EGFR kinase inhibitors and gastric acid suppressants in EGFR-mutant NSCLC: a retrospective database analysis of potential drug interaction

Abstract

Background: Erlotinib and gefitinib are weak base drugs whose absorption and clinical efficacy may be impaired by concomitant gastric acid suppressive (AS) therapy, yet proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2As) are widely indicated in non-small cell lung cancer (NSCLC) patients for the prevention and treatment of erlotinib-induced gastrointestinal injury and corticosteroid-associated gastric irritation. We assessed the clinical relevance of this potential drug-drug interaction (DDI) in a retrospective cohort of EGFR-mutant NSCLC patients.

Results: The AS usage rate was 35%. In the overall cohort, AS users did not experience poorer OS (HR: 1.47, 95% CI: 0.92 - 2.35, P = 0.10; median, 11.4 versus 17.5 months) or PFS (HR = 1.37, 95% CI: 0.89 - 2.12, P = 0.16; median, 7.6 versus 8.7 months) compared with non-users in multivariate Cox regression analysis. However, subgroup analyses indicated that AS usage was associated with significantly poorer OS and PFS in patients who had fewer or milder comorbidities (Charlson comorbidity index ≤ 2), those with Karnofsky performance status < 90, and never-smokers.

Materials and methods: A retrospective database analysis of 157 patients given erlotinib or gefitinib for EGFR-mutant advanced NSCLC from two institutions was conducted. Patients were classified as AS-users if the periods of AS and anti-EGFR therapy overlapped by ≥ 30%. Overall survival (OS) and progression-free survival (PFS) were assessed according to AS usage.

Conclusions: Concomitant AS therapy did not have an adverse impact on OS and/or PFS in the overall cohort. Our subgroup findings should be regarded exploratory and require replication in a large prospective cohort.

Keywords: NSCLC; drug-drug interactions; erlotinib; gastric acid suppression; gefitinib.

Figure 1. Kaplan-Meier Curve of Overall Survival in the Study Population and Forest Plot of Subgroup Analysis. Panel A.

shows the Kaplan-Meier survival curves for AS users and non-users. The median OS was 11.4 months among AS users compared to 17.5 months among non-users (HR = 1.47, 95% CI: 0.92 – 2.35, P = 0.10). Overall survival was adjusted for baseline imbalances and all potentially prognostic clinical characteristics (including patient age, presence of brain metastases, presence of liver metastases, smoking history, race, sex, Karnofsky performance status and Charlson comorbidity index). Panel B. shows the heterogeneity of the treatment effect across clinical and demographic subgroups. In most cases, HRs were consistent with that of the overall cohort; however, the HR for death was increased in females, symptomatic patients (KPS < 90), those with milder or fewer co-morbidities (CCI ≤ 2), and never-smokers who received AS therapy compared to those who did not.

Figure 2. Kaplan-Meier Curve of Progression-Free Survival in the Study Population and Forest Plot of Subgroup Analysis. Panel A.

shows the Kaplan-Meier survival curves for AS users and non-users. The median PFS was among 7.6 months among AS users compared to 8.7 months among non-users (HR = 1.37, 95% CI: 0.89 – 2.12, P = 0.16). There were no censored observations. Multivariate Cox regression was performed to adjust for baseline imbalances and potential confounding clinical variables, as in Figure 1. Panel B. shows the forest plot of the treatment effect in various patient subgroups. As in the case with overall survival, the hazard ratio for progression or death was increased among never-smokers, symptomatic from cancer (KPS < 90) or had fewer or milder co-morbidities (CCI ≤ 2).