Interactions between epidermal growth factor receptor tyrosine kinase inhibitors and proton-pump inhibitors/histamine type-2 receptor antagonists in non-small cell lung cancer: a systematic review and meta-analysis

Wilson Sim; Sneha Rajiv Jain; Wen Hui Lim; Yip Han Chin; Cheng Han Ng; Nicholas Syn; Kang Shiong Goh; Ross Soo; Lingzhi Wang; Boon Cher Goh

doi:10.21037/tlcr-21-378

Interactions between epidermal growth factor receptor tyrosine kinase inhibitors and proton-pump inhibitors/histamine type-2 receptor antagonists in non-small cell lung cancer: a systematic review and meta-analysis

Transl Lung Cancer Res. 2021 Aug;10(8):3567-3581. doi: 10.21037/tlcr-21-378.

Authors

Wilson Sim¹, Sneha Rajiv Jain¹, Wen Hui Lim¹, Yip Han Chin¹, Cheng Han Ng¹, Nicholas Syn¹, Kang Shiong Goh², Ross Soo³, Lingzhi Wang^{1

4}, Boon Cher Goh^{1

3

4}

Affiliations

¹ Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
² Department of Internal Medicine, National University Health System, Singapore, Singapore.
³ Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.
⁴ Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.

Abstract

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are increasingly used for advanced non-small cell lung cancer (NSCLC) as first-line therapy. The bioavailability and efficacy of oral EGFR-TKIs could be affected by acid suppression (AS) therapy such as PPIs and H2RAs which are reported to be over-prescribed. Hence, there is a need to investigate the effect of AS on the overall survival (OS), progression-free survival (PFS) and adverse effect profile in patients treated with EGFR TKIs.

Methods: An electronic database search of Medline and Embase was performed following PRISMA guidelines on 17 January 2021. Studies analyzing interactions between EGFR TKIs and PPIs/H2RAs in NSCLC patients were included. Abstracts, non-English or non-Japanese studies or studies using non-EGFR TKIs were excluded. Hazard ratios (HRs) were pooled using generic inverse variance random effects model. Effect sizes for dichotomous variables were pooled using Mantel-Haenszel random effects model. Significance was considered at P≤0.05. Heterogeneity was assessed with Cochran Q-test and I2 test. Publication bias was assessed with funnel plots. The assessment of quality and risk of bias of randomized and non-randomized studies were undertaken with RoB 2 and the ROBINS-I tool respectively.

Results: Out of 1,173 potentially relevant articles, 14 articles were included in the final analysis. The pooled prevalence of AS in patients taking EGFR TKI was 30.71% in 4,010 individuals. Patients who were treated only with EGFR TKI had significantly better OS (HR =1.46, 95% CI: 1.27-1.72; P<0.00001) and PFS (HR =1.63, 95% CI: 1.35-1.98; P<0.00001). The OS for EGFR mutation positive patients only was as similarly significant as the OS in all patients taking EGFR TKI, while the PFS in mutation positive patients was significantly worsened with AS. PPIs resulted in a significantly worsened OS and PFS but H2RAs did not produce significantly different OS and PFS between AS and non-AS users. There were no significant differences in the incidence of rash (OR =0.81, 95% CI: 0.50-1.32; P=0.40), diarrhoea (OR =1.03, 95% CI: 0.63-1.67; P=0.91) or other adverse effects.

Conclusions: Co-administration of AS medications with first-generation EGFR-TKIs in NSCLC worsens survival outcomes. Physicians should only prescribe AS medications when absolutely clinically indicated.

Keywords: Epidermal growth factor receptor (EGFR); acid suppression; drug interaction; tyrosine kinase inhibitors (TKI).