Int J Clin Exp Med 20169(9)17822-17831wwwijcemcom ISSN1940-5901IJCEM0033064

Original ArticleComparative survival analysis of the treatment options for TKI resistant advanced non-small cell lung cancer (NSCLC) patients a meta-analysis

Wei Xu1 Ranwei Li2 Xin Jin1 Jingjin Tan1 Ke Wang1

Departments of 1Respiratory Medicine 2Urinary Surgery The Second Affiliated Hospital of Jilin University Changchun Jilin China Equal contributors

Received May 31 2016 Accepted July 4 2016 Epub September 15 2016 Published September 30 2016

Abstract Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are established treatment for non-small cell lung cancer (NSCLC) However after initial response to the therapy acquired resistance develops for which limited treatment options are available The aim of this study was to perform a meta-analysis of efficacy and survival outcomes of various treatment options for NSCLC patients with acquired resistance to EGFR-TKIs Literature search was undertaken in several electronic databases and study selection was based on a priori eligibil-ity criteria Random effects meta-analyses and metaregression analyses were carried out to evaluate the outcomes and factors affecting the outcomes respectively Twenty-two studies (1098 NSCLC patientsrsquo data) were used in this meta-analysis Two major mutations exon 19 deletion and exon 21 L858R were found in 544 plusmn 157 and 354 plusmn 13 of the patients tested respectively The EGFR-TKI resistance mutation T790M was prevalent in about 51 of the patients having drug resistance In the EGFR-TKI resistant NSCLC patients overall progression-free survival (PFS) was 428 [95 CI 309 546] months after any treatment In the EGFR-TKI resistant NSCLC patients overall survival after any treatment was 1224 [1038 1409] months Partial response rate stable disease rate and dis-ease control rate to any therapy in the present study were 2852 [2058 3647] 3388 [2609 4168] and 59 [4714 7085] respectively With approximately 60 disease control rate overall chemotherapeutic interventions to advanced NSCLC patients with acquired mutations is associated with 43 months of PFS and approximately 1 year of overall survival There is no statistically significant difference between different types of interventions

Keywords Non-small cell lung cancer epidermal growth factor tyrosine kinase receptor inhibitors acquired resis-tance mutation survival

Introduction

Lung cancer is the leading cause of cancer-related mortality that accounts for approxi-mately 27 of deaths due to cancer [1] with nearly 14-16 million deaths each year [2] Two major types of diseases include small cell lung cancer (SCLC) accounting for 15-20 of the cases and non-small cell lung cancer (NSCLC) with prevalence rate of approximately 80-85 in all lung cancer [3]

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are well-super- ior in efficacy over chemotherapy and there- fore are the mainstay treatment for NSCLC with EGFR mutations [4 5] Activating muta-

tions in the tyrosine kinase domain of EGFR (deletion in exon 19L858R substitution in exon 21 etc) are the main determinants of the re- sponse to EGFR-TKI therapy which significant- ly improves the overall response rate and pro-gression-free survival (PFS) of treatment-naive patients with EGFR mutations [5-7]

However after an initial response patients acquire resistance after 10-14 months of con-trol over disease (as assessed by the response evaluation criteria in solid tumours progressive disease) and eventually present with cancer progression and symptomatic exacerbation [8 9] Several molecular mechanisms are discov-ered for the development of acquired resis-tance to EGFR-TKIs of which T790M missense

Therapies for advanced lung cancer with acquired resistance

17823 Int J Clin Exp Med 20169(9)17822-17831

mutation leading to the incorporation of methi-onine instead of threonine in the ATP binding site causing a conformational change mesen-chymal-epithelial transition factor (MET) proto-oncogene amplification and changes in histo-logical features are important determinants [10 11]

Gefitinib was the first commercially available oral EGFR-TKI to offer modest response rates [12 13] Buterlotinib was first EGFR-TKI to show a considerable survival benefit for advanced NSCLC patients (667 versus 47 months for placebo group) after the failure of at least one prior chemotherapy regimen [14 15] Second generation EGFR-TKIs such as afatanib offered limited clinical utility owing to toxicity concerns [16] Among the third generation EGFR-TKIs osimertinib (AZD9291) targets certain EGFR mutations including T790M and have better dose-limiting toxic profile [17]

Currently there is no targeted therapy or effec-tive treatment for NSCLC patients upon devel-opment of acquired resistance to EGFR-TKI and thence disease progression However several strategies are attempted to provide survival benefit to the patients and a number of studies have reported treatment regimens for NSCLC patients ranging from EGFR-TKI re-treatment to combinational treatments and non-EGFR-TKI chemotherapy The present study was designed to evaluate the effectiveness of such treatment regimens for NSCLC patients who developed resistance to an EGFR-TKI drug

Materials and methods

This systematic review was performed by following Cochrane Handbook for Systematic Reviews [18] and is reported in accordance with the Preferred Reporting Items for Sys- tematic reviews and Meta-Analysis (PRSIMA) guidelines [19]

Literature search strategy

A comprehensive search strategy was adapt- ed in order to acquire the relevant research articles from different electronic databases including PubMedMedline Embase OVID SP Google Scholar and ClinicalTrialsgov Impor- tant keywords and MeSH terms used for the literature search were Non-small cell lung can-cer (NSCLC) epidermal growth factor receptor

(EGFR) tyrosine kinase inhibitor (TKI) acqui- red resistance gefitinib erlotinib dasatinib afatinib rociletinib osimertinib chemotherapy treatment therapy mutation survival remis-sion response rate and disease control These key terms were used in different logical com- binations Same search strategy was used for each database Identified title and abstracts were reviewed by 3 authors (a b c) indepen-dently to screen for articles that met eligibi- lity criteria The search was restricted to re- search articles published before April 2016 in English language Additional research arti-cles were identified by the manual search from references sections of relevant original studies and review articles

Inclusion and exclusion criteria

The inclusion criterion was retrospective or prospective study examining the efficacy and survival outcomes of the treatment to advan- ced NSCLC patients with acquired resistance to a EGFR-TKI drug Studies were excluded if involved a) cell culture or physiological evalua-tions b) genetic techniques c) case reports and d) those which did not report efficacy andor survival outcomes

Meta-analysis endpoints

For the present meta-analysis the outcome measures were a) progression-free survival (PFS) b) over-all survival (OS) c) partial remis-sion (PR) rate stable disease (SD) rate re- sponse rate (RR) and disease control rate (DCR)

Data and analyses

Information regarding the study endpoints and outcomes type and dosage of the drugs and clinicalpathologicaldemographic characteris-tics were obtained from identified research articles and organized in datasheets To achi- eve an overall effect size and the effect sizes of the subgroups PFS OS PR rate SD rate RR and CDR values of the individual studies were pooled under random effects model to have an inverse variance weighted overall ef- fect size and the effect sizes of the subgroups Statistical significance between subgroup was assessed using a two-tailed z-test

Metaregression analyses were carried out with Stata software (version 12 College Station

Therapies for advanced lung cancer with acquired resistance

17824 Int J Clin Exp Med 20169(9)17822-17831

Texas) For the identification of factors affecting the efficacy of the therapy each of dependent variables (PFS OS RR and CDR) were tested against several independent variables includ-ing the number of patients in a study age gen-der smoking histological type (percent patients with adenocarcinomasquamous cell carcino-ma) and mutation (percent patients with exon 19 deletionexon 21 L858R) Restricted maxi-mum likelihood method was used for the metaregression analyses Between-study vari-ance was tested with tau2 and the percentage of between-study heterogeneity was assess- ed with I-squared (I2) index A p value of less than 01 was considered to show a significant relationship

Quality assessment of the included studies was carried out with Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies devised by the National Institute of Health of the United States For the assess-ment of publication bias Beggrsquos funnel plot and Eggerrsquos precision plot were studied and trim and filled method was applied to estimate missing number of studies

Results

The literature search led to the selection of 22 studies [20-41] after screening and applying eligibility criteria (Figure 1) from which 1098 NSCLC patientsrsquo data were used for the meta-

Figure 1 A flowchart of the study screening and selection process

Therapies for advanced lung cancer with acquired resistance

17825 Int J Clin Exp Med 20169(9)17822-17831

analyses These studies were either retrospec-tive or prospective in design The quality of these studies was adequate (Table S1) A sig-nificant publication bias was identified upon assessment with funnel plot asymmetry and trim and fill method (Figure 2A-D)

