Rapid Readout: 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

• 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.
• Methods
  • 283 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-ABL1IS in cohorts A and B. Pts could re-escalate to their original starting dose for loss of response.
    • The primary end point is ≤1% BCR-ABL1IS at 12 months; secondary end points include cytogenetic and molecular responses and safety outcomes.
• Results
  • 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-ABL1IS response rates by 36 months.
  • Subanalysis of pts across the 3 dosing arms showed that pts with T315I mutations had the highest ≤1% BCR-ABL1IS 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.
  • Across all 3 cohorts, 97 pts without T315I mutations (ie, no mutation or with mutations other than T315I) achieved ≤1% BCR-ABL1IS.
  • 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 months 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-ABL1IS maintained this response during the study.
    • Of those who lost response, 11 had T315I, 10/11 dose re-escalated; of those who re-escalated, 6/10 regained ≤1% BCR-ABL1IS after dose re-escalation.
  • The most common nonhematologic treatment-emergent adverse events (TEAEs) in the intent-to-treat population for all cohorts combined were arterial hypertension (28%), headache (18%), and increased lipase (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
  • 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-ABL1IS levels).
    • Regardless of T315I mutation status, most patients were able to maintain their response after dose reduction to 15 mg/day upon achieving BCR-ABL1IS ≤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 overall survival outcomes.
  • The data presented further support the benefit of using ponatinib post–second- generation TKI for pts with resistant disease regardless of baseline T315I mutation status.

Deininger MW, Apperley JF, Arthur CK, et al. 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. Poster presented at: American Society of Hematology annual meeting, December 11-14, 2021; Atlanta, GA. Abstract 307.