Gastric Acid Suppression Is Associated With Decreased Erlotinib Efficacy in Non–Small-Cell Lung Cancer

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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ACCEPTED MANUSCRIPT Acid Suppression and Erlotinib in NSCLC

(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<0.001) and 12.9 vs. 16.8 months (p=0.003), respectively. Factoring gender, subtype, and performance status

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in multivariate Cox proportional hazards ratios for PFS and OS between AS and non-AS groups were 1.83 (95% CI 1.48-2.25) and 1.37 (95% CI 1.11-1.69) respectively.

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CONCLUSION

This large population-based study suggests erlotinib efficacy may be linked with gastric pH and

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OS could be adversely affected. This is the first study demonstrating a possible negative clinical impact of co-administering erlotinib with AS therapy. Further prospective investigation is

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warranted.

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ACCEPTED MANUSCRIPT Acid Suppression and Erlotinib in NSCLC

Introduction Despite treatment advances, lung cancer remains the leading cause of cancer-related mortality.1 Cytotoxic chemotherapy has been the backbone of treating advanced non-small cell lung cancer (NSCLC). Recent

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strides in research have discovered the key role of the epidermal growth factor receptor (EGFR) pathway in driving lung cancer tumorigenesis and led to development of EGFR tyrosine kinase inhibitors (TKIs).2

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A commonly used EGFR TKI for advanced NSCLC is erlotinib. BR-21, a randomized phase III trial in advanced NSCLC patients who received first-line platinum-doublet chemotherapy, was the first trial to

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show erlotinib significantly improved both progression free (PFS) and overall survival (OS).3 Predictors of EGFR TKI therapy response include Asian ethnicity, female gender, non-smoking history, EGFR gene amplification, and/or presence of EGFR activating mutations. Post-hoc analysis of these data found the presence of an EGFR mutation did not improve overall survival despite increased response rates.4 BR-21 led to erlotinib adoption as a standard second- or third-line therapy in an unselected population with

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advanced NSCLC. Erlotinib following first-line platinum doublet chemotherapy as a “switch” maintenance approach has also been shown to improve PFS.5 In treatment naive, advanced NSCLC patients possessing an EGFR activating mutation, erlotinib demonstrated superior response rates and PFS

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compared to platinum-doublet chemotherapy.6,7

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By targeting specific cellular receptors, oral TKIs inherently have a more attractive side effect profile compared to cytotoxic chemotherapy. However, for oral medications, drug absorption can be affected by gastric acidity. During pre-clinical development, erlotinib was found to have pH-dependent solubility with a dissociation constant (pKa) of 5.4.8 This pH-dependent solubility is reflected in a study comparing erlotinib plasma concentrations in healthy volunteers who were or were not taking acid suppression (AS) therapy.9 Subjects received a 7-day course of omeprazole, a proton pump inhibitor (PPI), along with a single dose of erlotinib. There was a median decrease of 46% in the area under the concentration-time

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ACCEPTED MANUSCRIPT Acid Suppression and Erlotinib in NSCLC

curve (AUC) in PPI treated subjects. Similarly, a study investigating ranitidine, a histamine type-2 receptor antagonist (H2RA), showed ranitidine decreased erlotinib’s median AUC by 33% 8.

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In addition to preclinical data, a case report documents lower than expected erlotinib trough concentrations in a patient receiving intravenous pantoprazole.10 However, lower erlotinib trough

concentrations were not observed when oral pantoprazole was given. This difference was hypothesized to

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be due to decreased bioavailability of oral pantoprazole resulting in decreased effects on gastric acid production when compared to intravenous administration and consequently, having less effect on erlotinib

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absorption.

It is unclear whether decreased erlotinib absorption leads to altered clinical outcomes. Given gastroesophageal reflux disease (GERD) is highly prevalent, there is a large proportion of advanced NSCLC patients who are receiving both erlotinib and AS therapy concomitantly. The objective of this

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retrospective cohort study was to determine AS therapy effects on clinically relevant outcomes for advanced NSCLC patients receiving erlotinib.

