Efficacy and safety of ponatinib in patients with CP-CML who failed second-generation TKIs

In a combined analysis of 2 pivotal trials, comprising the largest number of patients with chronic-phase chronic myeloid leukaemia (CP-CML) who had failed second-generation tyrosine kinase inhibitors (TKIs), ponatinib demonstrated high response rates and robust survival outcomes [1].

Resistant patients with CP-CML who have failed ≥1 second-generation TKI have poor outcomes when they switch to another second-generation TKI. There is limited clinical evidence to support that switching to third-generation TKI therapy improves long-term clinical outcomes for these patients. The PACE and OPTIC trials evaluated outcomes with ponatinib in difficult-to-treat CP-CML patients [2,3].

In the PACE trial, patients with resistant and intolerant CP-CML who failed prior second-generation TKI therapy demonstrated deep and long-lasting responses to ponatinib [2]. A posthoc modelling analysis of the data from PACE suggested a relationship between dose and safety events, including arterial occlusive events. The prospective OPTIC trial evaluated response-based ponatinib dosing regimens to optimise its efficacy and safety in patients with CP-CML, including a highly resistant patient population. The interim analysis demonstrated a clinically manageable safety profile with response-based ponatinib dosing regimens in highly resistant CP-CML patients [3]. Dr Hagop Kantarjian (MD Anderson Cancer Center, Texas, USA) presented the efficacy and safety outcomes of ponatinib use over time in these 2 CP-CML patient populations.

Efficacy outcomes in OPTIC, with a response-adjusted dosing regimen (starting at 45 mg and reduction to 15 mg upon response), were consistent with those of PACE in patients with CP-CML who had failed prior second-generation TKI therapy. The ≤1% BCR-ABL1IS response rates increased over time and ranged from 42% to 52%. Progression-free survival and overall survival were 52% and 73%, respectively, in PACE (up to 5 years) and 81% and 93%, respectively, at the OPTIC interim analysis (up to 2 years) [1].

The overall incidences of arterial occlusive events and serious treatment-emergent adverse events as well as exposure-adjusted arterial occlusive events during the first 2 years were lower in OPTIC in comparison with PACE. Taken together, ponatinib demonstrated a favourable benefit-risk profile among all TKIs for resistant CP-CML patients who had failed prior second-generation TKIs, regardless of the mutation status [1].

The ongoing OPTIC study is evaluating lower starting doses of ponatinib (30 and 15 mg). Primary analysis of this study will provide a refined understanding of the benefit-risk profile of the 3 starting doses of ponatinib in CP-CML patients.

1. Kantarjian HM, et al. Efficacy and Safety of Ponatinib (PON) in Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML) Who Failed One or More Second-Generation (2G) Tyrosine Kinase Inhibitors (TKIs): Analyses Based on PACE and Optic. 62^nd ASH Annual Meeting, 5-8 December 2020. Abstract 647.
2. Cortes JE, et al. 2018;132:393-404.
3. Cortes JE, et al. J Clin Oncol 2020;38(15 Suppl):7502.

Posted on 18 February 20214 September 2023