Clinical Impact of Gastric Acid-Suppressing Medication Use on the Efficacy of Erlotinib and Gefitinib in Patients With Advanced Non–Small-Cell Lung Cancer Harboring EGFR Mutations

Original Study

Clinical Impact of Gastric Acid-Suppressing Medication Use on the Efficacy of Erlotinib and Gefitinib in Patients With Advanced NoneSmall-Cell Lung Cancer Harboring EGFR Mutations Yoshitaka Zenke,1,2 Kiyotaka Yoh,1 Shingo Matsumoto,1 Shigeki Umemura,1 Seiji Niho,1 Hironobu Ohmatsu,1 Koichi Goto,1 Yuichiro Ohe1,2 Abstract We retrospectively reviewed a total of 130 nonesmall-cell lung cancer patients harboring epidermal growth factor receptor (EGFR) mutation treated with EGFR-tyrosine kinase inhibitor who were receiving and not receiving gastric acid-suppressing medications (AS). The results showed that concurrent use of AS did not affect the efficacy or toxicity of EGFR-tyrosine kinase inhibitor in patients with advanced nonesmall-cell lung cancer harboring EGFR mutations. Background: Gastric acid-suppressing medications (AS), namely, proton pump inhibitors and histamine-2 receptor antagonists, increase gastric pH, which may reduce the absorption of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors—erlotinib and gefitinib. Patients and Methods: From 2008 to 2011, 130 consecutive patients with advanced nonesmall-cell lung cancer (NSCLC) harboring EGFR mutations were treated with either erlotinib or gefitinib at our institution. The clinical characteristics of the patients were reviewed, and the efficacy and toxicity of erlotinib and gefitinib were compared for patients receiving and not receiving AS. Results: Among the 130 patients, 47 received AS (AS users group), while the remaining 83 patients did not (AS non-users group). The overall response rate (ORR) and median progression-free survival (PFS) in the subject population was 60% and 10 months, respectively. In the AS users and nonusers groups, the ORR was 64% and 63% (P ¼ .92), while the median PFS was 8.7 and 10.7 months (P ¼ .13), respectively. No significant difference in either ORR or PFS was observed between the 2 groups. With regard to the toxicity, the frequencies of rash (83% vs. 86%; P ¼ .60) and diarrhea (34% vs. 29%; P ¼ .55) were similar for both groups. A multivariate analysis identified that AS use was not a significant factor for either PFS or OS. Conclusion: Concurrent use of AS did not affect the efficacy or toxicity of erlotinib and gefitinib in patients with advanced NSCLC harboring EGFR mutations. Clinical Lung Cancer, Vol. -, No. -, --- ª 2016 Elsevier Inc. All rights reserved. Keywords: Efficacy, Epidermal growth factor receptor -tyrosine kinase inhibitors, Gastric acid suppressing medications, Nonesmall-cell lung cancer, Toxicity

Introduction Lung cancer is the leading cause of death in patients with malignant tumors worldwide. Nonesmall-cell lung cancer (NSCLC) 1 Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan 2 Juntendo University Graduate School of Medicine, Tokyo, Japan

Submitted: Oct 7, 2015; Revised: Jan 18, 2016; Accepted: Jan 26, 2016 Address for correspondence: Yoshitaka Zenke, MD, Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan 277-0882 E-mail contact: [email protected]

1525-7304/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cllc.2016.01.006

accounts for approximately 85% of all lung cancers.1 Epidermal growth factor receptor (EGFR) mutations are present in 10%-50% of patients with stage IV NSCLC2 and are most prevalent in adenocarcinomas, east Asians, never-smokers, and women.3 In recent years, molecular-targeted therapies, such as EGFR-tyrosine kinase inhibitors (EGFR-TKIs), have gained attention for their potential to improve survival and reduce toxic adverse effects in the treatment of advanced NSCLC patients.4-6 Several trials have demonstrated a benefit in using EGFR-TKIs as first-line treatment for EGFRemutation-positive NSCLC patients and have accordingly changed the standard of therapy.6-10

