Efficacy, Safety, and End-of-Treatment Mutational Results From the 5-Year Follow-Up of the Phase 2 OPTIC Study in Patients With Chronic-Phase Chronic Myeloid Leukemia

Citation:

Abstract 2184313

The phase 2 OPTIC study (NCT02467270) evaluated a response-based ponatinib dosing strategy to optimize efficacy and safety in patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to ≥2 tyrosine kinase inhibitors (TKIs) or with the T315I mutation. A starting dose of 45 mg once daily (QD), reduced to 15 mg QD upon achieving BCR::ABL1^IS ≤1%, demonstrated an optimal benefit-to-risk profile and was approved by the US Food and Drug Administration. This abstract presents the 5-year follow-up results from OPTIC.

Patients with CP-CML resistant to ≥2 TKIs or harboring the T315I mutation were randomized to receive ponatinib starting doses of 45 mg, 30 mg, or 15 mg QD. In the 45-mg and 30-mg arms, dose reduction to 15 mg QD occurred upon achieving ≤1% BCR::ABL1^IS (major molecular response [MR2]).

The primary endpoint was achievement of BCR::ABL1^IS ≤1% at 12 months. Secondary endpoints included molecular response rates and safety outcomes, including adjudicated arterial occlusive events (AOEs). Exploratory mutational analyses were performed using blood samples at baseline and at end of treatment (EOT).

A total of 283 patients were randomized (45 mg, n=94; 30 mg, n=95; 15 mg, n=94). At data cutoff (May 15, 2024), 61 patients (22%) remained on ponatinib. By 60 months, MR2 was achieved in 60% (56/93), 41% (38/93), and 40% (36/91) of patients in the 45-mg, 30-mg, and 15-mg cohorts, respectively. Among patients with baseline T315I mutation, the MR2 rate in the 45-mg group was 64% (n=25), comparable to those without baseline mutations (60%; n=50). Median MR2 duration was not reached in any cohort.

Rates of BCR::ABL1^IS ≤0.01% at 60 months were 24% (22/93), 18% (17/93), and 19% (17/91), and rates of BCR::ABL1^IS ≤0.0032% were 13% (12/93), 14% (13/93), and 15% (14/91), respectively. Estimated 60-month progression-free survival rates were 63% (45 mg), 57% (30 mg), and 60% (15 mg), with overall survival rates similar across cohorts.

Among patients who reduced to 15 mg QD after achieving MR2, loss of response occurred in 31% (14/45) in the 45-mg group and 22% (6/27) in the 30-mg group. Of those who underwent dose re-escalation after MR2 loss, MR2 was regained in 69% (9/13) and 80% (4/5), respectively.

The most frequent grade 3/4 treatment-emergent adverse events (TEAEs) were thrombocytopenia (27%) and neutropenia (18%). Exposure-adjusted AOE rates per 100 patient-years (95% CI) were: 4.1 (1.8–6.4) for 45 mg, 3.8 (1.3–6.3) for 30 mg, and 2.0 (0.3–3.7) for 15 mg. Among 74 patients with no baseline mutations and EOT samples, BCR::ABL1 mutations were detected in 6 patients: 5/29 (15 mg), 0/24 (30 mg), and 1/21 (45 mg).

The long-term OPTIC results confirm the clinical benefit of response-based ponatinib dosing in patients with CP-CML resistant to ≥2 TKIs or with the T315I mutation. The FDA-approved strategy—initiating at 45 mg QD with dose reduction to 15 mg QD upon achieving MR2—demonstrates a favorable benefit-to-risk profile. Mutation analyses support the ability of ponatinib to suppress emerging mutations at the 45-mg starting dose.

Authors:

Jorge Cortes, MD¹; Michael Deininger, MD, PhD²; Jane Apperley, MD³; Andreas Hochhaus, MD⁴; Hugues de Lavallade, MD, PhD⁵; Jeffrey H. Lipton, MD, PhD⁶; Elza Lomaia, MD, PhD⁷; James McCloskey, MD⁸; Lori Maness, MD⁹; Michael Mauro, MD¹⁰; Beatriz Moiraghi, MD¹¹; Carolina Pavlovsky, MD¹²; Gianantonio Rosti, MD¹³; Philippe Rousselot, MD, PhD¹⁴; Maria Undurraga Sutton, MD¹⁵; Bo Chao, MS¹⁶; Alexander Vorog, MD16; Tammie Yeh, PhD16; Niti Patel, PhD16; Hagop Kantarjian, MD¹⁷

Affiliation:

¹Georgia Cancer Center at Augusta University; ²Versiti Blood Research Institute; ³Imperial College London; ⁴Universitätsklinikum Jena; ⁵King's College Hospital NHS Foundation; ⁶Princess Margaret Cancer Centre; ⁷Almazov National Medical Research Centre; ⁸The John Theurer Cancer Center at Hackensack Meridian Health; ⁹University of Nebraska Medical Center; ¹⁰Memorial Sloan Kettering Cancer Center; ¹¹Hospital Jose Maria Ramos Mejia; ¹²Fundaleu; ¹³IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori"; ¹⁴Centre Hospitalier de Versailles University de Versailles Saint-Quentin-en-Yvelines; ¹⁵Hospital del Salvador; ¹⁶Takeda Development Center Americas, Inc.; ¹⁷University of Texas MD Anderson Cancer Center

Cortes J, Apperley J, Lomaia E, Moiraghi B, et al. Ponatinib dose-ranging study in chronic-phase chronic myeloid leukemia: a randomized, open-label phase 2 clinical trial. Blood. 2021;138 (21):2042-2050. doi: 10.1182/blood.2021012082