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

Abstract

Background. The influence of concomitant use of gastric acid suppressants (AS) on survival of patients with non-small-cell lung cancer (NSCLC) treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inconsistent according to previous studies. We performed a meta-analysis to evaluate the effect of additional AS in patients with NSCLC taking TKIs. Methods. Relevant observational studies were identified by a search of Medline, Embase, and Web of Science databases. Only studies with multivariate analyses were included. A random-effect model was used to combine the results. Results. Thirteen retrospective studies with 12259 patients were included. Pooled results showed that concomitant use of AS was associated with worse progression-free survival (PFS, adjusted hazard ratio (HR): 1.57, 95% confidence interval (CI): 1.31 to 1.89, P < 0.001 ; I2 = 65%) and overall survival (OS, adjusted HR: 1.38, 95% CI: 1.19 to 1.61, P < 0.001 ; I2 = 70%) in NSCLC patients taking TKIs. Sensitivity analysis limited to studies including NSCLC with EGFR mutation showed consistent results (HR for PFS: 1.53, P = 0.003 ; HR for OS: 1.43, P = 0.001 ). Subgroup analyses indicated that the association between concomitant use of AS and poor survival was not significantly affected by the category of AS used (proton pump inhibitors or histamine type-2 receptor antagonists) or the country of the study (Asian or non-Asian, P for subgroup analysis all >0.05). Conclusions. Concomitant use of AS in patients with NSCLC taking TKIs may be associated with poor survival outcomes.

Despite warnings, co‐medication with proton pump inhibitors and dasatinib is common in chronic myeloid leukemia, but XS004, a novel oral dasatinib formulation, provides reduced pH‐dependence, minimizing undesirable drug–drug interactions

“…An important outstanding question is whether PPI co-medication leads to more treatment failures with clinical impact among dasatinib users as the plasma exposure reduces more than 40%-60% with crystalline-based products. 4,12,13 Co-medication of PPIs and TKIs with pH-dependent absorption has previously been shown to be associated with reduced survival among lung cancer patients treated with erlotinib, 36,[49][50][51] gefitinib, [50][51][52] or dacomitinib. 51 More recent studies with dacomitinib or gefitinib have failed to replicate an association between concomitant PPI use and overall survival.…”

“…4,12,13 Co-medication of PPIs and TKIs with pH-dependent absorption has previously been shown to be associated with reduced survival among lung cancer patients treated with erlotinib, 36,[49][50][51] gefitinib, [50][51][52] or dacomitinib. 51 More recent studies with dacomitinib or gefitinib have failed to replicate an association between concomitant PPI use and overall survival. 53,54 However, in the latter study, overall survival was decreased among "extensive users" of PPIs, defined as having at least one PPI prescription before and one prescription after cancer diagnosis.…”

Combination Use of First-Line Afatinib and Proton-Pump Inhibitors Reduces Overall Survival Among Patients with EGFFR Mutant Lung Cancer

“…Several systemic reviews and meta-analyses also demonstrated that antacids are significantly associated with increased mortality 1578 risk in patients with lung cancer receiving EGFR-TKIs. [20][21][22] However, data of afatinib and PPIs remained limited. Second-generation EGFR-TKIs, such as afatinib and dacomitinib, showed a better survival benefit than first-generation EGFR-TKIs, such as gefitinib and erlotinib.…”

“…6 Previous retrospective or cohort studies reported the negative impact of PPIs on first-generation EGFR-TKIs, [7][8][9][10][11][12][13][14][15][16][17][18][19] and several systemic review and meta-analysis report similar results. [20][21][22] However, clinical data to evaluate the negative impact of PPIs on second-generation TKIs, such as afatinib or dacomitinib, are limited. Therefore, this retrospective cohort study was designed using Chang Gung Research Database (CGRD) to evaluate the impact of PPIs on first-line afatinib treatment outcomes.…”