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Patients and Methods

Following institutional research ethics board approval, patients with stage IIIB or IV NSCLC receiving

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erlotinib from 2007 to 2012 through a large, centralized single institution (catchment population of > 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<0.0001, Figure 1). The median OS was also significantly inferior in the AS group (12.9 vs. 16.8 months; HR 1.38, p=0.003, Figure 2). With respect to the overall population, there was a nonstatistically significant improvement in median PFS and OS in female patients. PS and histologic subtype were prognostic since patients with ECOG PS ≤ 2 or adenocarcinoma had superior outcomes as compared to those with ECOG PS ≥ 3 and NOS subtype. Multivariate analysis by Cox proportional hazards modeling accounting for gender, histologic subtype and PS yielded hazard ratios for PFS and OS in the AS group of 1.83 (95% CI 1.48-2.25) and 1.37 (95% CI 1.11-1.69), respectively.

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ACCEPTED MANUSCRIPT Acid Suppression and Erlotinib in NSCLC

In addition, the presence of AS vs. no-AS therapy significantly impacted median PFS in all nonsquamous cell histologies: adenocarcinoma 1.6 vs. 2.5 months (p<0.001); poorly differentiated 0.8 vs. 1.9 months (p=0.02); and NOS 1.2 vs. 1.7 months (p=0.05). OS was similarly influenced between AS and no-AS

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groups: adenocarcinoma 12.8 vs. 17.4 months (p=0.005); poorly differentiated 7.5 vs. 14.5 months (p=0.05); and NOS 10.9 vs. 14.4 months (p=0.70). There was no difference in squamous histology

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regardless of AS status: PFS 1.5 vs. 2.1 months (p=0.21) and 13.5 vs. 16.1 months (p=0.93), respectively.

Of 124 patients in the AS therapy group, 9 patients received a H2RA medication while the remainder

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received a PPI. Comparison between H2RA vs. PPI subgroups yield PFS and OS of 1.8 vs. 1.3 months and 12.6 vs. 12.8 months, respectively (p=0.20 and 0.45, respectively).

EGFR mutation status

Because a large majority of patients in this cohort began treatment prior to standardization of EGFR

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mutation testing at the institution, only 20 were tested for the EGFR mutation (specifically exon 19 deletion or exon 21 point mutation). Of those tested, four patients had an EGFR mutation but none

Secondary endpoints

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received AS therapy.

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ORR, as defined by a minimum of partial response (PR), was 15.4% amongst all patients (Table IV). AS therapy was associated with poorer ORR, 5.6 vs. 18.5%, p=0.0005; where the most pronounced difference was present in adenocarcinoma patients (7.8 vs. 19.6%, p=0.02). Forty-four patients (8.7%) required a dose reduction with a similar proportion of patients in either AS or no-AS groups (7.3 vs. 9.4%, p=0.47, respectively). However, stopping erlotinib therapy due to toxicity was more prevalent in the no-AS group, 27 vs. 1 patient (7.1 vs. 0.8%, p=0.008). Presence of any TKI-related rash also reflects this difference wherein 242 patients (63.2%) receiving no-AS therapy developed an acneiform rash vs. 59

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ACCEPTED MANUSCRIPT Acid Suppression and Erlotinib in NSCLC

patients (47.6%) in those receiving AS groups (p=0.002). Prevalence of TKI-related diarrhea was insignificant (20.6 vs. 19.4%).

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Discussion Erlotinib’s drug monograph references potential interactions with AS therapy based on randomized, healthy volunteer studies where a drop in AUC occurs when erlotinib is co-administered with a PPI or

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H2RA.8,9 Despite this warning, questions whether concomitant administration of erlotinib and AS

therapy would lead to clinical consequences remained. Hilton et al. attempted to find an answer through a post-hoc analysis of BR-21, but trial survival and drug plasma concentration data did not suggest negative

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interactions in NSCLC patients.11 Because of this discrepancy in effects of AS therapy on erlotinib serum concentration, this retrospective study set out to determine if AS therapy affected erlotinib in “real-world” patients. Our analysis demonstrates a negative impact of AS therapy on erlotinib effectiveness.