Clinical Lung Cancer Month 2016

-1

Clinical Correlation of EGFR-TKI and AS for EGFR Mutation-Positive NSCLC Patients The solubility of erlotinib and gefitinib, as EGFR-TKIs, is pHdependent. Therefore, an alteration of the pH in the gastrointestinal tract could change EGFR-TKI exposure. In healthy volunteer studies, the concurrent administration of the proton-pump inhibitor (PPI), omeprazole, or the histamine 2 receptor agonist (H2RA), ranitidine, with erlotinib reduced both the area under the plasma concentration time curve and the maximum plasma concentration of erlotinib compared with erlotinib administered alone (under the plasma concentration time curve decrease: omeprazole, 46% and ranitidine, 33%; maximum plasma concentration decrease: omeprazole, 61% and ranitidine, 54% reduction).11 However, it is uncertain whether the co-administration of gastric acid-suppressing medications (AS) would have any clinically meaningful impact on erlotinib and gefitinib in NSCLC patients harboring EGFR mutations. In this retrospective study, we determined the impact of the concurrent use of AS with EGFR-TKIs—erlotinib and gefitinib—on the efficacy and toxicity in clinical practice of patients with advanced NSCLC harboring EGFR mutations. Moreover, we provide many opportunities to the clinicians for treating advanced NSCLC patients harboring EGFR mutations with co-administration of AS.

Patients and Methods Patient Selection Medical records were used to retrospectively review 130 consecutive cases of advanced or recurrent NSCLC harboring EGFR mutations treated with erlotinib and gefitinib at the National Cancer Center Hospital East between January 2008 and December 2011. Patients who were taking either erlotinib or gefitinib were evaluated for the period of initiation of EGFR-TKIs treatment with AS. EGFR mutations were identified by the peptide nucleic acidlocked nucleic acid polymerase chain reaction invader method. We divided the 130 patients into 2 subgroups: the AS users group and AS non-users group. Concomitant medications were reviewed for all records of PPIs or H2RAs, which were categorized as an AS agent. This study aimed to evaluate the overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety of NSCLC patients harboring EGFR mutations treated with EGFRTKIs and concurrently or sequentially taking either PPIs or H2RAs (AS users group) compared with those not taking PPIs or H2RAs (AS non-users group). All responses were defined according to the Response Evaluation Criteria in Solid Tumors. Toxicity was graded by using Common Terminology Criteria for Adverse Events version 4.0.

Statistical Analysis

2

-

The PFS was calculated from the date of initiating EGFR-TKI treatment to either the date of disease progression or the date of last contact. OS was defined as the interval from the date of initiating EGFR-TKI treatment to the date of death from any cause or the last follow-up. Survival curves were estimated by the Kaplan-Meier method, and the differences between the 2 groups were compared using the logrank test. All comparisons between proportions were performed with the c2 test or Fisher exact test, as appropriate. A multivariate analysis was conducted using the Cox proportional hazard model. P values less than .05 were considered statistically significant. Two-sided statistical tests were used in all analyses. This study was approved by the institutional review board of the National Cancer Center.

Clinical Lung Cancer Month 2016

Results Patient Characteristics The patient characteristics are listed in Table 1. Eighty-two patients (63%) were women and 84 (65%) were never-smokers, with ages ranging from 36 to 87 years (median, 64 years). Most patients had adenocarcinomas; only 1 patient had an adenosquamous carcinoma; and 2 patients had NSCLCs of unknown specifications. The most common mutation was L858R (49%), followed by exon 19 deletions (46%). A total of 117 patients received gefitinib 250 mg/ day, and 13 patients were treated with erlotinib 150 mg/day. The AS users group included 47 patients, while the AS non-users group included 83 patients. The AS users group had a statistically significant higher frequency of bone metastases than did the AS non-users group (53% vs. 20%; P < .01). Other baseline patient characteristics for the AS users and AS non-users groups were similar.

