Post Hoc Analysis of Responses to Ponatinib in Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML) By Baseline BCR-ABL1 Level and Baseline Mutation Status in the Optic Trial

Introduction: Ponatinib is a third-generation, pan-inhibitory tyrosine kinase inhibitor (TKI) designed to potently inhibit BCR-ABL1 with or without any single resistance mutation, including T315I. Patients (pts) with resistant disease or 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; ongoing) is a phase 2 trial evaluating the safety and efficacy of ponatinib in pts with CP-CML whose disease is resistant to 2 or more TKIs or who have a T315I mutation. Here, we present an in-depth post hoc analysis of OPTIC trial pt responses by baseline disease burden and mutation status.

Methods: Pts with CP-CML resistant to ≥2 TKIs or with the BCR-ABL1 T315I mutation were randomized to ponatinib starting doses of 45 mg (cohort A; 45 mg → 15 mg), 30 mg (B; 30 mg → 15 mg), and 15 mg (C) once daily. Doses were reduced to 15 mg after achievement of ≤1% BCR-ABL1^IS in cohorts A and B. Pts could re-escalate to their original starting dose for loss of response. The primary endpoint is ≤1% BCR-ABL1^IS at 12 months; secondary endpoints include cytogenetic and molecular responses and safety outcomes. In this analysis, outcomes are analyzed by baseline T315I mutation status and baseline disease burden in the intent-to-treat (ITT) population. BCR-ABL1 mutations were assessed by Sanger sequencing at a central laboratory (MolecularMD, Portland, OR, USA).

Results: 283 pts were randomized (A/B/C: n=94/95/94). At baseline, 84.1% of pts had a high (>10% BCR-ABL1 ^IS) disease burden; 23.8% had T315I mutation, 17.0% had a mutation other than T315I, and 57.8% had no mutation. The 45 mg →15 mg cohort showed the highest ≤1% BCR-ABL1^IS response rates by 36 months (Figure 1).

Subanalysis of pts across the 3 dosing arms showed that pts with T315I mutations had the highest ≤1% BCR-ABL1^IS response rates (60%) by 3 years with the 45 mg → 15 mg dose compared with the other cohorts, with a trend toward higher progression-free survival (PFS) in the 45 mg →15 mg arm (Table 1). Across all 3 cohorts, 97 pts without T315I mutations (ie, no mutation or with mutations other than T315I) achieved ≤1% BCR-ABL1^IS. Median duration of response (mDoR) for pts with a T315I mutation at baseline was 27 months for pts (n=15) in the 45 mg → 15 mg cohort and 12 mo for pts (n=5) in the 30 mg → 15 mg cohort. For pts without T315I mutations, the mDoR was not reached. Across all 3 cohorts, 79% of pts who achieved ≤1% BCR-ABL1^IS maintained this response during the study. A total of 25 patients lost responses (Table 2). Of those who lost response, 11 had T315I, 10/11 dose re-escalated; of those who re-escalated, 6/10 regained ≤1% BCR-ABL1^IS after dose re-escalation (Table 2). The most common nonhematologic treatment-emergent adverse events (TEAEs) in the ITT population for all cohorts combined were arterial hypertension (28%), headache (18%), and lipase increased (17%). The most common hematologic TEAEs were thrombocytopenia (40%), neutropenia (26%), and anemia (19%). Overall, 6.0% of pts experienced a treatment-emergent arterial occlusive event (TE-AOE); 4.6% experienced a Grade ≥3 TE-AOE.

Conclusions: Previous analyses established these largely resistant pts achieved high response rates when treated with ponatinib. Consistent with this, the OPTIC post hoc analysis showed clinical benefit across all 3 dosing regimens regardless of T315I mutation status at baseline; the 45 mg →15 mg cohort showed the highest response rates regardless of baseline disease burden (as assessed by BCR-ABL1^IS levels). Regardless of T315I mutation status, most patients were able to maintain their response after dose reduction to 15 mg/day upon achieving BCR-ABL1^IS ≤1%. Compared with patients without a T315I mutation, patients with a T315I mutation at baseline were more likely to lose their response upon dose reduction; however, 60% of responses were regained with dose re-escalation. For pts with T315I mutations, PFS was greater with 45 mg → 15 mg dosing compared with the other arms; for pts without T315I mutations, all 3 doses showed robust PFS and OS outcomes. The data presented further support the benefit of using ponatinib post–2nd generation TKI for pts with resistant disease regardless of baseline T315I mutation status.