Population pharmacokinetic and exposure-response analyses of pemigatinib in patients with advanced solid tumors including cholangiocarcinoma

Abstract

Pemigatinib is a selective, potent, oral inhibitor of fibroblast growth factor receptor (FGFR)1-3 with efficacy in patients with previously treated, advanced/metastatic cholangiocarcinoma (CCA) with FGFR2 alterations. A previously developed population pharmacokinetic (PK) model of pemigatinib was refined using an updated dataset with 467 participants from seven clinical studies, including patients with CCA. Updated PK model parameters were used to evaluate the association between pemigatinib exposure and efficacy and safety. Pemigatinib PK was adequately described by a two-compartment model with linear elimination and sequential zero- and first-order absorption. The final model successfully minimized, had a successful covariance step, and showed unbiased goodness-of-fit. Estimated first-order absorption rate constant and apparent clearance were 3.7/h and 10.7 L/h, respectively. Sex, baseline body weight, and concomitant use of phosphate binders, proton pump inhibitors, or histamine-2 antagonists significantly impacted PK parameters; however, the impact of covariates on PK exposure was not clinically significant. Steady-state pemigatinib exposure and mean change from baseline in serum phosphate concentration were associated with objective response rate in a bell-shaped relationship and were significantly associated with increased hyperphosphatemia. Pemigatinib exposure was associated with treatment-emergent adverse events, such as decreased appetite, nausea, and stomatitis, although the relationships were shallow. Overall, analyses indicate that 13.5 mg pemigatinib once daily in 21-day cycles (2 weeks on, 1 week off) offers a favorable benefit-risk profile in patients with advanced/metastatic or surgically unresectable CCA and is the optimal dose for clinical development.

FIGURE 1

(a) Prediction‐corrected and (b) Ordinary visual predictive check for the final population PK model. Black dots represent observed data points, the solid black line indicates the observed median, and the black dashed lines show the observed p5 and p95. The blue area represents the 95% PI of the simulated median, and pink areas indicate the 95% PI of the simulated p5 and p95. CI, confidence interval; PI, prediction interval; PK, pharmacokinetics; p5, 5th percentile; p95, 95th percentile.

FIGURE 2

Model‐predicted versus observed mean serum phosphate concentration change from baseline at C1D8 and C1D15 following once‐daily dosing of pemigatinib as monotherapy. The solid black curved line represents the simulated mean, and the dashed black curved lines represent the simulated 5% and 95% percentiles. AUC_ss, area under the concentration‐time curve at steady‐state; C, cycle; D, day.

FIGURE 3

Probability of objective response vs (a) mean serum phosphate concentration change from baseline at C1D8 and C1D15 and (b) pemigatinib AUC_ss following once‐daily dosing of 13.5 mg pemigatinib. Patients received a single daily dose of 13.5 mg pemigatinib. In (a), black squares represent observed first (0.5–2.1 mg/dL), second (2.1–2.7 mg/dL), third (2.7–3.5 mg/dL), and fourth (3.5–6.3 mg/dL) quartiles of serum phosphate concentration change from baseline. In (b), black squares represent first (817–1828 h·nM), second (1828–2351 h·nM), third (2351–3104 h·nM), and fourth (3104–8446 h·nM) quartiles of pemigatinib AUC_ss. AUC_ss, area under the concentration‐time curve at steady‐state; C, cycle; D, day.

FIGURE 4

Model‐predicted versus observed mean serum creatinine concentration percent change following once‐daily dosing of pemigatinib as monotherapy. The solid black curved line represents the simulated mean, and the dashed black curved lines represent the simulated 5% and 95% percentiles. AUC_ss, area under the concentration‐time curve at steady‐state.

FIGURE 5

Probability of incidence of clinically notable hyperphosphatemia vs pemigatinib AUCss following once‐daily dosing of pemigatinib. The squares represent the observed incidence rate at the first, second, third, and fourth quartiles of mean pemigatinib AUC_ss. Error bars represent 90% CIs. AUC_ss, area under the concentration‐time curve at steady‐state; CI, confidence interval; FGFR, fibroblast growth factor receptor; TEAE, treatment‐emergent adverse event.