Evaluation of the Effect of Proton Pump Inhibitors on the Efficacy of Dacomitinib and Gefitinib in Patients with Advanced Non-Small Cell Lung Cancer and EGFR-Activating Mutations

Jerry Li, Dana Nickens, Keith Wilner, Weiwei Tan, Jerry Li, Dana Nickens, Keith Wilner, Weiwei Tan

Abstract

Introduction: Dacomitinib and gefitinib are irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) indicated for the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) and EGFR-activating mutations. Pharmacokinetic (PK) studies in healthy volunteers suggested that acid-reducing drugs such as proton pump inhibitors (PPI) decreased dacomitinib and gefitinib exposure by limiting the pH-dependent absorption. This analysis retrospectively evaluates the effect of concomitant PPI use on dacomitinib exposure and on progression-free survival (PFS) and overall survival (OS) in patients treated with dacomitinib 45 mg QD or gefitinib 250 mg QD in a 1:1 randomized phase 3 study (ARCHER 1050).

Methods: The analysis grouped all patients (n = 452) treated in each arm of the study as non-PPI users, PPI users, or extensive PPI users. PFS and OS data were presented by Kaplan-Meier plots and analyzed using Cox proportional hazards models. Dacomitinib exposure was compared using a linear mixed-effects model.

Results: Results showed that dacomitinib PFS and OS did not differ significantly when comparing PPI users (N = 59) to non-PPI users (N = 152), while extensive PPI users (N = 24) had shorter PFS [hazard ratio (HR): 1.94, p = 0.011] and OS (HR: 1.77, p = 0.027) when compared to non-PPI users. For patients treated with gefitinib, PFS did not differ significantly when comparing PPI users (N = 51) and extensive PPI users (N = 19) to non-PPI users (N = 159); however, both PPI users (HR: 1.65, p = 0.007) and extensive PPI users (HR: 1.70, p = 0.050) had shorter OS when compared to non-PPI users. Further analysis by adjusting potential confounders indicated no statistically significant differences in PFS or OS between any PPI user vs. non-PPI user groups in the dacomitinib and gefitinib arms. PPI use did not appear to affect dacomitinib exposure.

Conclusion: In conclusion, PPI use in patients with NSCLC likely has minimal impact on dacomitinib or gefitinib efficacy despite decreased absorption of these drugs observed in PK studies.

Trial registration: ClinicalTrials.gov identifier, NCT01774721.

Keywords: Dacomitinib; EGFR inhibitor; Overall survival; Pharmacokinetics; Progression-free survival; Proton pump inhibitors.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Summary of patients grouped by PPI use in the intent-to-treat population randomized to dacomitinib or gefitinib treatment arms. Black boxes represent groups used in analyses. For the dacomitinib arm, the numbers of patients with evaluable Ctrough for PK analysis are included in the parentheses. PPI Record indicates any patient who had a PPI record. aSixteen patients in the dacomitinib arm and 15 patients in the gefitinib arm were not included in the analysis. These patients either only had a PPI record after stopping dacomitinib or gefitinib treatment, or their PPI records had no start or end date, making it impossible to determine whether those patients took PPIs concurrently with study treatment. PPI proton pump inhibitor; Ctrough,ss steady-state trough concentration
Fig. 2
Fig. 2
Steady-state dacomitinib trough concentrations at 45, 30, and 15 mg once daily across all PPI use groups. Red, green, and blue box and dots represent dacomitinib Ctrough,ss following at least 14 consecutive days of once daily dacomitinib dosing at 45, 30, and 15 mg, respectively. Ctrough,ss steady-state trough concentration; ng nanograms; mL milliliters; PPI proton pump inhibitor; mg milligrams
Fig. 3
Fig. 3
Kaplan–Meier plots of PFS for patients treated with a dacomitinib or b gefitinib based on PPI use groups. Red lines represent patients in the reference (non-PPI user) group, green lines represent the PPI user group, and blue lines represent patients in the extensive PPI user group. PFS progression-free survival; PPI proton pump inhibitor
Fig. 4
Fig. 4
Kaplan–Meier plots of OS for patients treated with a dacomitinib or b gefitinib based on PPI use groups. Red lines represent patients in the reference (non-PPI user) group, green lines represent the PPI user group, and blue lines represent patients in the extensive PPI user group. OS overall survival; PPI proton pump inhibitor

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