Important characteristics of the included stud-ies are presented in Table S2 Average age (mean plusmn standard deviation) of the patients was 6132 plusmn 102 years and 31 plusmn 14 of the patients were female Patients who ever smoked constituted 26 plusmn 18 of this popula-tion Histologically 906 plusmn 92 of the patients had adenocarcinoma and 4 plusmn 4 harboured squamous cell carcinoma Two major mutants (exon 19 deletion and exon 21 L858R) pre-vailed in 544 plusmn 157 and 354 plusmn 13 patients respectively The EGFR-TKI resistance mutation T790M was prevalent in about 51 of the patients facing drug resistance

In the EGFR-TKI resistant NSCLC patients over-all PFS with 95 confidence interval (CI) was 428 [309 546] months after the treatment

Treatment with EGFR-TKI in combination with chemotherapy was associated with maximum PFS (535 [318 751] months) followed by the treatment with an alternative EGFR-TKI alone (422 [251 593] months and retreatment with the same EGFR-TKI (386 [227 544] months (Figure 3) In the EGFR-TKI resistant NSCLC patients overall survival after any treat-ment was 1224 [1038 1409] months (Figure 4) There were no statistically significant differ-ences between the subgroups in progression-free survival or overall survival (Figures 3 4)

Partial response rate stable disease rate and disease control rate to any therapy in the pres-ent study were 2852 [2058 3647] 3388 [2609 4168] and 59 [4714 7085] respectively Subgroup meta-analyses of these variables are presented in Figures S1 S2 S3

In the metaregression analyses only the per-centage of patients with adenocarcinoma was significantly inversely associated with the over-all survival (coefficient -339 [-0717 004] P=0074) None of any other independent vari-

Figure 2 Funnel plots showing a significant publication bias with estimated number of missing studies as assessed by trim and fill method for the corresponding meta-analyses of (A) progression-free survival (B) overall survival (C) partial remission rate and (D) disease control rate

Therapies for advanced lung cancer with acquired resistance

17826 Int J Clin Exp Med 20169(9)17822-17831

able including age gender or mutation type was significantly associated with either overall progression-free survival or overall survival

Discussion

In the absence of any targeted therapy or ef- fective treatment for NSCLC patients with ac- quired resistance to EGFR-TKI as observed in the present meta-analysis any regimen includ-ing retreatment with a EGFR-TKI or treatment with an alternative EGFR-TKI either alone or in combination with non-EGFR-TKI chemotherapy can provide a survival benefit of approximately one year with approximately 43 months of pro-gression-free survival with no statistically sig-nificant between group differences

Addition of the bevacizumab (vascular endo-thelial growth factor monoclonal antibody) to palliative platinum-based chemotherapy achi-

eves response rates of 30 PFS of less than eight months and 1-year overall survival is not attained in all patients [42] Even with second-line therapies such as docetaxel or peme-trexed 2-year survival is achieved in a very few patients [43 44] Introduction of EGFR-TKIs such as gefitinib and erlotinib improved the out-comes when compared to conventional plati-num-based chemotherapy [4 8 45] especially in patients with relatively high incidence of EGFR mutations [46 47]

The heterogeneity in patients regarding their clinical course and response to different anti-cancer therapies plays important role in the success of an anti-NSCLC therapy [23] Somatic mutations in the EGFR gene are detected in 30 to 40 of Asian and 10 of white NSCLC patients [48 49] Seventy percent of lung ade-nocarcinoma patients with mutations in the

Figure 3 Forest graph showing the overall and subgroup-wise effect sizes of the progression-free survival (months) in the study population In study identity column Squist 2015 plusmn represents T790M mutation positivenegative patient groups

Therapies for advanced lung cancer with acquired resistance

17827 Int J Clin Exp Med 20169(9)17822-17831

EGFR gene exhibit a partial response upon EGFR-TKI such as erlotinib or gefitinib treat-ment [6]

In addition to T790M mutation [10 11] re- sistance to TKIs has also been shown to ma- nifest through MET which is a transmembrane receptor that binds to the ligand hepatocyte growth factorscatter factor (HGF) with high affinity Interaction of MET with avian v-erb-b2 erythroblastic leukemia viral oncogene homo-log 3 (ERBB3) causes sustained activation of the phosphatidylinositol 3rsquo-kinase-serinethre-onine kinase Akt (PI3KAKT) signalling path- way bypassing EGFR inhibition The MET ampli-fication has been reported to be a mechanism of EGFR-TKI resistance in 22 of cases in- dependent of T790M status [50-52] and ab- normal MET activation is associated with poor NSCLC prognosis [53]

Based on the indolent nature of T790M-posi- tive cells and rapid growth potential of T790M-

negative cells [54 55] it is postulated that EGFR-TKI-free interval can repopulate T790M-negative cells because of the withdrawal of the mutagenic pressure resulting in more cells to respond to EGFR-TKI re-challenge [34] Al- though negative T790M status of the tumour cells is considered predictive of EGFR-TKI re-challenge [56 57] in the present metaregre- ssion analyses T790M prevalence data were inadequate to study this phenomenon and an attempt with 6 studies data revealed no signi- ficant association between percentage of pa- tients with T790M mutations and PFS Never- theless newer EGFR-TKIs like rociletinib are found to be associated with better response rate even in T790M-positive patients [36]

In the present study a significant inverse rela-tionship between the incidence of adenocarci-noma and overall survival is observed Better survival is reported in patients with bronchio- alveolar adenocarcinoma than in patients with large cell tumours [58] Since approximately

Figure 4 Forest graph showing the overall and subgroup-wise effect sizes of the overall survival (months) in the study population

Therapies for advanced lung cancer with acquired resistance

17828 Int J Clin Exp Med 20169(9)17822-17831

90 of patients included in this meta-analysis had adenocarcinoma more data will be re- quired to evaluate this relationship

Taken together we have found that there were no statistically significant differences between the treatment subgroup regimens Although a difference of approximately 15 months in the progression-free survival has been noted between EGFR-TKI retreatment and EGFR-TKI with chemotherapy yet this difference was less (approximately 1 month) when overall sur-vival was analysed Thus it will be necessary to have some more well-designed studies before using combinational treatments as such regi-mens may expose patients to additional side effects Moreover because of genomic and pharmacogenomic variations in the patients study designs with more homogeneous patient characteristics will be required to identify patients for a specific type of therapy

Conclusion

With approximately 60 disease control rate overall chemotherapeutic interventions to ad- vanced NSCLC patients with acquired resis-tance is associated with less than 5 months of progression-free survival and approximate- ly 1 year of overall survival Partial response rate and stable disease rate are found to be 2852 [2058 3647] and 3388 [2609 4168] respectively

Acknowledgements

This study was supported by the grant from the National Natural Science Foundation of China (No 81071919) Norman Bethune Program of Jilin University (No 2012220) and The Na- tural Science Foundation of Jilin Province (No 20150101151JC)

Disclosure of conflict of interest

None

Address correspondence to Ke Wang Department of Respiratory Medicine The Second Affiliated Hos- pital of Jilin University No 218 Ziqiang Street Nanguan District Changchun 130041 Jilin China E-mail kewangchinaoutlookcom

References

[1] He Y Li D Song G Li Y Liang D Jin J Wen D and Shan B Lung cancer burden has in-

creased during the last 40 years in Hebei Province China Thorac Cancer 2016 7 323-332

[2] Ferlay J Soerjomataram I Dikshit R Eser S Mathers C Rebelo M Parkin DM Forman D and Bray F Cancer incidence and mortality worldwide sources methods and major pat-terns in GLOBOCAN 2012 Int J Cancer 2015 136 E359-386

[3] Gadgeel SM Personalized Therapy of Non-small Cell Lung Cancer (NSCLC) Adv Exp Med Biol 2016 890 203-222

[4] Rosell R Carcereny E Gervais R Vergnene- gre A Massuti B Felip E Palmero R Garcia-Gomez R Pallares C Sanchez JM Porta R Cobo M Garrido P Longo F Moran T Insa A De Marinis F Corre R Bover I Illiano A Dansin E de Castro J Milella M Reguart N Altavilla G Jimenez U Provencio M Moreno MA Terrasa J Munoz-Langa J Valdivia J Isla D Domine M Molinier O Mazieres J Baize N Garcia-Campelo R Robinet G Rodriguez-Abreu D Lopez-Vivanco G Gebbia V Ferrera-Delgado L Bombaron P Bernabe R Bearz A Artal A Cortesi E Rolfo C Sanchez-Ronco M Droz- dowskyj A Queralt C de Aguirre I Ramirez JL Sanchez JJ Molina MA Taron M Paz-Ares L Spanish Lung Cancer Group in collaboration with Groupe Francais de P-C and Associazione Italiana Oncologia T Erlotinib versus stand- ard chemotherapy as first-line treatment for European patients with advanced EGFR mu- tation-positive non-small-cell lung cancer (EU- RTAC) a multicentre open-label randomised phase 3 trial Lancet Oncol 2012 13 239-246

