Abstract: S172

Type: Oral Presentation

Session title: CML clinical

Background
In PACE (NCT01207440), heavily pretreated patients with chronic-phase chronic myeloid leukemia (CP-CML) demonstrated deep, lasting responses to ponatinib; long-term follow-up showed increasing rates of arterial occlusive events (AOEs). 

Aims
We present the first interim analysis results from OPTIC (NCT02467270), evaluating the association between ponatinib exposure, efficacy, and safety, and response-based dose-reduction in patients with CP-CML.

Methods
This ongoing, multicenter, randomized phase 2 trial enrolled patients with CP-CML resistant or intolerant to ≥2 tyrosine kinase inhibitors (TKIs) or with a T315I mutation to receive ponatinib at a starting dose of 45 mg (cohort A), 30 mg (B), and 15 mg (C) qd. Doses were reduced to 15 mg qd on achievement of ≤1% BCR-ABL1^IS at any time in cohorts A and B. Primary endpoint: ≤1% BCR-ABL1^IS at 12 months; secondary endpoints include cytogenetic response, molecular responses and rates of AOEs, venous thromboembolic events, and adverse events. The results are descriptive at this interim analysis and will be inferential by adjusting multiplicity across 3 cohorts at the final analysis. 

Results
Enrollment was completed with 283 patients randomized (A/B/C: n=94/95/94); median age 48 y (18–81 y). 26% had hypertension history; 2/43/55% received 1/2/≥3 TKIs; 40% had ≥1 baseline mutations, with 23% T315I. One patient in cohort B never started treatment and was not included in the safety population. At the interim analysis data cutoff (20 Jul 2019), 162 patients (57%) (n=57/51/54) remained on study treatment. Among 282 patients in the safety population, median duration of exposure was ≈1 year (A/B/C, 12.9/11.2/11.0 months). At 12 months, 39% (95% CI, 27.6, 50.6), 27% (17.6, 39.1), and 26% (16.5, 38.6) for A, B, and C, respectively, achieved ≤1% BCR-ABL1^IS. Additional efficacy results are presented in the Table. Dose reductions due to efficacy (A/B): 35/21%. Most common treatment-emergent adverse events in all patients (any grade/≥3): thrombocytopenia 39/27%, neutropenia 25/17%. Most common any-grade adverse events (≥25%) by cohort: A, thrombocytopenia (44%), neutropenia (29%); B, thrombocytopenia (38%), hypertension (31%); C, thrombocytopenia (36%). AOEs/serious AOEs were reported by (A, B, C) 5%/2%, 4%/3%, and 1%/0%. Dose reductions due to treatment-emergent adverse events (A/B/C): 44/31/28%; discontinuations due to treatment-emergent adverse events: 18/15/14%. There were 4 (1.4%) on-study deaths; 2 cases of sudden death in A and 2 cases of pneumonia in C; no deaths were due to AOEs.

Conclusion
Results from this OPTIC interim analysis show a trend toward dose-dependent efficacy and safety, and may provide a refined understanding of the ponatinib benefit:risk profile and its relation to dose. Mature data from continued follow-up may support an alternate dosing regimen for patients with CP-CML.

Session topic: 08. Chronic myeloid leukemia - Clinical

Keyword(s): Chronic myeloid leukemia, Clinical trial, Molecular response, Tyrosine kinase inhibitor