Response‐Based Dosing for Ponatinib: Model‐Based Analyses of the Dose‐Ranging OPTIC Study
Michael J. Hanley, Paul M. Diderichsen, Benjamin E. Rich, Anna Largajolli, Emilie Schindler, Alexander Vorog, Karthik Venkatakrishnan, Neeraj Gupta
Abstract
Optimizing Ponatinib Treatment in CP‐CML (OPTIC) was a randomized, phase II dose‐optimization trial of ponatinib in chronic phase‐chronic myeloid leukemia (CP‐CML) resistant to ≥ 2 tyrosine kinase inhibitors or with T315I mutation. Patients were randomized to starting doses of 45‐, 30‐, or 15‐mg ponatinib once daily. Patients receiving 45‐ or 30‐mg reduced to 15‐mg upon achievement of ≤ 1% BCR::ABL1 IS (≥ molecular response with 2‐log reduction (MR2)). The exposure‐molecular response relationship was described using a four‐state, discrete‐time Markov model. Time‐to‐event models were used to characterize the relationship between exposure and arterial occlusive events (AOEs), grade ≥ 3 neutropenia, and thrombocytopenia. Increasing systemic exposures were associated with increasing probability of transitioning from no response to ≥ MR1, and from MR1 to ≥ MR1, with odds ratios of 1.63 (95% confidence interval (CI), 1.06–2.73) and 2.05 (95% CI, 1.53–2.89) for a 15‐mg dose increase, respectively. Ponatinib exposure was a significant predictor of AOEs (hazard ratio (HR) 2.05, 95% CI, 1.43–2.93, for a 15‐mg dose increase). In the exposure‐safety models for neutropenia and thrombocytopenia, exposure was a significant predictor of grade ≥ 3 thrombocytopenia (HR 1.31, 95% CI, 1.05–1.64, for a 15‐mg dose increase). Model‐based simulations predicted a clinically meaningful higher rate of ≥ MR2 response at 12 months for the 45‐mg starting dose (40.4%) vs. 30‐mg (34%) and 15‐mg (25.2%). The exposure–response analyses supported a ponatinib starting dose of 45 mg with reduction to 15 mg at response for patients with CP‐CML.