title: 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.
  
  
  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.
authors.affiliation: Department of Haematology-Oncology, National University Cancer Institute, Singapore.
authors.forename: Nesaretnam Barr
authors.initials: NB
authors.lastname: Kumarakulasinghe
authors.affiliation: Department of Haematology-Oncology, National University Cancer Institute, Singapore.|Cancer Science Institute of Singapore, National University of Singapore, Singapore.|Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Syn
authors.affiliation: Department of Radiation Oncology, National University Cancer Institute, Singapore.
authors.forename: Yu Yang
authors.initials: YY
authors.lastname: Soon
authors.affiliation: Department of General Surgery, Tan Tock Seng Hospital, Singapore.
authors.forename: Atasha
authors.initials: A
authors.lastname: Asmat
authors.affiliation: National Registry of Diseases Office, Health Promotion Board, Singapore.
authors.forename: Huili
authors.initials: H
authors.lastname: Zheng
authors.affiliation: National Registry of Diseases Office, Health Promotion Board, Singapore.
authors.forename: En Yun
authors.initials: EY
authors.lastname: Loy
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.|Department of Pathology, National University Health System, Singapore.
authors.forename: Brendan
authors.initials: B
authors.lastname: Pang
authors.affiliation: Department of Haematology-Oncology, National University Cancer Institute, Singapore.|Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Ross Andrew
authors.initials: RA
authors.lastname: Soo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality; D016009:Chi-Square Distribution; D016208:Databases, Factual; D018450:Disease Progression; D018572:Disease-Free Survival; D004347:Drug Interactions; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology*; D005260:Female; D000077156:Gefitinib; D006801:Humans; D053208:Kaplan-Meier Estimate; D017567:Karnofsky Performance Status; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D054328:Proton Pump Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011799:Quinazolines / Q000494:pharmacology*; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D012846:Singapore; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D054328:Proton Pump Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: NSCLC; drug-drug interactions; erlotinib; gastric acid suppression; gefitinib