Post Hoc Analysis of Patient Responses by T315I Mutation Status From the 3-Year Update of the OPTIC Trial: A Dose-Optimization Study of 3 Starting Doses of Ponatinib

Topic: 8. Chronic myeloid leukemia - Clinical Background: Ponatinib is the only pan-BCR::ABL1 inhibitory tyrosine kinase inhibitor (TKI) designed to potently inhibit native and all single resistance–mutation variants of BCR::ABL1, including T315I. Patients with T315I BCR::ABL1 mutations respond inadequately to earlier-generation BCR::ABL1 TKIs, leading to poor survival outcomes. OPTIC (Optimizing Ponatinib Treatment in CP-CML, NCT02467270) is a Phase 2 trial evaluating the efficacy and safety of ponatinib using a novel response-based dose-adjustment strategy in patients with chronic-phase chronic myeloid leukemia (CP-CML) whose disease is resistant to ≥2 TKIs or who harbor the T315I mutation. Aims: Here we present a post hoc analysis of the 3-year OPTIC trial patient responses by T315I mutation status. Methods: Patients with CP-CML resistant to ≥2 TKIs or with the BCR::ABL1 T315I mutation were randomized to ponatinib starting doses of 45, 30, or 15 mg once daily. In the 45-mg and 30-mg cohorts, doses were reduced to 15 mg with achievement of ≤1% BCR::ABL1IS. The primary endpoint was ≤1% BCR::ABL1IS at 12 months; secondary endpoints included molecular responses and safety outcomes. Progression-free survival (PFS) and overall survival (OS) probabilities by 36 months were estimated using the Kaplan-Meier methodology. Here we analyzed outcomes by baseline T315I mutation status. BCR::ABL1 mutations were assessed by Sanger sequencing. Results: Overall, 282 patients (99% resistant) received ponatinib (45 mg/30 mg/15 mg: n=94/94/94); 23.4% had the T315I mutation. In patients with no mutation, the T315I mutation, and mutation other than T315I, the highest percentage of patients achieving ≤1% BCR::ABL1IS by 36 months was in the 45-mg cohort: 60%, 64%, and 56%, respectively (Table). In patients with the T315I mutation, 32% (8/25) and 10% (2/20) in the 45-mg and 30-mg cohorts had their dose re-escalated after loss of response; of these patients, 75% and 50% re-achieved ≤1% BCR::ABLIS, respectively. In patients with no mutation, 6% (3/50) and 5% (3/58) in the 45-mg and 30-mg cohorts had their dose re-escalated after loss of response; of these patients, 67% and 100% re-achieved ≤1% BCR::ABLIS, respectively. In patients with a mutation other than T315I, 12.5% (2/16) in the 45-mg cohort had their dose re-escalated after loss of response and 50% (1/2) of these patients re-achieved ≤1% BCR::ABLIS; no patients in the 30-mg cohort lost response. Among patients with the T315I mutation, the 45-mg cohort had a higher 3-year PFS rate (75%) than the 30-mg (40%) or 15-mg (61%) cohorts; the 3-year OS rate was similar in the 45-mg (86%) and 15-mg (85%) cohorts (Table). Most-common Grade ≥3 treatment-emergent adverse events were thrombocytopenia (27%), neutropenia (18%), and anemia (8%). Incidences of Grade 3–4 arterial occlusive events (AOEs) in the 45-, 30-, and 15-mg cohorts were 6%, 6%, and 4%, respectively; there were no Grade 5 AOEs. Summary/Conclusion: This post hoc analysis from the 3-year update of the OPTIC trial demonstrated robust long-term efficacy of ponatinib and manageable safety across mutation subgroups. A ponatinib starting dose of 45 mg with reduction to 15 mg upon achievement of ≤1% BCR::ABL1IS provided the optimal benefit:risk ratio regardless of mutation status, which is consistent with the results from the primary analysis.Keywords: Chronic myeloid leukemia