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Pharmacologically, interactions between AS therapy and erlotinib are likely related to both solubility and pKa. Erlotinib has a reported pKa of 5.4 and is only very slightly soluble reaching maximal solubility (0.4 mg/ml) in solutions with pH = 2.9 Given that the most common form of AS therapy, PPIs, yields a median

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gastric pH > 5, erlotinib would have substantially reduced ability to dissolve.12 In addition, based on their greater ability to reduce gastric acidity, raise gastric pH and treat GERD, PPIs likely affect erlotinib

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solubility more than H2RAs.13 This pharmacokinetic inference is reflected in healthy volunteer studies in which erlotinib’s AUC decreased by only 33% when co-administered with an H2RA compared to 46% with PPI treatment.8 When the BR-21 trial was conducted, PPIs were not as prevalent and patients were more likely to receive H2RA therapy. Based on differing effectiveness at raising gastric pH, the difference between our results and the post-hoc analysis of BR-21 may be explained by differing prevalence of PPI vs. H2RA use.11 PPIs today though, are clearly dominant as AS-therapy standard, making H2RAs uncommon. This dominance was the case in our review as well (Table III). It should be noted that both PPIs and H2RAs were included in our comparison of AS vs. no-AS therapy. Examining

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ACCEPTED MANUSCRIPT Acid Suppression and Erlotinib in NSCLC

for a difference of impact on erlotinib was of interest between these two drug types, but such small numbers of H2RA use preclude any further conclusions.

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Whether or not PPIs are markers for poorer prognosis is unclear in light of nearly identical Charlson comorbidity indices between AS and non-AS therapy groups in this cohort (Table I) – countering

suggestions that AS therapy is a marker of general health.AS therapy still appeared to have effects on

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erlotinib clinical outcomes even when considering other prognostic risk factors in multivariate analysis. Further, secondary endpoint analysis suggests that AS therapy’s effect is related to drug exposure given

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significant differences in ORR, rash development, and treatment-limiting toxicity (Table IV). Whether a threshold exists as to how much concomitant AS therapy may impact erlotinib could not be addressed by a sensitivity analysis in this retrospective study given a large majority (81%) of AS-therapy patients received 100% prescription overlap with erlotinib (Table III).

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Closer examination of both preceding studies in healthy volunteers and BR-21 may also provide another explanation for differences seen in AS-therapy effect. Erlotinib is typically started at 150 mg daily for all individuals.8 There are conflicting reports regarding the effect of age, gender, and bodyweight on erlotinib

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pharmacokinetics.14 In healthy volunteers examining bioequivalence, erlotinib was found to have a much higher AUC and half-life in women as compared to men.15 Elderly patients also appear to have more

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toxicity with the TKI as compared to 70-year-old patients.16 Both of these suggest substantial interindividual variability in plasma concentrations of drug. The healthy volunteer study examined for AStherapy effect within each individual.8 In doing so, their analysis would have controlled for gender and patient size differences in terms of height and weight. On the other hand, taking average plasma concentrations across a broad population would not take these factors into consideration, such as in a post-hoc analysis. As a retrospective study, this review lacked the ability to take pharmacokinetic data examining for intra-individual erlotinib plasma concentration differences before and after AS-therapy.

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Regardless, doing so likely would have been unfeasible in this cohort due to the fact that all patients on AS-therapy had started erlotinib while already having a PPI or H2RA prescribed.