Treatment Efficacy The summary of response is presented in Table 2. ORR was 60% for the whole population. ORRs for the AS users and AS non-users groups were 62% and 59%, respectively (P ¼ .89), with no significant difference between the 2 groups. Overall, the median follow-up time was 36.0 months (range, 10.1-85.2 months). The median PFS was 10.0 months (95% confidence interval [CI], 8.710.5 months; Figure 1A), and the median OS was 24.3 months (95% CI, 20.6-27.4 months; Figure 1B). The median PFS periods for the AS users and AS non-users groups were 8.7 months (95% CI, 7.2-9.3 months) and 10.7 months (95% CI, 9.0-12.1 months; P ¼ .13), respectively (Figure 1C). In addition, the median OS periods for the AS users and AS non-users groups were 20.1 months (95% CI, 12.8-27.4 months) and 24.3 (95% CI, 20.8-33.5 months; P ¼ .07), respectively (Figure 1D). Regarding PFS, differences between the AS users and AS non-users group were not statistically significant, whereas the AS non-users group showed a better OS than did the AS users group. In addition, we also analyzed the patients of the AS users group in detail; their characteristics are listed in Table 3. Median duration of AS use with EGFR-TKIs was 12.1 months (range, 1.0-32.1 months). Twenty-seven patients (57.4%) were administered PPIs; 20 patients (42.6%) were administered H2RAs. Most patients were concurrently administered AS and EGFR-TKI (85.1%). The median PFS and ORR in patients who were administered a PPI and an H2RA were 8.75 months (95% CI, 5.4-12.0 months) and 51.8% for the PPI-administered patients (P ¼ .99) and 8.7 months (95% CI, 7.2-9.3 months) and 75.0% for the H2RAadministered patients (P ¼ .10). On the other hand, the median PFS and ORR in patients with concurrent and sequential use (taken together but several days later) in the AS users group were 8.7 months (95% CI, 7.8-10.1 months) and 65% for concurrent use (P ¼ .16) and 8.2 months (95% CI, 1.8-9.0 months) and 50% for sequential use (P ¼ .47), with no significant differences between the groups.

Univariate and Multivariate Analysis for PFS and OS Univariate analyses were performed according to the Cox proportional hazard model to determine the predictive and prognostic value of certain characteristics for PFS and OS (Table 4). Never having smoked ranked as a significant prognostic factor for OS,

Yoshitaka Zenke et al Table 1 Patient Characteristics Patient Characteristic

No. of Patients (%) (n [ 130)

AS Users Group (%) (n [ 47)

AS Non-Users Group (%) (n [ 83)

P-Value

Gender Male

48 (37)

17 (36)

31 (37)

Female

82 (63)

30 (64)

52 (63)

64 (36-87)

62 (45-84)

64 (36-87)

Never smokers

84 (65)

30 (64)

53 (64)

Ever smokers

46 (35)

17 (36)

30 (36)

.82

Age Median (range) Smoking status .99

ECOG performance status 0

30 (23)

9 (19)

21 (25)

1

80 (62)

27 (57)

54 (65)

2

15 (11)

8 (17)

6 (7)

3

5 (4)

3 (7)

2 (3)

.19

Histology Adenocarcinoma

127 (97)

45 (95)

82 (99)

Adenosquamous carcinoma

1 (1)

0 (0)

1 (1)

NSCLC, not otherwise specified

2 (2)

2 (5)

0 (0)

.12

Clinical stage IIIB

2 (2)

0 (0)

2 (3)

IV

107 (82)

37 (79)

70 (84)

21 (16)

10 (21)

11 (13)

Post-surgically relapsed

.29

EGFR mutation status Exon 19 deletion

60 (46)

25 (53)

35 (42)

Exon 21 L858R mutation

64 (49)

19 (40)

45 (54)

6 (5)

3 (7)

3 (4)

Gefitinib

117 (90)

39 (83)

78 (94)

Erlotinib

13 (10)

8 (17)

5 (6)

0

54 (41)

21 (45)

33 (40)

1

55 (42)

22 (47)

33 (40)

2

21 (17)

4 (8)

17 (20)

Bone

43 (32)

25 (53)

17 (20)

Brain

23 (17)

9 (19)

14 (14)

Lung

36 (27)

10 (21)

26 (31)

Liver

9 (7)

5 (10)

4 (4)

33 (25)

11 (23)

22 (25)

