg after achieving ≤1% BCR::ABL1^IS, 29% (13/45) in the 45-mg cohort and 23% (6/26) in the 30-mg cohort lost the response after dose reduction. Of the pts in the 45-mg and 30-mg cohorts who had dose re-escalation after loss of ≤1% BCR::ABL1^IS response, 69% (9/13) and 80% (4/5), respectively, regained a ≤1% BCR::ABL1^IS response. The most common grade 3/4 treatment-emergent adverse events were thrombocytopenia (27%), neutropenia (18%), and hypertension (10%). Exposure-adjusted AOE rates per 100 pt-years (95% confidence interval) were similar across the 3 cohorts: 45 mg, 4.1 (1.8–6.4); 30 mg, 3.4 (1.0–5.8); 15 mg, 1.2 (0.0–2.5). For the first time, EOT mutation analyses will be shared. Among 74 pts with no baseline mutation and available EOT data, only 6 had BCR::ABL1 mutations detected; 5 received the 15-mg starting dose and 1 had the 45-mg starting dose (E255K).

Conclusion: Long-term results from OPTIC highlight the clinical benefits of ponatinib in patients with CP-CML resistant to ≥2 TKIs or harboring a T315I mutation. These results are consistent with previous OPTIC analyses and demonstrate that the approved ponatinib starting dose of 45 mg QD with reduction to 15 mg QD upon attainment of ≤1% BCR::ABL1^IS provides the optimal benefit:risk ratio. Mutation data from EOT samples support ponatinib suppression of emerging mutations at the approved 45-mg starting dose.