[5] Zhou C Wu YL Chen G Feng J Liu XQ Wang C Zhang S Wang J Zhou S Ren S Lu S Zhang L Hu C Hu C Luo Y Chen L Ye M Huang J Zhi X Zhang Y Xiu Q Ma J Zhang L and You C 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 12 735-742

[6] Mok TS Wu YL Thongprasert S Yang CH Chu DT Saijo N Sunpaweravong P Han B Margono B Ichinose Y Nishiwaki Y Ohe Y Yang JJ Chewaskulyong B Jiang H Duffield EL Wat- kins CL Armour AA and Fukuoka M Gefitinib or carboplatin-paclitaxel in pulmonary adeno-carcinoma N Engl J Med 2009 361 947-957

[7] Sequist LV Yang JC Yamamoto N OrsquoByrne K Hirsh V Mok T Geater SL Orlov S Tsai CM Boyer M Su WC Bennouna J Kato T Gor- bunova V Lee KH Shah R Massey D Zazulina V Shahidi M and Schuler M Phase III study of afatinib or cisplatin plus pemetrexed in pa-tients with metastatic lung adenocarcinoma

Therapies for advanced lung cancer with acquired resistance

17824 Int J Clin Exp Med 20169(9)17822-17831

Texas) For the identification of factors affecting the efficacy of the therapy each of dependent variables (PFS OS RR and CDR) were tested against several independent variables includ-ing the number of patients in a study age gen-der smoking histological type (percent patients with adenocarcinomasquamous cell carcino-ma) and mutation (percent patients with exon 19 deletionexon 21 L858R) Restricted maxi-mum likelihood method was used for the metaregression analyses Between-study vari-ance was tested with tau2 and the percentage of between-study heterogeneity was assess- ed with I-squared (I2) index A p value of less than 01 was considered to show a significant relationship

Quality assessment of the included studies was carried out with Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies devised by the National Institute of Health of the United States For the assess-ment of publication bias Beggrsquos funnel plot and Eggerrsquos precision plot were studied and trim and filled method was applied to estimate missing number of studies

Results

The literature search led to the selection of 22 studies [20-41] after screening and applying eligibility criteria (Figure 1) from which 1098 NSCLC patientsrsquo data were used for the meta-

Figure 1 A flowchart of the study screening and selection process

Therapies for advanced lung cancer with acquired resistance

17825 Int J Clin Exp Med 20169(9)17822-17831

analyses These studies were either retrospec-tive or prospective in design The quality of these studies was adequate (Table S1) A sig-nificant publication bias was identified upon assessment with funnel plot asymmetry and trim and fill method (Figure 2A-D)

Important characteristics of the included stud-ies are presented in Table S2 Average age (mean plusmn standard deviation) of the patients was 6132 plusmn 102 years and 31 plusmn 14 of the patients were female Patients who ever smoked constituted 26 plusmn 18 of this popula-tion Histologically 906 plusmn 92 of the patients had adenocarcinoma and 4 plusmn 4 harboured squamous cell carcinoma Two major mutants (exon 19 deletion and exon 21 L858R) pre-vailed in 544 plusmn 157 and 354 plusmn 13 patients respectively The EGFR-TKI resistance mutation T790M was prevalent in about 51 of the patients facing drug resistance

In the EGFR-TKI resistant NSCLC patients over-all PFS with 95 confidence interval (CI) was 428 [309 546] months after the treatment

Treatment with EGFR-TKI in combination with chemotherapy was associated with maximum PFS (535 [318 751] months) followed by the treatment with an alternative EGFR-TKI alone (422 [251 593] months and retreatment with the same EGFR-TKI (386 [227 544] months (Figure 3) In the EGFR-TKI resistant NSCLC patients overall survival after any treat-ment was 1224 [1038 1409] months (Figure 4) There were no statistically significant differ-ences between the subgroups in progression-free survival or overall survival (Figures 3 4)

Partial response rate stable disease rate and disease control rate to any therapy in the pres-ent study were 2852 [2058 3647] 3388 [2609 4168] and 59 [4714 7085] respectively Subgroup meta-analyses of these variables are presented in Figures S1 S2 S3

In the metaregression analyses only the per-centage of patients with adenocarcinoma was significantly inversely associated with the over-all survival (coefficient -339 [-0717 004] P=0074) None of any other independent vari-

Figure 2 Funnel plots showing a significant publication bias with estimated number of missing studies as assessed by trim and fill method for the corresponding meta-analyses of (A) progression-free survival (B) overall survival (C) partial remission rate and (D) disease control rate

Therapies for advanced lung cancer with acquired resistance

17826 Int J Clin Exp Med 20169(9)17822-17831

able including age gender or mutation type was significantly associated with either overall progression-free survival or overall survival

Discussion

In the absence of any targeted therapy or ef- fective treatment for NSCLC patients with ac- quired resistance to EGFR-TKI as observed in the present meta-analysis any regimen includ-ing retreatment with a EGFR-TKI or treatment with an alternative EGFR-TKI either alone or in combination with non-EGFR-TKI chemotherapy can provide a survival benefit of approximately one year with approximately 43 months of pro-gression-free survival with no statistically sig-nificant between group differences

Addition of the bevacizumab (vascular endo-thelial growth factor monoclonal antibody) to palliative platinum-based chemotherapy achi-

eves response rates of 30 PFS of less than eight months and 1-year overall survival is not attained in all patients [42] Even with second-line therapies such as docetaxel or peme-trexed 2-year survival is achieved in a very few patients [43 44] Introduction of EGFR-TKIs such as gefitinib and erlotinib improved the out-comes when compared to conventional plati-num-based chemotherapy [4 8 45] especially in patients with relatively high incidence of EGFR mutations [46 47]

The heterogeneity in patients regarding their clinical course and response to different anti-cancer therapies plays important role in the success of an anti-NSCLC therapy [23] Somatic mutations in the EGFR gene are detected in 30 to 40 of Asian and 10 of white NSCLC patients [48 49] Seventy percent of lung ade-nocarcinoma patients with mutations in the

Figure 3 Forest graph showing the overall and subgroup-wise effect sizes of the progression-free survival (months) in the study population In study identity column Squist 2015 plusmn represents T790M mutation positivenegative patient groups

Therapies for advanced lung cancer with acquired resistance

17827 Int J Clin Exp Med 20169(9)17822-17831

EGFR gene exhibit a partial response upon EGFR-TKI such as erlotinib or gefitinib treat-ment [6]

In addition to T790M mutation [10 11] re- sistance to TKIs has also been shown to ma- nifest through MET which is a transmembrane receptor that binds to the ligand hepatocyte growth factorscatter factor (HGF) with high affinity Interaction of MET with avian v-erb-b2 erythroblastic leukemia viral oncogene homo-log 3 (ERBB3) causes sustained activation of the phosphatidylinositol 3rsquo-kinase-serinethre-onine kinase Akt (PI3KAKT) signalling path- way bypassing EGFR inhibition The MET ampli-fication has been reported to be a mechanism of EGFR-TKI resistance in 22 of cases in- dependent of T790M status [50-52] and ab- normal MET activation is associated with poor NSCLC prognosis [53]

Based on the indolent nature of T790M-posi- tive cells and rapid growth potential of T790M-

negative cells [54 55] it is postulated that EGFR-TKI-free interval can repopulate T790M-negative cells because of the withdrawal of the mutagenic pressure resulting in more cells to respond to EGFR-TKI re-challenge [34] Al- though negative T790M status of the tumour cells is considered predictive of EGFR-TKI re-challenge [56 57] in the present metaregre- ssion analyses T790M prevalence data were inadequate to study this phenomenon and an attempt with 6 studies data revealed no signi- ficant association between percentage of pa- tients with T790M mutations and PFS Never- theless newer EGFR-TKIs like rociletinib are found to be associated with better response rate even in T790M-positive patients [36]

In the present study a significant inverse rela-tionship between the incidence of adenocarci-noma and overall survival is observed Better survival is reported in patients with bronchio- alveolar adenocarcinoma than in patients with large cell tumours [58] Since approximately