Other mutation

.29

EGFR-TKI .044

Prior regimen .21

Metastatic site

Pleural effusion

<.01

Abbreviations: AS ¼ Gastric acid-suppressing medication; ECOG ¼ Eastern Cooperative Oncology Group; EGFR ¼ epidermal growth factor receptor; NSCLC ¼ nonesmall-cell lung cancer; TKI ¼ tyrosine kinase inhibitor.

while exon 19 deletions and not having received AS administration also tended to serve as prognostic factors for OS. A multivariate analysis was performed using the Cox proportional hazard model to determine the predictive and prognostic factors for PFS and OS (Table 5). Young age, never-smokers, good performance status (PS), and harboring EGFR exon 19 deletions were identified as statistically significantly independent prognostic factors for OS (P ¼ .01, P < .01, P < .01, and P ¼ .04, respectively).

Although patients in the AS users group tended to have a poor prognosis, the difference was not significant. Moreover, AS use was not a significant factor for PFS in either univariate or multivariate analysis.

Adverse Events The most common adverse events were rashes, diarrhea, and raised concentrations of aminotransferases (Table 6). Adverse events

Clinical Lung Cancer Month 2016

-3

Clinical Correlation of EGFR-TKI and AS for EGFR Mutation-Positive NSCLC Patients Table 2 Best Response to Treatment AS Users Group (%) (n [ 47) CR PR SD PD NE ORR DCR

3 26 12 4 2 29 41

(6) (56) (26) (8) (4) (62) (91)

AS Non-Users Group (%) (n [ 83) 0 49 26 4 4 49 75

(0) (60) (32) (4) (4) (59) (95)

P-Value

.89

Abbreviations: AS ¼ Gastric acid-suppressing medication; CR ¼ complete response; DCR ¼ disease control rate; NE ¼ not evaluated; ORR ¼ overall response rate; PD ¼ progression disease; PR ¼ partial response; SD ¼ stable disease.

were not significantly different for the AS users and AS non-users group. There was no significant difference in the ratio of dose reduction or interruption for the toxicity in the AS users and AS non-users group (18% vs. 20%, respectively; P ¼ .58). Only 1 patient in the AS non-users group developed interstitial lung disease but received corticosteroid therapy and improved. No treatmentrelated death was observed in either group.

Discussion Many international multicenter randomized controlled trials6-10 have demonstrated that treatment with EGFR-TKIs presents an extended PFS compared with chemotherapy when used as first-line therapy for metastatic NSCLC harboring certain activating EGFR mutations. Moreover, the presence of EGFR mutations is known to

predict the efficacy of EGFR-TKIs. The drug information of EGFRTKIs, such as gefitinib and erlotinib, recommends not to use them with AS because AS have the potential to reduce the absorption of EGFR-TKIs. In the current study, we clearly showed that concurrent use of AS did not clinically affect the efficacy of gefitinib and erlotinib in patients with advanced NSCLC harboring EGFR mutations. To our knowledge, this is the first report on the impact of the use of AS with EGFR-TKI in patients harboring EGFR mutations. The use of AS, including PPIs and H2RAs, is common in gastrointestinal (GI) disease when treating gastroesophageal reflux disease12 and H. pylori infections.13 In patients with advanced NSCLC, AS are frequently used to medically prevent gastrointestinal dysfunction as many patients receive benzimidazole—non-steroidal anti-inflammatory drugs (NSAIDs) and/or steroid drugs to control pain. AS are mainly excreted via urine without being metabolized by either CYP2C19 or CYP3A4.14 Reduced oral absorption and lower systemic exposure because of decreased gastric acidity in the presence of AS has been reported for a number of drugs, including dasatinib,15,16 nilotinib,17 and erlotinib.18 However, it is uncertain whether concurrent use of AS affects the clinical outcome. Hilton et al reported that the coadministration of AS and erlotinib did not appear to have a significant impact on the median plasma drug levels or the clinical outcomes.19 Their results suggesting that AS use did not affect the efficacy of either gefitinib or erlotinib were similar to those of our study. While their data was collected from the BR.21 trial on concomitant medication use, the EGFR mutation status was unknown. With regard to OS and PFS, it is necessary to separately analyze this considering the EGFR mutation status. In particular, the use of EGFR-TKIs in patients harboring EGFR mutations is crucial with the effect of AS because

