Abstract: S153

Type: Oral Presentation

Session title: Response, resistance and treatment-free remission in CML

Background
PON, a third-generation tyrosine kinase inhibitor (TKI), demonstrated deep and long-lasting responses and survival in patients (pts) with chronic-phase chronic myeloid leukemia (CP-CML) resistant/intolerant to second-generation TKI therapy (PACE; NCT01207440); post hoc analysis suggested a relationship between dose and both adverse events and response. Here we present the primary analysis of OPTIC (NCT02467270), an ongoing, randomized, phase 2 trial with a novel response-based dosing regimen of PON in pts with resistant/intolerant CP-CML. 

Aims
Evaluate the safety and efficacy of ponatinib response–based dosing regimens in patients with resistant/intolerant CP-CML.

Methods
Informed consent was obtained and pts with CP-CML resistant/intolerant to ≥2 TKIs or with the BCR-ABL1 T315I mutation were randomized to PON 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 with achievement of ≤1% BCR-ABL1^IS in cohorts A and B. The primary endpoint is ≤1% BCR-ABL1^IS at 12 mo; secondary endpoints include cytogenetic and molecular responses and safety outcomes. AOEs were adjudicated prospectively by an independent review committee.

Results
283 pts were randomized (A/B/C: n=94/95/94) and had the following baseline characteristics: median age 48 y (18‒81 y); 98% received ≥2 (55% ≥3) TKIs; 99% had resistant disease; 40% had ≥1 baseline mutations (23% T315I). At the primary analysis with 32 mo median follow-up, 134 pts (47%; n=50/41/43) remained on treatment and 204 pts (72%) had PON exposure ≥12 mo. At 12 mo, 44% (41/93) in A, 29% (27/93) in B, and 23% (21/91) in C achieved ≤1% BCR-ABL1^IS (Table); primary endpoint was met by cohort A. Dose reductions to 15 mg after achieving response (A/B) were 48/30%.

Most common grades ≥3 TEAEs were thrombocytopenia, 27%; neutropenia, 17%; and anemia, 7%. AOEs/serious AOEs were reported in cohorts A (10%/4%), B (5%/4%), and C (3%/3%). Dose reductions or discontinuations for TEAEs (A/B/C) were 46/35/32% and 19/16/14%, respectively.

Conclusion
The OPTIC primary analysis demonstrates the optimal benefit:risk profile for PON was achieved with a response-based dosing regimen starting with 45 mg/d, followed by dose reduction to 15 mg/d upon achieving ≤1% BCR-ABL1^IS; 30 mg →15 mg and 15 mg cohorts may provide benefit, especially in pts without T315I mutation (Table). The observed ≤1% BCR-ABL1^IS responses are supported by robust survival outcomes in pts with CP-CML resistant to second-generation BCR-ABL1 TKI therapy, both with and without BCR-ABL1 mutations.

Keyword(s): BCR-ABL, Chronic myeloid leukemia, Clinical trial, Tyrosine kinase inhibitor