Figure 4 Forest graph showing the overall and subgroup-wise effect sizes of the overall survival (months) in the study population

Therapies for advanced lung cancer with acquired resistance

17828 Int J Clin Exp Med 20169(9)17822-17831

90 of patients included in this meta-analysis had adenocarcinoma more data will be re- quired to evaluate this relationship

Taken together we have found that there were no statistically significant differences between the treatment subgroup regimens Although a difference of approximately 15 months in the progression-free survival has been noted between EGFR-TKI retreatment and EGFR-TKI with chemotherapy yet this difference was less (approximately 1 month) when overall sur-vival was analysed Thus it will be necessary to have some more well-designed studies before using combinational treatments as such regi-mens may expose patients to additional side effects Moreover because of genomic and pharmacogenomic variations in the patients study designs with more homogeneous patient characteristics will be required to identify patients for a specific type of therapy

Conclusion

With approximately 60 disease control rate overall chemotherapeutic interventions to ad- vanced NSCLC patients with acquired resis-tance is associated with less than 5 months of progression-free survival and approximate- ly 1 year of overall survival Partial response rate and stable disease rate are found to be 2852 [2058 3647] and 3388 [2609 4168] respectively

Acknowledgements

This study was supported by the grant from the National Natural Science Foundation of China (No 81071919) Norman Bethune Program of Jilin University (No 2012220) and The Na- tural Science Foundation of Jilin Province (No 20150101151JC)

Disclosure of conflict of interest

None

Address correspondence to Ke Wang Department of Respiratory Medicine The Second Affiliated Hos- pital of Jilin University No 218 Ziqiang Street Nanguan District Changchun 130041 Jilin China E-mail kewangchinaoutlookcom

References

[1] He Y Li D Song G Li Y Liang D Jin J Wen D and Shan B Lung cancer burden has in-

creased during the last 40 years in Hebei Province China Thorac Cancer 2016 7 323-332

[2] Ferlay J Soerjomataram I Dikshit R Eser S Mathers C Rebelo M Parkin DM Forman D and Bray F Cancer incidence and mortality worldwide sources methods and major pat-terns in GLOBOCAN 2012 Int J Cancer 2015 136 E359-386

[3] Gadgeel SM Personalized Therapy of Non-small Cell Lung Cancer (NSCLC) Adv Exp Med Biol 2016 890 203-222

[4] Rosell R Carcereny E Gervais R Vergnene- gre A Massuti B Felip E Palmero R Garcia-Gomez R Pallares C Sanchez JM Porta R Cobo M Garrido P Longo F Moran T Insa A De Marinis F Corre R Bover I Illiano A Dansin E de Castro J Milella M Reguart N Altavilla G Jimenez U Provencio M Moreno MA Terrasa J Munoz-Langa J Valdivia J Isla D Domine M Molinier O Mazieres J Baize N Garcia-Campelo R Robinet G Rodriguez-Abreu D Lopez-Vivanco G Gebbia V Ferrera-Delgado L Bombaron P Bernabe R Bearz A Artal A Cortesi E Rolfo C Sanchez-Ronco M Droz- dowskyj A Queralt C de Aguirre I Ramirez JL Sanchez JJ Molina MA Taron M Paz-Ares L Spanish Lung Cancer Group in collaboration with Groupe Francais de P-C and Associazione Italiana Oncologia T Erlotinib versus stand- ard chemotherapy as first-line treatment for European patients with advanced EGFR mu- tation-positive non-small-cell lung cancer (EU- RTAC) a multicentre open-label randomised phase 3 trial Lancet Oncol 2012 13 239-246

[5] Zhou C Wu YL Chen G Feng J Liu XQ Wang C Zhang S Wang J Zhou S Ren S Lu S Zhang L Hu C Hu C Luo Y Chen L Ye M Huang J Zhi X Zhang Y Xiu Q Ma J Zhang L and You C 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 12 735-742

[6] Mok TS Wu YL Thongprasert S Yang CH Chu DT Saijo N Sunpaweravong P Han B Margono B Ichinose Y Nishiwaki Y Ohe Y Yang JJ Chewaskulyong B Jiang H Duffield EL Wat- kins CL Armour AA and Fukuoka M Gefitinib or carboplatin-paclitaxel in pulmonary adeno-carcinoma N Engl J Med 2009 361 947-957

[7] Sequist LV Yang JC Yamamoto N OrsquoByrne K Hirsh V Mok T Geater SL Orlov S Tsai CM Boyer M Su WC Bennouna J Kato T Gor- bunova V Lee KH Shah R Massey D Zazulina V Shahidi M and Schuler M Phase III study of afatinib or cisplatin plus pemetrexed in pa-tients with metastatic lung adenocarcinoma

Therapies for advanced lung cancer with acquired resistance

17825 Int J Clin Exp Med 20169(9)17822-17831

analyses These studies were either retrospec-tive or prospective in design The quality of these studies was adequate (Table S1) A sig-nificant publication bias was identified upon assessment with funnel plot asymmetry and trim and fill method (Figure 2A-D)

Important characteristics of the included stud-ies are presented in Table S2 Average age (mean plusmn standard deviation) of the patients was 6132 plusmn 102 years and 31 plusmn 14 of the patients were female Patients who ever smoked constituted 26 plusmn 18 of this popula-tion Histologically 906 plusmn 92 of the patients had adenocarcinoma and 4 plusmn 4 harboured squamous cell carcinoma Two major mutants (exon 19 deletion and exon 21 L858R) pre-vailed in 544 plusmn 157 and 354 plusmn 13 patients respectively The EGFR-TKI resistance mutation T790M was prevalent in about 51 of the patients facing drug resistance

In the EGFR-TKI resistant NSCLC patients over-all PFS with 95 confidence interval (CI) was 428 [309 546] months after the treatment

Treatment with EGFR-TKI in combination with chemotherapy was associated with maximum PFS (535 [318 751] months) followed by the treatment with an alternative EGFR-TKI alone (422 [251 593] months and retreatment with the same EGFR-TKI (386 [227 544] months (Figure 3) In the EGFR-TKI resistant NSCLC patients overall survival after any treat-ment was 1224 [1038 1409] months (Figure 4) There were no statistically significant differ-ences between the subgroups in progression-free survival or overall survival (Figures 3 4)

Partial response rate stable disease rate and disease control rate to any therapy in the pres-ent study were 2852 [2058 3647] 3388 [2609 4168] and 59 [4714 7085] respectively Subgroup meta-analyses of these variables are presented in Figures S1 S2 S3

In the metaregression analyses only the per-centage of patients with adenocarcinoma was significantly inversely associated with the over-all survival (coefficient -339 [-0717 004] P=0074) None of any other independent vari-

Figure 2 Funnel plots showing a significant publication bias with estimated number of missing studies as assessed by trim and fill method for the corresponding meta-analyses of (A) progression-free survival (B) overall survival (C) partial remission rate and (D) disease control rate

Therapies for advanced lung cancer with acquired resistance

17826 Int J Clin Exp Med 20169(9)17822-17831

able including age gender or mutation type was significantly associated with either overall progression-free survival or overall survival

Discussion

In the absence of any targeted therapy or ef- fective treatment for NSCLC patients with ac- quired resistance to EGFR-TKI as observed in the present meta-analysis any regimen includ-ing retreatment with a EGFR-TKI or treatment with an alternative EGFR-TKI either alone or in combination with non-EGFR-TKI chemotherapy can provide a survival benefit of approximately one year with approximately 43 months of pro-gression-free survival with no statistically sig-nificant between group differences

Addition of the bevacizumab (vascular endo-thelial growth factor monoclonal antibody) to palliative platinum-based chemotherapy achi-

eves response rates of 30 PFS of less than eight months and 1-year overall survival is not attained in all patients [42] Even with second-line therapies such as docetaxel or peme-trexed 2-year survival is achieved in a very few patients [43 44] Introduction of EGFR-TKIs such as gefitinib and erlotinib improved the out-comes when compared to conventional plati-num-based chemotherapy [4 8 45] especially in patients with relatively high incidence of EGFR mutations [46 47]

The heterogeneity in patients regarding their clinical course and response to different anti-cancer therapies plays important role in the success of an anti-NSCLC therapy [23] Somatic mutations in the EGFR gene are detected in 30 to 40 of Asian and 10 of white NSCLC patients [48 49] Seventy percent of lung ade-nocarcinoma patients with mutations in the

Figure 3 Forest graph showing the overall and subgroup-wise effect sizes of the progression-free survival (months) in the study population In study identity column Squist 2015 plusmn represents T790M mutation positivenegative patient groups