Figure 1 Kaplan-Meier Survival Curves of Progression-Free Survival (PFS) and Overall Survival (OS). A, PFS for All 130 Patients Harboring Epidermal Growth Factor Receptor (EGFR) Mutations; B, OS for All 130 Patients Harboring EGFR Mutations; C, Comparison of PFS Between Gastric Acid-Suppressing Medication (AS) Users and AS Non-Users for Patients Harboring EGFR Mutations; D, Comparison of OS Between AS Users and AS Non-Users for Patients Harboring EGFR Mutations

4

-

Clinical Lung Cancer Month 2016

Yoshitaka Zenke et al advanced NSCLC harboring EGFR mutations. In fact, there were also patients from the previous phase I study who achieved a partial response at 100 mg/day erlotinib and 225 mg/day gefitinib, and these patients may be harboring EGFR mutations. Therefore, if the change in EGFR-TKI pharmacokinetics by AS is consistent with the reduced absorption by increasing gastric PH, we considered that it was enough to yield an antitumor effect clinically. In addition, the toxicity of the AS non-users group was similar to that of the AS users group. On the other hand, JIn et al reported that EGFR-TKIs enhance cell sensitivity to AS via Hif-1a downregulation and induce synergistic cell death using cell line.22 As a result, co-treatment of these inhibitors is potentially effective in some AS users for synergy. The AS non-users group presented with a longer OS compared with the AS users group. One possibility is that this reflects comorbidities where AS use may be indicated, such as aspirin for cardiovascular and cerebrovascular disease, dexamethasone for symptomatic NSCLC, gastroesophageal reflux secondary to obesity, or treatment for duodenal or gastric ulcers. Particularly, the patients with bone metastases often take NSAIDs for the pain control and clinician use AS for the prevention of gastric ulcer by the side effect of NSAIDs. Therefore, AS users group have higher frequency of bone metastases. In addition, the fact that the AS non-users group tended to include never smokers, good PS, and patients harboring

Table 3 Characteristic of the AS Users Group (n [ 47) No. of Patients (%) Gastric acid-suppressing medication PPI

27 (57.4)

H2RA

20 (42.6)

Duration of AS use (months) Median (range)

12.1 (1.0-32.1)

AS combination time Concurrent

40 (85.1)

Sequential

7 (14.9)

Abbreviations: AS ¼ Gastric acid-suppressing medication; H2RA ¼ histamine 2 receptor antagonist; PPI ¼ proton pump inhibitor.

it is a key drug which can be dramatically effective. In our study, we only analyzed patients harboring EGFR mutations; however, no apparent impact of AS on either PFS or OR was observed. The following is a possible explanation for our results. As a result of a phase I study in the Japanese population, the recommended doses of gefitinib and erlotinib are 250 mg/day20 and 150 mg/day,21 respectively. However, these phase I studies were conducted in solid malignant tumors, and the effective doses may be different for

Table 4 Univariate Analysis for Progression-Free Survival and Overall Survival PFS Variable

OS

HR

95% CI

P-Value

HR

95% CI

P-Value

1.01

0.69-1.47

.98

1.21

0.80-1.81

.35

0.97

0.65-1.43

.90

0.86

0.48-1.53

.61

1.37

0.77-2.28

.25

2.40

1.39-3.92

<.01

1.22

0.83-1.78

.28

1.80

1.20-2.71

<.01

1.23

0.83-1.81

.29

1.48

0.98-2.27

.06

0.75

0.51-1.11

.15

1.01

0.67-1.54

.92

1.24

0.81-1.85

.30

1.28

0.82-1.95

.26

1.33

0.90-1.96

.14

1.45

0.95-2.18

.08

Age >65 65 Gender Male Female PS 2-3 0-1 Smoking history Ever smokers Never smokers EGFR mutation L858R Exon 19 deletions Prior therapy Present None Bone metastasis Present None AS use Present None Abbreviations: AS ¼ Gastric acid-suppressing medication; EGFR ¼ epidermal growth factor receptor; HR ¼ hazard ratio; OS ¼ overall survival; PFS ¼ progression-free survival; PS ¼ performance status.

