Acid suppression drugs counteract EGFR-TKIs for NSCLC treatment

Acid suppression (AS) medications, such as proton pump inhibitors (PPIs) and histamine type-2 receptor antagonists (H2RAs), weaken the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in nonsmall cell lung cancer (NSCLC), resulting in worse survival outcomes, according to a recent Singapore meta-analysis.

“In current practice, physicians should err on the side of caution when prescribing patients undergoing anticancer treatment with EGFR-TKIs for NSCLC, and only prescribe [AS] medications when absolutely clinically indicated and opt for a lower strength of AS,” the researchers said.

An electronic search of the Medline and Embase databases yielded 14 articles eligible for analysis. The pooled sample included 1,197 NSCLC treated with EGFR-TKIs along with AS medications, and 3,298 patients treated with EGFR-TKIs alone. Pooled prevalence rates of PPI and H2RA use were 19.33 percent and 25.13 percent, respectively.

Overall survival (OS) rates were nearly 50-percent better in patients treated with EGFR-TKIs alone vs in conjunction with AS (hazard ratio [HR], 1.46, 95 percent confidence interval [CI], 1.27–1.72; p<0.00001). [Transl Lung Cancer Res 2021;10:3567-3581]

Progression-free survival (PFS) was significantly better after treatment with EGFR-TKI alone (HR, 1.63, 95 percent CI, 1.35–1.98; p<0.00001). The analyses for OS and PFS included a pooled sample of 3,694 and 2,433, respectively, and both yielded symmetrical funnel plots, indicating no publication bias.

Subgroup analysis revealed that the detrimental effect of AS medications on survival outcomes were driven mainly by PPIs. For instance, PPI use led to significantly worse OS (HR, 1.98, 95 percent CI, 1.33–2.94; p=0.0007), an effect absent when focusing on H2RA use (HR, 1.04, 95 percent CI, 0.70–1.55; p=0.28). PPIs (HR, 3.39, 95 percent CI, 2.18–5.26; p<0.00001) but not H2RAs (HR, 1.48, 95 percent CI, 0.63–3.49; p=0.37) also worsened PFS. Notably, PPIs had a significantly stronger detrimental effect on OS than H2RAs (p=0.03).

In terms of tolerability, EGFR-TKI treatment with or without AS led to comparable rates of rashes (odds ratio [OR], 0.81, 95 percent CI, 0.50–1.32; p=0.40) and diarrhoea (OR, 1.03, 95 percent CI, 0.63–1.67; p=0.91). Other common side effects included vomiting, loss of appetite, oral ulcers, interstitial lung disease, and stomatitis, all of which developed at similar frequencies between treatment groups.

“The findings of this study are limited to NSCLC patients receiving first-generation EGFR-TKIs” such as erlotinib and gefitinib, and results may not be applicable to other types, such as afatinib, nor to second- and third-generation EGFR-TKIs, the researchers pointed out.

“Furthermore, as an intrinsic limitation of retrospective studies, AS therapy was not randomized and heterogeneity could be introduced in terms of patient baseline characteristics,” they added. Further studies are thus needed to elucidate the interaction more clearly between AS drugs and EGFR-TKIs, particularly as regards the different types of AS medications, the characteristics of cancer, and possible dose-dependent interactions.