Therapies for advanced lung cancer with acquired resistance

17827 Int J Clin Exp Med 20169(9)17822-17831

EGFR gene exhibit a partial response upon EGFR-TKI such as erlotinib or gefitinib treat-ment [6]

In addition to T790M mutation [10 11] re- sistance to TKIs has also been shown to ma- nifest through MET which is a transmembrane receptor that binds to the ligand hepatocyte growth factorscatter factor (HGF) with high affinity Interaction of MET with avian v-erb-b2 erythroblastic leukemia viral oncogene homo-log 3 (ERBB3) causes sustained activation of the phosphatidylinositol 3rsquo-kinase-serinethre-onine kinase Akt (PI3KAKT) signalling path- way bypassing EGFR inhibition The MET ampli-fication has been reported to be a mechanism of EGFR-TKI resistance in 22 of cases in- dependent of T790M status [50-52] and ab- normal MET activation is associated with poor NSCLC prognosis [53]

Based on the indolent nature of T790M-posi- tive cells and rapid growth potential of T790M-

negative cells [54 55] it is postulated that EGFR-TKI-free interval can repopulate T790M-negative cells because of the withdrawal of the mutagenic pressure resulting in more cells to respond to EGFR-TKI re-challenge [34] Al- though negative T790M status of the tumour cells is considered predictive of EGFR-TKI re-challenge [56 57] in the present metaregre- ssion analyses T790M prevalence data were inadequate to study this phenomenon and an attempt with 6 studies data revealed no signi- ficant association between percentage of pa- tients with T790M mutations and PFS Never- theless newer EGFR-TKIs like rociletinib are found to be associated with better response rate even in T790M-positive patients [36]

In the present study a significant inverse rela-tionship between the incidence of adenocarci-noma and overall survival is observed Better survival is reported in patients with bronchio- alveolar adenocarcinoma than in patients with large cell tumours [58] Since approximately

Figure 4 Forest graph showing the overall and subgroup-wise effect sizes of the overall survival (months) in the study population

Therapies for advanced lung cancer with acquired resistance

17828 Int J Clin Exp Med 20169(9)17822-17831

90 of patients included in this meta-analysis had adenocarcinoma more data will be re- quired to evaluate this relationship

Taken together we have found that there were no statistically significant differences between the treatment subgroup regimens Although a difference of approximately 15 months in the progression-free survival has been noted between EGFR-TKI retreatment and EGFR-TKI with chemotherapy yet this difference was less (approximately 1 month) when overall sur-vival was analysed Thus it will be necessary to have some more well-designed studies before using combinational treatments as such regi-mens may expose patients to additional side effects Moreover because of genomic and pharmacogenomic variations in the patients study designs with more homogeneous patient characteristics will be required to identify patients for a specific type of therapy

Conclusion

With approximately 60 disease control rate overall chemotherapeutic interventions to ad- vanced NSCLC patients with acquired resis-tance is associated with less than 5 months of progression-free survival and approximate- ly 1 year of overall survival Partial response rate and stable disease rate are found to be 2852 [2058 3647] and 3388 [2609 4168] respectively

Acknowledgements

This study was supported by the grant from the National Natural Science Foundation of China (No 81071919) Norman Bethune Program of Jilin University (No 2012220) and The Na- tural Science Foundation of Jilin Province (No 20150101151JC)

Disclosure of conflict of interest

None

Address correspondence to Ke Wang Department of Respiratory Medicine The Second Affiliated Hos- pital of Jilin University No 218 Ziqiang Street Nanguan District Changchun 130041 Jilin China E-mail kewangchinaoutlookcom

References

[1] He Y Li D Song G Li Y Liang D Jin J Wen D and Shan B Lung cancer burden has in-

creased during the last 40 years in Hebei Province China Thorac Cancer 2016 7 323-332

[2] Ferlay J Soerjomataram I Dikshit R Eser S Mathers C Rebelo M Parkin DM Forman D and Bray F Cancer incidence and mortality worldwide sources methods and major pat-terns in GLOBOCAN 2012 Int J Cancer 2015 136 E359-386

[3] Gadgeel SM Personalized Therapy of Non-small Cell Lung Cancer (NSCLC) Adv Exp Med Biol 2016 890 203-222

[4] Rosell R Carcereny E Gervais R Vergnene- gre A Massuti B Felip E Palmero R Garcia-Gomez R Pallares C Sanchez JM Porta R Cobo M Garrido P Longo F Moran T Insa A De Marinis F Corre R Bover I Illiano A Dansin E de Castro J Milella M Reguart N Altavilla G Jimenez U Provencio M Moreno MA Terrasa J Munoz-Langa J Valdivia J Isla D Domine M Molinier O Mazieres J Baize N Garcia-Campelo R Robinet G Rodriguez-Abreu D Lopez-Vivanco G Gebbia V Ferrera-Delgado L Bombaron P Bernabe R Bearz A Artal A Cortesi E Rolfo C Sanchez-Ronco M Droz- dowskyj A Queralt C de Aguirre I Ramirez JL Sanchez JJ Molina MA Taron M Paz-Ares L Spanish Lung Cancer Group in collaboration with Groupe Francais de P-C and Associazione Italiana Oncologia T Erlotinib versus stand- ard chemotherapy as first-line treatment for European patients with advanced EGFR mu- tation-positive non-small-cell lung cancer (EU- RTAC) a multicentre open-label randomised phase 3 trial Lancet Oncol 2012 13 239-246

[5] Zhou C Wu YL Chen G Feng J Liu XQ Wang C Zhang S Wang J Zhou S Ren S Lu S Zhang L Hu C Hu C Luo Y Chen L Ye M Huang J Zhi X Zhang Y Xiu Q Ma J Zhang L and You C 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 12 735-742

[6] Mok TS Wu YL Thongprasert S Yang CH Chu DT Saijo N Sunpaweravong P Han B Margono B Ichinose Y Nishiwaki Y Ohe Y Yang JJ Chewaskulyong B Jiang H Duffield EL Wat- kins CL Armour AA and Fukuoka M Gefitinib or carboplatin-paclitaxel in pulmonary adeno-carcinoma N Engl J Med 2009 361 947-957

[7] Sequist LV Yang JC Yamamoto N OrsquoByrne K Hirsh V Mok T Geater SL Orlov S Tsai CM Boyer M Su WC Bennouna J Kato T Gor- bunova V Lee KH Shah R Massey D Zazulina V Shahidi M and Schuler M Phase III study of afatinib or cisplatin plus pemetrexed in pa-tients with metastatic lung adenocarcinoma

Therapies for advanced lung cancer with acquired resistance

17826 Int J Clin Exp Med 20169(9)17822-17831

able including age gender or mutation type was significantly associated with either overall progression-free survival or overall survival

Discussion

In the absence of any targeted therapy or ef- fective treatment for NSCLC patients with ac- quired resistance to EGFR-TKI as observed in the present meta-analysis any regimen includ-ing retreatment with a EGFR-TKI or treatment with an alternative EGFR-TKI either alone or in combination with non-EGFR-TKI chemotherapy can provide a survival benefit of approximately one year with approximately 43 months of pro-gression-free survival with no statistically sig-nificant between group differences

Addition of the bevacizumab (vascular endo-thelial growth factor monoclonal antibody) to palliative platinum-based chemotherapy achi-

eves response rates of 30 PFS of less than eight months and 1-year overall survival is not attained in all patients [42] Even with second-line therapies such as docetaxel or peme-trexed 2-year survival is achieved in a very few patients [43 44] Introduction of EGFR-TKIs such as gefitinib and erlotinib improved the out-comes when compared to conventional plati-num-based chemotherapy [4 8 45] especially in patients with relatively high incidence of EGFR mutations [46 47]

The heterogeneity in patients regarding their clinical course and response to different anti-cancer therapies plays important role in the success of an anti-NSCLC therapy [23] Somatic mutations in the EGFR gene are detected in 30 to 40 of Asian and 10 of white NSCLC patients [48 49] Seventy percent of lung ade-nocarcinoma patients with mutations in the

Figure 3 Forest graph showing the overall and subgroup-wise effect sizes of the progression-free survival (months) in the study population In study identity column Squist 2015 plusmn represents T790M mutation positivenegative patient groups

Therapies for advanced lung cancer with acquired resistance

17827 Int J Clin Exp Med 20169(9)17822-17831

EGFR gene exhibit a partial response upon EGFR-TKI such as erlotinib or gefitinib treat-ment [6]