Clinical Lung Cancer Month 2016

-5

Clinical Correlation of EGFR-TKI and AS for EGFR Mutation-Positive NSCLC Patients Table 5 Multivariate Analysis for Progression-Free Survival and Overall Survival PFS

OS

HR

95% CI

P-Value

HR

95% CI

1.11

0.72-1.70

.63

1.74

1.07-2.80

.02

0.83

0.49-1.39

.48

0.90

0.52-1.59

.73

1.25

0.68-2.17

.45

2.28

1.26-3.90

<.01

1.45

0.85-2.17

.17

2.30

1.28-4.10

<.01

1.30

0.88-1.94

.18

1.57

1.01-2.45

.04

0.71

0.46-1.09

.12

1.11

0.70-1.72

.64

1.22

0.76-1.92

.39

1.04

0.60-1.76

.87

1.15

0.73-1.79

.51

1.41

0.83-2.35

.19

Variable

P-Value

Age >65 65 Gender Male Female PS 2-3 0-1 Smoking history Ever smokers Never smokers EGFR mutation L858R Exon 19 deletions Prior therapy Present None Bone metastasis Present None AS use Present None Abbreviations: AS ¼ Gastric acid-suppressing medication; EGFR ¼ epidermal growth factor receptor; HR ¼ hazard ratio; OS ¼ overall survival; PFS ¼ progression-free survival; PS ¼ performance status.

exon 19 deletions in our study may also influence OS. Another possibility is that because the ratios of post-treatment for each group are different, this may have influenced OS. The ratio of posttreatment and EGFR-TKIs re-challenge of the AS non-users group tended to be higher than that of the AS users group (65%, 35% vs. 53%, 23%, respectively; P ¼ .18, .13).

Table 6 Adverse Events All Adverse Events Rash Diarrhea Raised aminotransferase Oral ulcer Loss of appetite Nausea Vomiting Interstitial lung disease

6

-

AS Users Group (%) (n [ 47) 39 (83) 16 (34) 8 (17) 5 4 3 2 0

(10) (8) (6) (4) (0)

Conclusion AS Non-Users Group (%) (n [ 83)

P-Value

72 (86) 24 (29) 14 (16)

.60 .55 .98

14 2 3 2 1

.44 .18 .66 .61 e

(16) (2) (3) (2) (0.01)

Abbreviation: AS ¼ Gastric acid-suppressing medication.

Clinical Lung Cancer Month 2016

This study is limited by the retrospective nature of the data. First, we did not measure the plasma concentration of EGFR-TKIs for the groups; therefore, it is uncertain whether its values actually decreased in the AS users group. Second, the sample size was relatively small, specifically for the AS users group. Further evaluation of the long-term efficacy of EGFR-TKIs with concurrent use of AS in a larger patient population is warranted to confirm these findings.

In this study, concurrent use of AS did not affect the efficacy or toxicity of erlotinib and gefitinib in patients with advanced NSCLC harboring EGFR mutations. It provides data that can guide expectations for clinicians treating advanced NSCLC patients harboring EGFR mutations with co-administration of AS. A larger population study is needed to confirm our present findings, including pharmacokinetics analysis.

Clinical Practice Points  AS increase gastric pH, which may reduce the absorption of the

EGFR-TKIs, erlotinib and gefitinib. It is uncertain whether the co-administration of AS would have any clinically meaningful impact on erlotinib and gefitinib in NSCLC patients harboring EGFR mutations.

