Population Pharmacokinetic and Exposure-Response Analyses for Ponatinib in the Phase 3 PhALLCON Study

Abstract

In March 2024, ponatinib received accelerated FDA approval for the treatment of newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) in combination with chemotherapy based on the Phase 3 PhALLCON study (NCT03589326), which demonstrated a higher rate of minimal residual disease (MRD)-negative complete remission (CR) at the end of induction (EOI) with ponatinib (34.4%) versus imatinib (16.7%; p = 0.002). Patients received ponatinib (30 mg QD with reduction to 15 mg QD upon achievement of MRD-negative CR at EOI) or imatinib (600 mg QD) combined with 20 cycles of reduced-intensity chemotherapy (induction: 3 cycles; consolidation: 6 cycles; and maintenance: 11 cycles). Ponatinib pharmacokinetics (PK) were similar in patients in PhALLCON and patients in a previous population PK analysis. Bayesian re-estimation of the previously developed population PK model adequately described PhALLCON PK data. Exposure-efficacy analyses did not identify a significant relationship between ponatinib exposure and the probability of MRD-negative CR at EOI (p = 0.619), suggesting a consistent efficacy benefit across exposures. Ponatinib exposure was not a significant predictor of arterial occlusive events, venous thromboembolic events, thrombocytopenia, or lipase increase (p > 0.05). However, higher exposures were associated with a higher probability of hypertension (p = 0.0340) and alanine aminotransferase (ALT) increase (p = 0.0034). Dose reduction from 30 to 15 mg was predicted to decrease the odds of experiencing hypertension by 37.7% and ALT increase by 44.2%. Collectively, exposure-response analyses support a favorable benefit-risk profile of the approved ponatinib dosage (30 mg QD reduced to 15 mg QD upon achievement of MRD-negative CR at EOI), combined with chemotherapy, for frontline treatment of Ph + ALL.

Keywords: dose–response; oncology; pharmacokinetics; pharmacometrics; population PK‐PD.

FIGURE 1

Prediction‐corrected visual predictive check of the final Bayesian re‐estimation PK model for the PhALLCON study. The black circles (lines) represent the median (90th percentile range) of observed ponatinib plasma concentrations. The colored shaded regions represent the 95% CIs of predicted 5th (pink), 50th (blue), and 95th (green) percentiles of ponatinib plasma concentrations. CI, confidence interval; PK, pharmacokinetic; VPC, visual predictive check.

FIGURE 2

Comparison of individual‐predicted exposures at the 5th and 95th percentiles for continuous covariates or between groups for categorical covariates with the overall PhALLCON study population. The dashed black line represents a relative change in ponatinib exposure of 0. The blue bar shows the 90th percentile range (i.e., 5th to 95th percentile) of ponatinib exposures relative to the median of individual predicted exposures. The pink circles and error bars show exposures and 95% CI at the given covariate values compared with exposure at the median (for continuous covariates) or most common (for categorical covariates) covariate value. ALT, alanine aminotransferase; CI, confidence interval.

FIGURE 3

Observed and model‐predicted probability of achieving MRD‐negative CR at the end of induction versus ponatinib exposure. The solid (dashed) black lines represent the model‐predicted probability of being a responder (95% CI). The filled black circles (error bars) represent the observed proportion of responders (95% CI) for each ponatinib exposure quartile and the imatinib arm (filled circle at 0 exposure). The gray open circles indicate data from individual patients. n/N is the number of patients with an event/total number of patients in each ponatinib exposure quartile or the imatinib arm. CI, confidence interval; CR, complete remission; MRD, minimal residual disease.

FIGURE 4

Observed and model‐predicted proportion of patients with grade ≥ 1 (a) AOEs, (b) VTEs, (c) thrombocytopenia, or (d) lipase increase. The solid (dashed) black lines represent the model‐predicted probability of the AE (95% CI). The filled black circles (error bars) represent the observed proportion of patients with the AE (95% CI) for each ponatinib exposure quartile and the imatinib arm (filled circle at 0 exposure). The gray open circles indicate data from individual patients. n/N is the number of patients with an event/total number of patients in each ponatinib exposure quartile or the imatinib arm. AE, adverse event; AOEs, arterial occlusive events; CI, confidence interval; VTEs, venous thromboembolic events.

FIGURE 5

Observed and model‐predicted proportion of patients with grade ≥ 1 (a) hypertension or (b) ALT increase. The solid (dashed) black lines represent the model‐predicted probability of the AE (95% CI). The filled black circles (error bars) represent the observed proportion of patients with the AE (95% CI) for each ponatinib exposure quartile and the imatinib arm (filled circle at 0 exposure). The gray open circles indicate data from individual patients. n/N is the number of patients with an event/total number of patients in each ponatinib exposure quartile or the imatinib arm. AE, adverse event; ALT, alanine aminotransferase; CI, confidence interval.