In addition to T790M mutation [10 11] re- sistance to TKIs has also been shown to ma- nifest through MET which is a transmembrane receptor that binds to the ligand hepatocyte growth factorscatter factor (HGF) with high affinity Interaction of MET with avian v-erb-b2 erythroblastic leukemia viral oncogene homo-log 3 (ERBB3) causes sustained activation of the phosphatidylinositol 3rsquo-kinase-serinethre-onine kinase Akt (PI3KAKT) signalling path- way bypassing EGFR inhibition The MET ampli-fication has been reported to be a mechanism of EGFR-TKI resistance in 22 of cases in- dependent of T790M status [50-52] and ab- normal MET activation is associated with poor NSCLC prognosis [53]

Based on the indolent nature of T790M-posi- tive cells and rapid growth potential of T790M-

negative cells [54 55] it is postulated that EGFR-TKI-free interval can repopulate T790M-negative cells because of the withdrawal of the mutagenic pressure resulting in more cells to respond to EGFR-TKI re-challenge [34] Al- though negative T790M status of the tumour cells is considered predictive of EGFR-TKI re-challenge [56 57] in the present metaregre- ssion analyses T790M prevalence data were inadequate to study this phenomenon and an attempt with 6 studies data revealed no signi- ficant association between percentage of pa- tients with T790M mutations and PFS Never- theless newer EGFR-TKIs like rociletinib are found to be associated with better response rate even in T790M-positive patients [36]

In the present study a significant inverse rela-tionship between the incidence of adenocarci-noma and overall survival is observed Better survival is reported in patients with bronchio- alveolar adenocarcinoma than in patients with large cell tumours [58] Since approximately

Figure 4 Forest graph showing the overall and subgroup-wise effect sizes of the overall survival (months) in the study population

Therapies for advanced lung cancer with acquired resistance

17828 Int J Clin Exp Med 20169(9)17822-17831

90 of patients included in this meta-analysis had adenocarcinoma more data will be re- quired to evaluate this relationship

Taken together we have found that there were no statistically significant differences between the treatment subgroup regimens Although a difference of approximately 15 months in the progression-free survival has been noted between EGFR-TKI retreatment and EGFR-TKI with chemotherapy yet this difference was less (approximately 1 month) when overall sur-vival was analysed Thus it will be necessary to have some more well-designed studies before using combinational treatments as such regi-mens may expose patients to additional side effects Moreover because of genomic and pharmacogenomic variations in the patients study designs with more homogeneous patient characteristics will be required to identify patients for a specific type of therapy

Conclusion

With approximately 60 disease control rate overall chemotherapeutic interventions to ad- vanced NSCLC patients with acquired resis-tance is associated with less than 5 months of progression-free survival and approximate- ly 1 year of overall survival Partial response rate and stable disease rate are found to be 2852 [2058 3647] and 3388 [2609 4168] respectively

Acknowledgements

This study was supported by the grant from the National Natural Science Foundation of China (No 81071919) Norman Bethune Program of Jilin University (No 2012220) and The Na- tural Science Foundation of Jilin Province (No 20150101151JC)

Disclosure of conflict of interest

None

Address correspondence to Ke Wang Department of Respiratory Medicine The Second Affiliated Hos- pital of Jilin University No 218 Ziqiang Street Nanguan District Changchun 130041 Jilin China E-mail kewangchinaoutlookcom

References

[1] He Y Li D Song G Li Y Liang D Jin J Wen D and Shan B Lung cancer burden has in-

creased during the last 40 years in Hebei Province China Thorac Cancer 2016 7 323-332

[2] Ferlay J Soerjomataram I Dikshit R Eser S Mathers C Rebelo M Parkin DM Forman D and Bray F Cancer incidence and mortality worldwide sources methods and major pat-terns in GLOBOCAN 2012 Int J Cancer 2015 136 E359-386

[3] Gadgeel SM Personalized Therapy of Non-small Cell Lung Cancer (NSCLC) Adv Exp Med Biol 2016 890 203-222

[4] Rosell R Carcereny E Gervais R Vergnene- gre A Massuti B Felip E Palmero R Garcia-Gomez R Pallares C Sanchez JM Porta R Cobo M Garrido P Longo F Moran T Insa A De Marinis F Corre R Bover I Illiano A Dansin E de Castro J Milella M Reguart N Altavilla G Jimenez U Provencio M Moreno MA Terrasa J Munoz-Langa J Valdivia J Isla D Domine M Molinier O Mazieres J Baize N Garcia-Campelo R Robinet G Rodriguez-Abreu D Lopez-Vivanco G Gebbia V Ferrera-Delgado L Bombaron P Bernabe R Bearz A Artal A Cortesi E Rolfo C Sanchez-Ronco M Droz- dowskyj A Queralt C de Aguirre I Ramirez JL Sanchez JJ Molina MA Taron M Paz-Ares L Spanish Lung Cancer Group in collaboration with Groupe Francais de P-C and Associazione Italiana Oncologia T Erlotinib versus stand- ard chemotherapy as first-line treatment for European patients with advanced EGFR mu- tation-positive non-small-cell lung cancer (EU- RTAC) a multicentre open-label randomised phase 3 trial Lancet Oncol 2012 13 239-246

[5] Zhou C Wu YL Chen G Feng J Liu XQ Wang C Zhang S Wang J Zhou S Ren S Lu S Zhang L Hu C Hu C Luo Y Chen L Ye M Huang J Zhi X Zhang Y Xiu Q Ma J Zhang L and You C 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 12 735-742

[6] Mok TS Wu YL Thongprasert S Yang CH Chu DT Saijo N Sunpaweravong P Han B Margono B Ichinose Y Nishiwaki Y Ohe Y Yang JJ Chewaskulyong B Jiang H Duffield EL Wat- kins CL Armour AA and Fukuoka M Gefitinib or carboplatin-paclitaxel in pulmonary adeno-carcinoma N Engl J Med 2009 361 947-957

[7] Sequist LV Yang JC Yamamoto N OrsquoByrne K Hirsh V Mok T Geater SL Orlov S Tsai CM Boyer M Su WC Bennouna J Kato T Gor- bunova V Lee KH Shah R Massey D Zazulina V Shahidi M and Schuler M Phase III study of afatinib or cisplatin plus pemetrexed in pa-tients with metastatic lung adenocarcinoma

Therapies for advanced lung cancer with acquired resistance

17827 Int J Clin Exp Med 20169(9)17822-17831

EGFR gene exhibit a partial response upon EGFR-TKI such as erlotinib or gefitinib treat-ment [6]

In addition to T790M mutation [10 11] re- sistance to TKIs has also been shown to ma- nifest through MET which is a transmembrane receptor that binds to the ligand hepatocyte growth factorscatter factor (HGF) with high affinity Interaction of MET with avian v-erb-b2 erythroblastic leukemia viral oncogene homo-log 3 (ERBB3) causes sustained activation of the phosphatidylinositol 3rsquo-kinase-serinethre-onine kinase Akt (PI3KAKT) signalling path- way bypassing EGFR inhibition The MET ampli-fication has been reported to be a mechanism of EGFR-TKI resistance in 22 of cases in- dependent of T790M status [50-52] and ab- normal MET activation is associated with poor NSCLC prognosis [53]

Based on the indolent nature of T790M-posi- tive cells and rapid growth potential of T790M-

negative cells [54 55] it is postulated that EGFR-TKI-free interval can repopulate T790M-negative cells because of the withdrawal of the mutagenic pressure resulting in more cells to respond to EGFR-TKI re-challenge [34] Al- though negative T790M status of the tumour cells is considered predictive of EGFR-TKI re-challenge [56 57] in the present metaregre- ssion analyses T790M prevalence data were inadequate to study this phenomenon and an attempt with 6 studies data revealed no signi- ficant association between percentage of pa- tients with T790M mutations and PFS Never- theless newer EGFR-TKIs like rociletinib are found to be associated with better response rate even in T790M-positive patients [36]

In the present study a significant inverse rela-tionship between the incidence of adenocarci-noma and overall survival is observed Better survival is reported in patients with bronchio- alveolar adenocarcinoma than in patients with large cell tumours [58] Since approximately

Figure 4 Forest graph showing the overall and subgroup-wise effect sizes of the overall survival (months) in the study population

Therapies for advanced lung cancer with acquired resistance

17828 Int J Clin Exp Med 20169(9)17822-17831

90 of patients included in this meta-analysis had adenocarcinoma more data will be re- quired to evaluate this relationship