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We have recently demonstrated a similar interaction between AS therapy and sunitinib.17 In metastatic renal cell carcinoma (mRCC) patients, sunitinib, a multi-targeted TKI, is a first-line option not previously thought to have issues with higher gastric pH. Amongst 231 sunitinib-treated, mRCC patients

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retrospectively reviewed, AS therapy also negatively impacted PFS and OS with a detriment of 4.3 vs. 5.4 months and 9.4 vs. 14.3 months respectively compared to no-AS therapy patients. Hilton et al. suggest that poorer outcomes of NSCLC patients concurrently receiving AS therapy may be related to an

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unidentified prognostic marker.11 That explanation would imply an impact on OS. However, it does not clearly explain differences seen in PFS between AS and no-AS groups as an impact on PFS would suggest a reduction in treatment efficacy. In light of an effect on a significantly different sunitinib-treated mRCC population, a more unifying hypothesis for impairing PFS and OS outcomes is an interaction

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between AS therapy and TKIs. Moreover, long-term follow-up of chronic PPI users did not find PPI use to affect prognosis 18. A large prospective observational study of over 5000 patients investigating GERD patients’ outcomes also failed to demonstrate a difference in mortality as compared to no-GERD

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patients.19

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In this retrospective analysis, use of AS was strongly associated with poorer PFS and OS. Although the magnitude of differences in PFS and OS between AS and no-AS were small, significantly higher ORR, presence of TKI-related rash, and treatment-limiting toxicity may further imply this difference is related to drug exposure. Moreover the greater impact of AS on OS than PFS is likely because measurement of PFS is driven by the frequency of radiological assessments that varied due to clinical practice in this retrospective review. This variability in timing radiographic assessments may also explain why female gender significantly affected OS but not PFS (Table II).Patients were also occasionally treated with erlotinib beyond radiological progression if they were clinically benefiting and/or had less disease burden

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than at the start of erlotinib. This concept of treating beyond radiological progression has been examined and may improve OS in small case-control series.23,24 While randomized trial data are not yet available to corroborate this finding, treatment beyond progression may play a role in the discrepancy between PFS

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and OS in this study.

Drug interactions pose a significant challenge in clinical management of patients on TKIs. Given the

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prevalence of obesity and alcohol consumption with an overlapping risk factor of smoking between lung cancer and gastrointestinal illnesses, termination of AS therapy in these patients may lead to poor compliance of either erlotinib or AS therapy cessation and thus affect quality of life and survival.

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Paradoxically, dyspepsia and abdominal discomfort are possible erlotinib side effects 8 and this may be perceived as GERD although it is an erlotinib-related toxicity. Some patients may develop GERD-like symptoms because the erlotinib dose may exceed the maximum-tolerated dose (MTD). This possibility challenges the notion of whether patients of varying sizes should receive a set dose of erlotinib. One

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method of combating gastrointestinal effects related to erlotinib may be alternative dosing from the maximum tolerated dosing upfront for all patients, but evaluating this approach may require a prospective

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model.

A limitation of our study is the inability to compare patients with activating EGFR mutations between AS

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and no-AS groups. Though four patients were found to harbor mutations in the no-AS group compared to none in those receiving AS, drawing conclusions regarding EGFR mutation prevalence in either group or its effect on outcomes is premature given such a small sampling of only twenty patients tested. Although erlotinib is dosed at its MTD, the presence of an EGFR mutation may allow much lower erlotinib doses than are standard to be effective, thereby circumventing reduced erlotinib absorption caused by AS therapy.25 Ideally, collecting erlotinib drug levels in patients with and without AS would have been of interest and may have helped explain the impact on PFS and OS. Ultimately, determining an interaction between AS therapy and erlotinib may be best tested in a randomized trial. Despite these limitations,

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differences in outcomes, particularly OS, is clinically relevant and an important finding for those patients receiving erlotinib and AS therapy.

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Conclusion In summary, our retrospective cohort is one of the first studies to demonstrate a negative interaction on clinical outcomes between acid suppression therapy and erlotinib. This impact is hypothesized to be a

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result of decreased drug absorption and therefore exposure to erlotinib. Despite inherent pitfalls of a retrospective analysis, our large population study highlights an effect not well appreciated previously.

