Interim analysis (IA) of OPTIC: A dose-ranging study of three ponatinib (PON) starting doses.

Abstract

7502 Background: In PACE (NCT01207440) heavily pretreated patients (pts) with chronic-phase CML (CP-CML) had deep, lasting responses to PON; long-term follow-up showed increasing rates of arterial occlusive events (AOEs). We present IA results from OPTIC (NCT02467270), evaluating the association between PON exposure, efficacy, and safety, and response-based dose reduction in pts with CP-CML. Methods: This ongoing, multicenter, randomized phase 2 trial enrolled pts with CP-CML resistant or intolerant to ≥2 TKIs or with a T315I mutation to receive PON 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-ABL1IS in A/B. Primary endpoint: 12 mo ≤1% BCR-ABL1IS; secondary endpoints include cytogenetic and molecular response and AOE, VTE, and TEAE rates. Results are descriptive at this IA and will be inferential by adjusting multiplicity across 3 cohorts at final analysis. Results: 283 pts were 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 (BL) mutations, with 23% T315I. At IA data cutoff (20 Jul 2019), 162 pts (57%; n = 57/51/54) remained on study treatment. Among 282 pts in the safety population, median duration of exposure was ≈1 y (A/B/C, 12.9/11.2/11.0 mo). At 12 mo, 39% (95% CI, 27.6, 50.6), 27% (17.6, 39.1), and 26% (16.5, 38.6) in A, B, and C, respectively, achieved ≤1% BCR-ABL1IS. Additional efficacy in Table. Dose reductions due to efficacy (A/B): 35/21%. Most common TEAEs (any grade/≥3): thrombocytopenia 39/27%, neutropenia 25/17%. AOEs/serious AOEs were reported by (A, B, C) 5%/2%, 4%/3%, and 1%/0%. Dose reductions due to TEAEs: (A/B/C): 44/31/28%; discontinuations due to TEAEs: 18/15/14%. There were 4 (1.4%) on-study deaths; A, sudden death, n = 2; C, pneumonia, n = 2; no deaths were due to AOEs. Clinical trial information: NCT01207440 . Conclusions: OPTIC IA shows a trend toward dose-dependent efficacy and safety and may provide a refined understanding of the PON benefit:risk profile and its relation to dose. Data from longer follow-up may support an alternate dosing regimen for pts with CP-CML. [Table: see text]

Third-line therapy for chronic myeloid leukemia: current status and future directions

“…Ponatinib is thus a valuable option for patients who have received prior therapy, but safety considerations have limited its use. An ongoing study (NCT02467270, OPTIC study) is assessing the optimal dose schedule for ponatinib to strike a balance between efficacy and safety [ 63 ]. In this study, patients were randomized to receive either ponatinib at 45 mg daily (cohort A), 30 mg daily (cohort B), or 15 mg daily (cohort C).…”

“…AOEs occurred in 5%, 4%, and 1% of patients in cohorts A, B, and C, respectively, with serious AOEs reported in 2%, 3%, and 0%, respectively. Discontinuations due to TEAEs occurred in 18%, 15%, and 14% of patients in cohorts A, B, and C, respectively, with 4 (1.4%) deaths on study [ 63 ]. Ponatinib was recently approved for use in patients who have failed ≥ 2 TKIs, with dose reductions down to 15 mg daily upon achievement of response [ 38 ].…”

Dosing Strategies for Improving the Risk-Benefit Profile of Ponatinib in Patients With Chronic Myeloid Leukemia in Chronic Phase

“…The available literature on the use of ponatinib at a low dosage is limited and there are only a few clinical publications available, mainly concerning real-life experiences. The optimal risk-benefit profile of ponatinib at doses lower than the licensed starting dose of 45 mg/day was evaluated in the PACE trial ( 5 , 11 ), and is under investigation in the ongoing open-label phase 2 OPTIC (Optimizing Ponatinib Treatment In CML) trial (NCT02467270) ( 12 , 13 ).…”

“…The interim analysis (IA) of the OPTIC trial reinforced the concept that an initial treatment with 45 mg daily may induce higher response rates, especially in resistant patients, but suggest that higher dose may increase the incidence of cardiovascular events, even with a short treatment duration ( 12 , 13 ). OPTIC is an ongoing, multicenter, randomized phase 2 trial which is investigating three starting doses of ponatinib (45 mg, 30 mg, 15 mg) in 282 patients, 94 patients in each treatment cohort, with chronic-phase CML resistant or intolerant to at least two TKIs, or carrying the T315I mutation.…”

How to manage CML patients with comorbidities

“…The probability of achieving BCR-ABL1/ ABL1 #1% is greater with 45 mg daily (39%) than with 30 mg (27%) or 15 mg (27%), with AOEs reported in 5%, 4% and 1%, respectively. 39 Thus, I would probably use 45 mg and reduce to 15 mg once transcript levels of #1% are achieved, with adequate monitoring and management of comorbidities.…”