Taken together we have found that there were no statistically significant differences between the treatment subgroup regimens Although a difference of approximately 15 months in the progression-free survival has been noted between EGFR-TKI retreatment and EGFR-TKI with chemotherapy yet this difference was less (approximately 1 month) when overall sur-vival was analysed Thus it will be necessary to have some more well-designed studies before using combinational treatments as such regi-mens may expose patients to additional side effects Moreover because of genomic and pharmacogenomic variations in the patients study designs with more homogeneous patient characteristics will be required to identify patients for a specific type of therapy

Conclusion

With approximately 60 disease control rate overall chemotherapeutic interventions to ad- vanced NSCLC patients with acquired resis-tance is associated with less than 5 months of progression-free survival and approximate- ly 1 year of overall survival Partial response rate and stable disease rate are found to be 2852 [2058 3647] and 3388 [2609 4168] respectively

Acknowledgements

This study was supported by the grant from the National Natural Science Foundation of China (No 81071919) Norman Bethune Program of Jilin University (No 2012220) and The Na- tural Science Foundation of Jilin Province (No 20150101151JC)

Disclosure of conflict of interest

None

Address correspondence to Ke Wang Department of Respiratory Medicine The Second Affiliated Hos- pital of Jilin University No 218 Ziqiang Street Nanguan District Changchun 130041 Jilin China E-mail kewangchinaoutlookcom

References

[1] He Y Li D Song G Li Y Liang D Jin J Wen D and Shan B Lung cancer burden has in-

creased during the last 40 years in Hebei Province China Thorac Cancer 2016 7 323-332

[2] Ferlay J Soerjomataram I Dikshit R Eser S Mathers C Rebelo M Parkin DM Forman D and Bray F Cancer incidence and mortality worldwide sources methods and major pat-terns in GLOBOCAN 2012 Int J Cancer 2015 136 E359-386

[3] Gadgeel SM Personalized Therapy of Non-small Cell Lung Cancer (NSCLC) Adv Exp Med Biol 2016 890 203-222

[4] Rosell R Carcereny E Gervais R Vergnene- gre A Massuti B Felip E Palmero R Garcia-Gomez R Pallares C Sanchez JM Porta R Cobo M Garrido P Longo F Moran T Insa A De Marinis F Corre R Bover I Illiano A Dansin E de Castro J Milella M Reguart N Altavilla G Jimenez U Provencio M Moreno MA Terrasa J Munoz-Langa J Valdivia J Isla D Domine M Molinier O Mazieres J Baize N Garcia-Campelo R Robinet G Rodriguez-Abreu D Lopez-Vivanco G Gebbia V Ferrera-Delgado L Bombaron P Bernabe R Bearz A Artal A Cortesi E Rolfo C Sanchez-Ronco M Droz- dowskyj A Queralt C de Aguirre I Ramirez JL Sanchez JJ Molina MA Taron M Paz-Ares L Spanish Lung Cancer Group in collaboration with Groupe Francais de P-C and Associazione Italiana Oncologia T Erlotinib versus stand- ard chemotherapy as first-line treatment for European patients with advanced EGFR mu- tation-positive non-small-cell lung cancer (EU- RTAC) a multicentre open-label randomised phase 3 trial Lancet Oncol 2012 13 239-246

[5] Zhou C Wu YL Chen G Feng J Liu XQ Wang C Zhang S Wang J Zhou S Ren S Lu S Zhang L Hu C Hu C Luo Y Chen L Ye M Huang J Zhi X Zhang Y Xiu Q Ma J Zhang L and You C 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 12 735-742

[6] Mok TS Wu YL Thongprasert S Yang CH Chu DT Saijo N Sunpaweravong P Han B Margono B Ichinose Y Nishiwaki Y Ohe Y Yang JJ Chewaskulyong B Jiang H Duffield EL Wat- kins CL Armour AA and Fukuoka M Gefitinib or carboplatin-paclitaxel in pulmonary adeno-carcinoma N Engl J Med 2009 361 947-957

[7] Sequist LV Yang JC Yamamoto N OrsquoByrne K Hirsh V Mok T Geater SL Orlov S Tsai CM Boyer M Su WC Bennouna J Kato T Gor- bunova V Lee KH Shah R Massey D Zazulina V Shahidi M and Schuler M Phase III study of afatinib or cisplatin plus pemetrexed in pa-tients with metastatic lung adenocarcinoma

Therapies for advanced lung cancer with acquired resistance

17828 Int J Clin Exp Med 20169(9)17822-17831

90 of patients included in this meta-analysis had adenocarcinoma more data will be re- quired to evaluate this relationship

Taken together we have found that there were no statistically significant differences between the treatment subgroup regimens Although a difference of approximately 15 months in the progression-free survival has been noted between EGFR-TKI retreatment and EGFR-TKI with chemotherapy yet this difference was less (approximately 1 month) when overall sur-vival was analysed Thus it will be necessary to have some more well-designed studies before using combinational treatments as such regi-mens may expose patients to additional side effects Moreover because of genomic and pharmacogenomic variations in the patients study designs with more homogeneous patient characteristics will be required to identify patients for a specific type of therapy

Conclusion

With approximately 60 disease control rate overall chemotherapeutic interventions to ad- vanced NSCLC patients with acquired resis-tance is associated with less than 5 months of progression-free survival and approximate- ly 1 year of overall survival Partial response rate and stable disease rate are found to be 2852 [2058 3647] and 3388 [2609 4168] respectively

Acknowledgements

This study was supported by the grant from the National Natural Science Foundation of China (No 81071919) Norman Bethune Program of Jilin University (No 2012220) and The Na- tural Science Foundation of Jilin Province (No 20150101151JC)

Disclosure of conflict of interest

None

Address correspondence to Ke Wang Department of Respiratory Medicine The Second Affiliated Hos- pital of Jilin University No 218 Ziqiang Street Nanguan District Changchun 130041 Jilin China E-mail kewangchinaoutlookcom

References

[1] He Y Li D Song G Li Y Liang D Jin J Wen D and Shan B Lung cancer burden has in-

creased during the last 40 years in Hebei Province China Thorac Cancer 2016 7 323-332

[2] Ferlay J Soerjomataram I Dikshit R Eser S Mathers C Rebelo M Parkin DM Forman D and Bray F Cancer incidence and mortality worldwide sources methods and major pat-terns in GLOBOCAN 2012 Int J Cancer 2015 136 E359-386

[3] Gadgeel SM Personalized Therapy of Non-small Cell Lung Cancer (NSCLC) Adv Exp Med Biol 2016 890 203-222

[4] Rosell R Carcereny E Gervais R Vergnene- gre A Massuti B Felip E Palmero R Garcia-Gomez R Pallares C Sanchez JM Porta R Cobo M Garrido P Longo F Moran T Insa A De Marinis F Corre R Bover I Illiano A Dansin E de Castro J Milella M Reguart N Altavilla G Jimenez U Provencio M Moreno MA Terrasa J Munoz-Langa J Valdivia J Isla D Domine M Molinier O Mazieres J Baize N Garcia-Campelo R Robinet G Rodriguez-Abreu D Lopez-Vivanco G Gebbia V Ferrera-Delgado L Bombaron P Bernabe R Bearz A Artal A Cortesi E Rolfo C Sanchez-Ronco M Droz- dowskyj A Queralt C de Aguirre I Ramirez JL Sanchez JJ Molina MA Taron M Paz-Ares L Spanish Lung Cancer Group in collaboration with Groupe Francais de P-C and Associazione Italiana Oncologia T Erlotinib versus stand- ard chemotherapy as first-line treatment for European patients with advanced EGFR mu- tation-positive non-small-cell lung cancer (EU- RTAC) a multicentre open-label randomised phase 3 trial Lancet Oncol 2012 13 239-246

[5] Zhou C Wu YL Chen G Feng J Liu XQ Wang C Zhang S Wang J Zhou S Ren S Lu S Zhang L Hu C Hu C Luo Y Chen L Ye M Huang J Zhi X Zhang Y Xiu Q Ma J Zhang L and You C 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 12 735-742

[6] Mok TS Wu YL Thongprasert S Yang CH Chu DT Saijo N Sunpaweravong P Han B Margono B Ichinose Y Nishiwaki Y Ohe Y Yang JJ Chewaskulyong B Jiang H Duffield EL Wat- kins CL Armour AA and Fukuoka M Gefitinib or carboplatin-paclitaxel in pulmonary adeno-carcinoma N Engl J Med 2009 361 947-957