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Moreover, given the large focus of the oncologic world on oral targeted therapies, effects of gastric acidity on drug absorption may have implications for current and future oral anti-cancer therapies. Studies are warranted to determine if this effect applies to other TKIs.

Clinical Practice Points

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• With increasing focus on more targeted therapy, such as tyrosine kinase inhibitors (TKIs), knowledge of drug interactions have focused predominantly on liver metabolism. Issues with solubility had been hypothesized and shown in certain TKIs but conflicting reports existed regarding erlotinib.

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• This retrospective review demonstrates a negative impact on outcomes in advanced non-small cell lung cancer patients concurrently receiving gastric acid suppressants (AS) and erlotinib. These

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findings are consistent with our previous work showing similar poorer outcomes in renal cell cancer patients concurrently receiving sunitinib and AS. AS likely causes an increase in gastric pH leading to decreased drug solubility and ultimately less absorbed into the bloodstream of patients, which may also be reflected in lower ORR, treatment-limiting toxicity, and development of TKI-related rash in this study. • Caution should be had for not only oncologists prescribing TKIs in patients who are already receiving an acid suppressant, but also to general practitioners who may inadvertently prescribe acid suppressants outside of a patient’s cancer care. 13

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Acknowledgements None

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Conflicts of Interest All authors have no conflicts to declare. Role of Funding Source

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No funding was provided for this study.

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Demographic Age, median

Non-AS group (383)

AS group (124)

p-value

64

65

0.70

64

Gender, #

0.76 235 (46%)

179 (47%)

56 (45%)

Female

272 (54%)

204 (53%)

68 (55%)

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Male

Pathologic subtype, #

0.23

318 (63%)

240 (63%)

78 (63%)

Squamous

106 (21%)

82 (21%)

24 (19%)

Poorly differentiated

43 (8%)

31 (8%)

12 (10%)

Large Cell

11 (2%)

11 (3%)

Not otherwise specified (NOS)

29 (6%)

19 (5%)

M AN U

Stage, #

SC

Adenocarcinoma

0 (0%)

10 (8%)

IIIB

89 (18%)

70 (18%)

19 (15%)

IV

418 (82%)

313 (82%)

105 (85%)

ECOG PS, # 11 (2%)

1 2 3 4

EP

Adjusted Charlson Comorbidity Index, median (range) Lines of chemotherapy prior to erlotinib, median nd

2 line 3rd line

AC C

1st line erlotinib, #

0.11

9 (2%)

2 (2%)

163 (32%)

128 (33%)

35 (28%)

237 (47%)

168 (44%)

69 (56%)

94 (19%)

76 (20%)

18 (15%)

2 (<1%)

2 (<1%)

0

4

4

4

(0-9)

(0-9)

(1-9)

1

1

1

0.21

21 (4%)

16 (4%)

5 (4%)

0.61

359 (71%)

267 (70%)

92 (74%)

127 (25%)

100 (26%)

27 (22%)

TE D

0

Type of chemotherapy received, # Platinum doublet

0.45

0.70

0.53 449 (88%)

338 (88%)

111 (89%)

Single agent (vinorelbine)

38 (7%)

29 (8%)

9 (7%)

Pemetrexed

65 (13%)

48 (13%)

17 (14%)

Docetaxel

56 (11%)

47 (12%)

9 (7%)

