Accepted Manuscript Gastric acid suppression is associated with decreased erlotinib efficacy in non-small cell lung cancer Michael P. Chu, Sunita Ghosh, Carole R. Chambers, Naveen Basappa, Charles A. Butts, Quincy Chu, David Fenton, Anil A. Joy, Randeep Sangha, Michael Smylie, Michael B. Sawyer PII:

S1525-7304(14)00147-8

DOI:

10.1016/j.cllc.2014.07.005

Reference:

CLLC 297

To appear in:

Clinical Lung Cancer

Received Date: 5 June 2014 Revised Date:

28 July 2014

Accepted Date: 29 July 2014

Please cite this article as: Chu MP, Ghosh S, Chambers CR, Basappa N, Butts CA, Chu Q, Fenton D, Joy AA, Sangha R, Smylie M, Sawyer MB, Gastric acid suppression is associated with decreased erlotinib efficacy in non-small cell lung cancer, Clinical Lung Cancer (2014), doi: 10.1016/ j.cllc.2014.07.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Acid Suppression and Erlotinib in NSCLC

Gastric acid suppression is associated with decreased erlotinib efficacy in non-small cell lung cancer Michael P Chu1

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Sunita Ghosh1 Carole R Chambers2 Naveen Basappa1

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Charles A Butts1 Quincy Chu1

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David Fenton3 Anil A Joy1 Randeep Sangha1 Michael Smylie1 Michael B Sawyer1 1

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Department of Medical Oncology, Cross Cancer Institute, University of Alberta, Canada Department of Pharmacy, Tom Baker Cancer Centre, University of Calgary, Canada 3 Department of Medical Oncology, BC Cancer Agency, Vancouver Island Centre, Victoria, British Columbia, Canada 2

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Disclaimers: None Sources of funding: None Abstract Word Count: 247 Word count: 3,000 Number of figures and tables: 2 figures and 4 tables Conflicts of Interest: None Key Words: erlotinib; proton pump inhibitors; drug interactions; non-small cell lung cancer Presented in part at the World Conference on Lung Cancer, Sydney, New South Wales, Australia, October 27-30, 2013. Corresponding author: Michael B Sawyer, Medical Oncology, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta, Canada T6G 1Z2 Phone: (780)432-8248; Fax: (780)432-8888; Email: [email protected]

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ACCEPTED MANUSCRIPT Acid Suppression and Erlotinib in NSCLC

MicroAbstract Tyrosine kinase inhibitors (TKIs) are the focus in oncology research. As oral drugs, TKIs often have pH-dependent solubility – suggesting interactions with gastric acid suppressants (AS). This

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retrospective review of 507 advanced non-small cell lung cancer patients treated with erlotinib demonstrates negative outcomes in patients concurrently receiving AS; a finding also seen with

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sunitinib. Caution is required in this underappreciated interaction.

Abstract

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BACKGROUND

Erlotinib is a key therapy for advanced non-small cell lung cancer (NSCLC). Concurrent acid suppression (AS) therapy with tyrosine kinase inhibitors (TKIs) may reduce TKI plasma levels. Given gastroesophageal reflux disease prevalence, this retrospective analysis was undertaken to

PATIENTS AND METHODS

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determine if co-administering erlotinib with AS affected NSCLC outcomes.

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Advanced NSCLC patients receiving erlotinib from 2007-2012 at a large, centralized, cancer institution were retrospectively reviewed. Pertinent demographics were collected and

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concomitant AS treatment was defined as AS prescription dates overlapping with ≥ 20% of erlotinib treatment duration. Patients who received erlotinib for ≥ 1 week were analyzed for progression free survival (PFS) and overall survival (OS).

RESULTS Stage IIIB/IV NSCLC patients (n=544) were identified and 507 had adequate data for review. Median age was 64 years and 272 were female. Adenocarcinoma (318, 64%) and squamous

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(106, 21%) were predominant subtypes; 124 patients received concomitant AS. In this unselected population, median PFS and OS in AS vs. non-AS groups were 1.4 vs. 2.3 months (p 1.8 million) were reviewed. The 6th American Joint Committee on Cancer (AJCC TNM) staging edition was used to describe patient stage. Patients who received ≤ 1 week of erlotinib were excluded from this study.