Yoshitaka Zenke et al  We retrospectively reviewed a total of 130 NSCLC patients

harboring EGFR mutation with treated erlotinib and gefitinib. The efficacy and toxicity of erlotinib and gefitinib were compared between patients receiving and not receiving AS. In the AS users and non-users groups, the ORR was 64% and 63% (P ¼ .92), while the median PFS was 8.7 and 10.7 months (P ¼ .13), respectively. No significant difference in either ORR or PFS was observed between the 2 groups. With regard to the toxicity, the frequencies of rash (83% vs. 86%; P ¼ .60) and diarrhea (34% vs. 29%; P ¼ .55) were similar for both groups. Concurrent use of AS did not affect the efficacy or toxicity of erlotinib and gefitinib in patients with advanced NSCLC harboring EGFR mutations.  There are many patients needing AS because of comorbidities in clinical practice. The results of concurrent use of AS provides data that can guide expectations for clinicians treating advanced NSCLC patients harboring EGFR mutations with EGFR-TKI. A larger population study is needed to confirm our present findings, including pharmacokinetics analysis.

Acknowledgments This work was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor, and Welfare of Japan.

Disclosure The author have stated that they have no conflicts of interest.

References 1. Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000. The global picture. Eur J Cancer 2001; 37(Suppl 8):S4-66. 2. Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009; 361:958-67. 3. Mitsudomi T, Yatabe Y. Mutations of the epidermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensitivity in lung cancer. Cancer Sci 2007; 98: 1817-24. 4. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350:2129-39.

5. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004; 304:1497-500. 6. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361:947-57. 7. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for nonsmall-cell lung cancer with mutated EGFR. N Engl J Med 2010; 362:2380-8. 8. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 2010; 11:121-8. 9. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011; 12:735-42. 10. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012; 13:239-46. 11. Canada R. Prescribing information Tarceva (erlotinib), Available at: http://www. accessdata.fda.gov/drugsatfda_docs/label/2013/021743s018lbl.pdf. Accessed: February 22, 2016. 12. Talley NJ. American Gastroenterological Association medical position statement: evaluation of dyspepsia. Gastroenterology 2005; 129:1753-5. 13. Asaka M, Sugiyama T, Kato M, et al. A multicenter, double-blind study on triple therapy with lansoprazole, amoxicillin and clarithromycin for eradication of Helicobacter pylori in Japanese peptic ulcer patients. Helicobacter 2001; 6:254-61. 14. Gladziwa U, Klotz U, Baumer K, Zollinger R, Mann H, Sieberth HG. Pharmacokinetics of epoetin (recombinant human erythropoietin) after long term therapy in patients undergoing haemodialysis and haemofiltration. Clin Pharmacokinet 1993; 25:145-53. 15. Eley T, Luo FR, Agrawal S, et al. Phase I study of the effect of gastric acid pH modulators on the bioavailability of oral dasatinib in healthy subjects. J Clin Pharmacol 2009; 49:700-9. 16. Takahashi N, Miura M, Niioka T, Sawada K. Influence of H2-receptor antagonists and proton pump inhibitors on dasatinib pharmacokinetics in Japanese leukemia patients. Cancer Chemother Pharmacol 2012; 69:999-1004. 17. Yin OQ, Gallagher N, Fischer D, et al. Effect of the proton pump inhibitor esomeprazole on the oral absorption and pharmacokinetics of nilotinib. J Clin Pharmacol 2010; 50:960-7. 18. Tarceva (erlotinib prescribing information). Farmingdale, NY: OSI Pharmaceuticals, LLC; 2010. 19. Hilton JF, Tu D, Seymour L, Shepherd FA, Bradbury PA. An evaluation of the possible interaction of gastric acid suppressing medication and the EGFR tyrosine kinase inhibitor erlotinib. Lung Cancer 2013; 82:136-42. 20. Nakagawa K, Tamura T, Negoro S, et al. Phase I pharmacokinetic trial of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (Iressa, ZD1839) in Japanese patients with solid malignant tumors. Ann Oncol 2003; 14:922-30. 21. Yamamoto N, Horiike A, Fujisaka Y, et al. Phase I dose-finding and pharmacokinetic study of the oral epidermal growth factor receptor tyrosine kinase inhibitor Ro50-8231 (erlotinib) in Japanese patients with solid tumors. Cancer Chemother Pharmacol 2008; 61:489-96. 22. Jin HO, Hong SE, Kim CS, et al. Combined effects of EGFR tyrosine kinase inhibitors and vATPase inhibitors in NSCLC cells. Toxicol Appl Pharmacol 2015; 287:17-25.

Clinical Lung Cancer Month 2016

-7