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

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

Concomitant Gastric Acid Suppressants on the Survival of Patients with Non-Small-Cell Lung Cancer Treated with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: A Meta-Analysis

“…As shown in Table 1 , thirteen cohort studies [ 11 – 23 ] including 12259 patients with NSCLC that were treated with TKIs were included. Since one study reported two cohorts of patients taking dacomitinib or gefitinib, respectively [ 22 ], these two datasets were included independently in the meta-analysis. These studies were published between 2013 and 2021 and performed in Canada [ 11 , 12 ], Spain [ 16 ], the United States [ 18 , 22 ], Japan [ 15 , 23 ], Singapore [ 14 ], and China [ 13 , 17 , 19 – 21 ], respectively.…”

“…Since one study reported two cohorts of patients taking dacomitinib or gefitinib, respectively [ 22 ], these two datasets were included independently in the meta-analysis. These studies were published between 2013 and 2021 and performed in Canada [ 11 , 12 ], Spain [ 16 ], the United States [ 18 , 22 ], Japan [ 15 , 23 ], Singapore [ 14 ], and China [ 13 , 17 , 19 – 21 ], respectively. All of the studies were retrospective cohort studies and included patients with advanced NSCLC treated with TKIs.…”

“…The mean ages of the patients varied between 61 and 76 years, and the proportions of males varied between 28 and 65%. In most of the included studies, the first-generation EGFR-TKIs such as erlotinib and gefitinib were used except for two studies, in which some of the patients also used the second-generation EGFR-TKIs such as afatinib and dacomitinib [ 21 , 22 ]. Concomitant use of AS was validated by medical or prescription records in most of the studies except for one study, which was self-reported [ 11 ].…”

“…Concomitant use of AS was validated by medical or prescription records in most of the studies except for one study, which was self-reported [ 11 ]. Concomitant use of PPIs or H2RAs was defined as exposure in most of the included studies except for four studies, which observed the concomitant use of PPIs [ 17 , 18 , 22 ] or H2RAs [ 23 ] only. Variables including age, sex, performance status, clinical stage, smoking history, comorbidities, and metastatic status were adjusted to a varying degree among the included studies.…”

“…Ten studies reported the association between concomitant AS and PFS in NSCLC patients taking TKIs [ 11 – 16 , 19 , 20 , 22 , 23 ]. Pooled results with a random-effect model showed that concomitant AS was independently associated with a worse PFS in NSCLC patients taking TKIs (adjusted HR: 1.57, 95% CI: 1.31 to 1.89, P < 0.001; I 2 = 65%; Figure 2(a) ).…”