Variables including age at diagnosis, gender, histological subtype, stage at diagnosis (using 6th edition AJCC system), ECOG performance status (PS), prior treatments, date of progression, and method of determining progressive disease (radiographic or clinical) were collected. Histological subtype was

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ACCEPTED MANUSCRIPT Acid Suppression and Erlotinib in NSCLC

classified as follows: adenocarcinoma, squamous cell, large cell, poorly differentiated, or not otherwise specified (NOS).

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In Alberta, Canada, a central database is used to document prescription medications. This database was interrogated to determine which patients received AS therapies. Information collected included AS therapy type (PPI, H2RA), prescription dates, method of dosing (continuous or as needed), and dose.

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Patients were considered to be receiving concomitant AS therapy if their AS prescription overlapped with erlotinib administration by ≥ 20% of the time. Given a 46% decrease in AUC with one week of concomitant PPI use in healthy volunteers, one week would constitute 13% of the median PFS (erlotinib

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treatment duration) on the BR-21 study.3,8 Therefore ≥ 20% co-administration duration was chosen arbitrarily to include a margin of error and standardize inclusion into the AS therapy group on our study.

Clinical outcome data were collected from both paper and electronic medical records. PFS and OS were

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analyzed in an intention-to-treat fashion using methods of Kaplan-Meier. Patients who were lost to follow-up or who stopped erlotinib early due to toxicity were included in statistical analysis. Secondary endpoints included objective response rates (ORR), incidence of any rash and diarrhea, incidence of dose

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reduction, and incidence of treatment-limiting toxicity. Statistical analysis was performed with Statistical Analysis System (SAS) version 9.3 from SAS Institute Incorporated, Cary, North Carolina. All p-values

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were calculated using two-sided statistical testing and Cox proportional hazards ratios with 95% confidence intervals.

Results Patients

Between January 2007 and December 2012, 544 advanced NSCLC patients received erlotinib and 507 were considered eligible for this retrospective analysis. There were 235 (46%) male patients and 272 (54%) female. Median age of patients was 64 years (range 28-86). Most patients (n=418 patients, 82%)

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ACCEPTED MANUSCRIPT Acid Suppression and Erlotinib in NSCLC

had stage IV disease with the remainder having stage IIIB disease. A significant proportion of patients were PS 1 (32.1%) or PS 2(46.7%). Though there was a higher proportion of patients with ECOG PS ≤ 2 in the AS-group (86 vs. 79%), this did not meet statistical significance (p=0.11). The majority of patients

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(71%) received chemotherapy prior to receiving erlotinib, of which platinum-doublets were most commonly used (88%). Histological subtypes included 64% adenocarcinoma, 21% squamous cell, 2% large cell, 8% poorly differentiated, and 6% NOS. Eleven patients (3%) were lost to follow-up in the non-

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AS group compared to one (1%) in the AS-group. There was no statistically significant differences in NSCLC baseline characteristics or Charlson comorbidity index (adjusted for all patients on study having

Prevalence and Effect of Acid Suppression

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advanced NSCLC) between AS and non-AS groups (Table I).

Twenty-five percent of patients (n=124) received AS therapy and the most common therapeutic was a PPI (n=115, 93%) with only 9 patients receiving H2RA (7%). Eighty-one percent (n=100) had complete

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overlap between AS therapy prescription dates and erlotinib therapy with nearly all patients receiving continuous AS therapy dosing (n=120, 97%, see Table III).

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The impact of acid suppression on survival was compared to other clinical characteristics (Table II). The median PFS in the AS group was significantly lower than the non-AS group (1.4 vs. 2.3 months; hazard

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ratio [HR] 1.71, p

Gastric Acid suppression is associated with decreased erlotinib efficacy in non-small-cell lung cancer.

Erlotinib is a key therapy for advanced NSCLC. Concurrent AS therapy with TKIs might reduce TKI plasma levels. Because of gastroesophageal reflux dise...
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