Table I: Patient demographics and clinical characteristics

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Variable

p-value

Multivariate analysis Hazard 95% CI ratio

p-value

EP

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SC

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Age (>65 0.92 years) ECOG PS (3- 2.52 2.00-3.18 <0.0001 2.63 2.09-3.33 <0.0001 4) Female 0.88 0.74-1.05 0.15 0.93 0.77-1.11 0.42 gender Squamous 1.24 0.93-1.66 0.15 1.41 1.05-1.89 0.02 cell subtype Stage IIIB 0.94 0.78-1.14 0.51 Line of 1.04 0.85-1.28 0.69 erlotinib (2nd) Acid 1.71 1.39-2.11 <0.0001 1.83 1.48-2.25 <0.0001 Suppression OS Age (>65 0.82 0.68-0.98 0.03 years) ECOG PS (3- 2.47 1.96-3.12 <0.0001 2.47 1.95-3.11 <0.0001 4) Female 0.81 0.68-0.97 0.02 0.91 0.75-1.10 0.31 gender Squamous 1.11 0.82-1.49 0.50 1.11 0.82-1.49 0.51 cell subtype Stage IIIB 0.83 0.68-1.01 0.06 Line of 1.59 1.29-1.97 <0.0001 erlotinib (2nd) Acid 1.38 1.12-1.70 0.003 1.37 1.11-1.69 0.003 Suppression Table II: Univariate and multivariate analyses of variables assessing for impact on progression free survival (PFS) and overall survival (OS); 95% CI = 95% confidence interval

AC C

PFS

Univariate Analysis Hazard 95% CI Ratio 0.99 0.83-1.18

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AC C

EP

TE D

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SC

RI PT

Type of Acid Suppression Number of patients (124) Proton Pump Inhibitor Pantoprazole (40 mg) 53 (43%) Omeprazole (20 mg) 36 (29%) Lansoprazole (30 mg) 20 (16%) Rabeprazole (20 mg) 6 (5%) Antihistamine Ranitidine (150 mg) 9 (7%) Type of prescription Continuous (twice daily dosing) 18 (15%) Continuous (once daily dosing) 102 (82%) As needed (PRN) 4 (3%) Duration of Overlap 100% 100 (81%) 80-99% 5 (4%) 60-79% 4 (3%) 40-59% 3 (2%) 20-39% 12 (10%) Table III: Acid suppression patient prescription history

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AC C

EP

TE D

M AN U

SC

RI PT

Secondary Endpoint AS therapy (124) No AS therapy (383) p-value ORR, number (%) 7 (5.6%) 71 (18.5%) 0.0005 Adenocarcinoma 6 (7.8%) 47 (19.6%) 0.02 Squamous Cell 1 (4.2%) 14 (17.1%) 0.11 Carcinoma Other cell type 0 10 (16.4%) 0.06 Required Dose Reduction 9 (7.3%) 36 (9.4%) 0.47 Adenocarcinoma 7 (9.1%) 28 (11.7%) NS Squamous Cell 1 (4.2%) 4 (4.9%) NS Carcinoma Other cell type 1 (4.5%) 4 (6.6%) NS Treatment-limiting toxicity 1 (0.1%) 27 (7.0%) 0.008 Adenocarcinoma 0 23 (9.6%) 0.005 Squamous Cell 0 2 (2.4%) 0.44 Carcinoma Other cell type 1 (4.5%) 2 (3.3%) 0.59 TKI-related rash 59 (47.6%) 242 (63.2%) 0.002 Adenocarcinoma 37 (48.1%) 152 (63.3%) 0.02 Squamous Cell 8 (33%) 55 (67.1%) 0.003 Carcinoma Other cell type 14 (63.6%) 35 (57.4%) 0.61 TKI-related diarrhea 24 (19.4%) 79 (20.6%) 0.78 Adenocarcinoma 18 (23.4%) 49 (20.4%) NS Squamous Cell 6 (25.0%) 19 (23.2%) NS Carcinoma Other cell type 0 11 (18.0%) 0.03 Table IV: Secondary Endpoints between erlotinib-treated patients receiving acid suppression (AS) therapy and no-AS therapy

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SC

RI PT

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AC C

EP

TE D

Figure 1: Kaplan-Meier Curve between Acid Suppression and No-Acid Suppression groups.

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SC

RI PT

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AC C

EP

TE D

Figure 2: Overall Survival between Acid suppression and No-Acid Suppression Groups