PMID- 34120312
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20211203
IS  - 2366-1089 (Electronic)
IS  - 2366-1070 (Print)
IS  - 2366-1089 (Linking)
VI  - 9
IP  - 2
DP  - 2021 Dec
TI  - Evaluation of the Effect of Proton Pump Inhibitors on the Efficacy of Dacomitinib 
      and Gefitinib in Patients with Advanced Non-Small Cell Lung Cancer and 
      EGFR-Activating Mutations.
PG  - 525-539
LID - 10.1007/s40487-021-00156-2 [doi]
AB  - INTRODUCTION: Dacomitinib and gefitinib are irreversible epidermal growth factor 
      receptor (EGFR) tyrosine kinase inhibitors (TKI) indicated for the first-line 
      treatment of patients with advanced non-small cell lung cancer (NSCLC) and 
      EGFR-activating mutations. Pharmacokinetic (PK) studies in healthy volunteers 
      suggested that acid-reducing drugs such as proton pump inhibitors (PPI) decreased 
      dacomitinib and gefitinib exposure by limiting the pH-dependent absorption. This 
      analysis retrospectively evaluates the effect of concomitant PPI use on 
      dacomitinib exposure and on progression-free survival (PFS) and overall survival 
      (OS) in patients treated with dacomitinib 45 mg QD or gefitinib 250 mg QD in a 
      1:1 randomized phase 3 study (ARCHER 1050). METHODS: The analysis grouped all 
      patients (n = 452) treated in each arm of the study as non-PPI users, PPI users, 
      or extensive PPI users. PFS and OS data were presented by Kaplan-Meier plots and 
      analyzed using Cox proportional hazards models. Dacomitinib exposure was compared 
      using a linear mixed-effects model. RESULTS: Results showed that dacomitinib PFS 
      and OS did not differ significantly when comparing PPI users (N = 59) to non-PPI 
      users (N = 152), while extensive PPI users (N = 24) had shorter PFS [hazard ratio 
      (HR): 1.94, p = 0.011] and OS (HR: 1.77, p = 0.027) when compared to non-PPI 
      users. For patients treated with gefitinib, PFS did not differ significantly when 
      comparing PPI users (N = 51) and extensive PPI users (N = 19) to non-PPI users 
      (N = 159); however, both PPI users (HR: 1.65, p = 0.007) and extensive PPI users 
      (HR: 1.70, p = 0.050) had shorter OS when compared to non-PPI users. Further 
      analysis by adjusting potential confounders indicated no statistically 
      significant differences in PFS or OS between any PPI user vs. non-PPI user groups 
      in the dacomitinib and gefitinib arms. PPI use did not appear to affect 
      dacomitinib exposure. CONCLUSION: In conclusion, PPI use in patients with NSCLC 
      likely has minimal impact on dacomitinib or gefitinib efficacy despite decreased 
      absorption of these drugs observed in PK studies. TRIAL REGISTRATION: 
      ClinicalTrials.gov identifier, NCT01774721.
CI  - (c) 2021. The Author(s).
FAU - Li, Jerry
AU  - Li J
AD  - Pharmacometrics, Pfizer Inc, 500 Arcola Road, Collegeville, PA, USA.
FAU - Nickens, Dana
AU  - Nickens D
AD  - Pharmacometrics, Pfizer Inc, 10555 Science Center Drive, San Diego, CA, USA.
FAU - Wilner, Keith
AU  - Wilner K
AD  - Oncology, Pfizer Inc, 10555 Science Center Drive, San Diego, CA, USA.
FAU - Tan, Weiwei
AU  - Tan W
AUID- ORCID: 0000-0001-8915-1152
AD  - Clinical Pharmacology, Pfizer Inc, 10555 Science Center Drive, CB10/002/2533, San 
      Diego, CA, 92121, USA. Weiwei.tan@pfizer.com.
LA  - eng
SI  - ClinicalTrials.gov/NCT01774721
PT  - Journal Article
DEP - 20210613
PL  - New Zealand
TA  - Oncol Ther
JT  - Oncology and therapy
JID - 101677510
PMC - PMC8593125
OTO - NOTNLM
OT  - Dacomitinib
OT  - EGFR inhibitor
OT  - Overall survival
OT  - Pharmacokinetics
OT  - Progression-free survival
OT  - Proton pump inhibitors
EDAT- 2021/06/14 06:00
MHDA- 2021/06/14 06:01
PMCR- 2021/06/13
CRDT- 2021/06/13 21:07
PHST- 2021/04/14 00:00 [received]
PHST- 2021/05/22 00:00 [accepted]
PHST- 2021/06/14 06:00 [pubmed]
PHST- 2021/06/14 06:01 [medline]
PHST- 2021/06/13 21:07 [entrez]
PHST- 2021/06/13 00:00 [pmc-release]
AID - 10.1007/s40487-021-00156-2 [pii]
AID - 156 [pii]
AID - 10.1007/s40487-021-00156-2 [doi]
PST - ppublish
SO  - Oncol Ther. 2021 Dec;9(2):525-539. doi: 10.1007/s40487-021-00156-2. Epub 2021 Jun 
      13.