[7] Sequist LV Yang JC Yamamoto N OrsquoByrne K Hirsh V Mok T Geater SL Orlov S Tsai CM Boyer M Su WC Bennouna J Kato T Gor- bunova V Lee KH Shah R Massey D Zazulina V Shahidi M and Schuler M Phase III study of afatinib or cisplatin plus pemetrexed in pa-tients with metastatic lung adenocarcinoma

Therapies for advanced lung cancer with acquired resistance

17829 Int J Clin Exp Med 20169(9)17822-17831

with EGFR mutations J Clin Oncol 2013 31 3327-3334

[8] Maemondo M Inoue A Kobayashi K Sugawara S Oizumi S Isobe H Gemma A Harada M Yoshizawa H Kinoshita I Fujita Y Okinaga S Hirano H Yoshimori K Harada T Ogura T Ando M Miyazawa H Tanaka T Saijo Y Hagiwara K Morita S Nukiwa T North-East Japan Study Group Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR N Engl J Med 2010 362 2380-2388

[9] Rosell R Cecere F Cognetti F Cuello M Sanchez JM Taron M Reguart N and Jablons D Future directions in the second-line treat-ment of non-small cell lung cancer Semin Oncol 2006 33 S45-51

[10] Pao W Miller VA Politi KA Riely GJ Somwar R Zakowski MF Kris MG and Varmus H Acquired resistance of lung adenocarcino- mas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase do- main PLoS Med 2005 2 e73

[11] Kobayashi S Boggon TJ Dayaram T Janne PA Kocher O Meyerson M Johnson BE Eck MJ Tenen DG and Halmos B EGFR mutation and resistance of non-small-cell lung cancer to ge-fitinib N Engl J Med 2005 352 786-792

[12] Kris MG Natale RB Herbst RS Lynch TJ Jr Prager D Belani CP Schiller JH Kelly K Spiridonidis H Sandler A Albain KS Cella D Wolf MK Averbuch SD Ochs JJ and Kay AC Efficacy of gefitinib an inhibitor of the epider-mal growth factor receptor tyrosine kinase in symptomatic patients with non-small cell lung cancer a randomized trial JAMA 2003 290 2149-2158

[13] Fukuoka M Yano S Giaccone G Tamura T Nakagawa K Douillard JY Nishiwaki Y Vans- teenkiste J Kudoh S Rischin D Eek R Horai T Noda K Takata I Smit E Averbuch S Ma- cleod A Feyereislova A Dong RP and Base- lga J Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected] J Clin Oncol 2003 21 2237-2246

[14] Shepherd FA Rodrigues Pereira J Ciuleanu T Tan EH Hirsh V Thongprasert S Campos D Maoleekoonpiroj S Smylie M Martins R van Kooten M Dediu M Findlay B Tu D Johnston D Bezjak A Clark G Santabarbara P Sey- mour L National Cancer Institute of Canada Clinical Trials G Erlotinib in previously treat- ed non-small-cell lung cancer N Engl J Med 2005 353 123-132

[15] Johnson JR Cohen M Sridhara R Chen YF Williams GM Duan J Gobburu J Booth B Benson K Leighton J Hsieh LS Chidambaram N Zimmerman P and Pazdur R Approval sum-

mary for erlotinib for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen Clin Cancer Res 2005 11 6414-6421

[16] Tan CS Gilligan D and Pacey S Treatment ap-proaches for EGFR-inhibitor-resistant patients with non-small-cell lung cancer Lancet Oncol 2015 16 e447-459

[17] Greig SL Osimertinib First Global Approval Drugs 2016 76 263-273

[18] Gu P Ran JJ and Yu L Electrical Stimulation for hemiplegic shoulder function A systematic re-view and meta-analysis of 15 randomized con-trolled trials Arch Phys Med Rehabil 2016 [Epub ahead of print]

[19] Moher D Liberati A Tetzlaff J Altman DG and Group P Preferred reporting items for system-atic reviews and meta-analyses the PRISMA statement Int J Surg 2010 8 336-341

[20] Asahina H Oizumi S Inoue A Kinoshita I Ishida T Fujita Y Sukoh N Harada M Maemondo M Saijo Y Dosaka-Akita H Isobe H Nukiwa T Nishimura M Hokkaido Lung Cancer Clinical Study G Phase II study of gefi-tinib readministration in patients with ad-vanced non-small cell lung cancer and previ-ous response to gefitinib Oncology 2010 79 423-429

[21] Chen Q Quan Q Ding L Hong X Zhou N Liang Y and Wu H Continuation of epidermal growth factor receptor tyrosine kinase inhibitor treat-ment prolongs disease control in non-small-cell lung cancers with acquired resistance to EGFR tyrosine kinase inhibitors Oncotarget 2015 6 24904-24911

[22] Cho BC Im CK Park MS Kim SK Chang J Park JP Choi HJ Kim YJ Shin SJ Sohn JH Kim H and Kim JH Phase II study of erlotinib in ad-vanced non-small-cell lung cancer after failure of gefitinib J Clin Oncol 2007 25 2528-2533

[23] Costa DB Nguyen KS Cho BC Sequist LV Jackman DM Riely GJ Yeap BY Halmos B Kim JH Janne PA Huberman MS Pao W Tenen DG and Kobayashi S Effects of erlotinib in EGFR mutated non-small cell lung cancers with resis-tance to gefitinib Clin Cancer Res 2008 14 7060-7067

[24] Goldberg SB Oxnard GR Digumarthy S Muzikansky A Jackman DM Lennes IT and Sequist LV Chemotherapy with Erlotinib or chemotherapy alone in advanced non-small cell lung cancer with acquired resistance to EGFR tyrosine kinase inhibitors Oncologist 2013 18 1214-1220

[25] Hata A Katakami N Yoshioka H Fujita S Kunimasa K Nanjo S Otsuka K Kaji R Tomii K Iwasaku M Nishiyama A Hayashi H Morita S and Ishida T Erlotinib after gefitinib failure in

Therapies for advanced lung cancer with acquired resistance

17830 Int J Clin Exp Med 20169(9)17822-17831

relapsed non-small cell lung cancer clinical benefit with optimal patient selection Lung Cancer 2011 74 268-273

[26] Janne PA Yang JC Kim DW Planchard D Ohe Y Ramalingam SS Ahn MJ Kim SW Su WC Horn L Haggstrom D Felip E Kim JH Frewer P Cantarini M Brown KH Dickinson PA Ghiorghiu S and Ranson M AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer N Engl J Med 2015 372 1689-1699

[27] Johnson ML Riely GJ Rizvi NA Azzoli CG Kris MG Sima CS Ginsberg MS Pao W and Miller VA Phase II trial of dasatinib for patients with acquired resistance to treatment with the epi-dermal growth factor receptor tyrosine kinase inhibitors erlotinib or gefitinib J Thorac Oncol 2011 6 1128-1131

[28] Koizumi T Agatsuma T Ikegami K Suzuki T Kobayashi T Kanda S Yoshikawa S Kubo K Shiina T Takasuna K Matsuo A Hayasaka M Morikawa M and Ameshima S Prospective study of gefitinib readministration after che-motherapy in patients with advanced non-small-cell lung cancer who previously respond-ed to gefitinib Clin Lung Cancer 2012 13 458-463

[29] Kuo CH Lin SM Lee KY Chung FT Hsieh MH Fang YF Yu CT and Kuo HP Subsequent che-motherapy improves survival outcome in ad-vanced non-small-cell lung cancer with ac-quired tyrosine kinase inhibitor resistance Clin Lung Cancer 2010 11 51-56

[30] Landi L Tiseo M Chiari R Ricciardi S Rossi E Galetta D Novello S Milella M DrsquoIncecco A Minuti G Tibaldi C Salvini J Facchinetti F Haspinger ER Cortinovis D Santo A Banna G Catino A GiajLevra M Crino L de Marinis F and Cappuzzo F Activity of the EGFR-HER2 dual inhibitor afatinib in EGFR-mutant lung cancer patients with acquired resistance to re-versible EGFR tyrosine kinase inhibitors Clin Lung Cancer 2014 15 411-417 e414

[31] Lee Y Kim HY Lee SH Lim KY Lee GK Yun T Han JY Kim HT and Lee JS Clinical signifi-cance of heterogeneity in response to retreat-ment with epidermal growth factor receptor ty-rosine kinase inhibitors in patients with lung cancer acquiring secondary resistance to the drug Clin Lung Cancer 2014 15 145-151

[32] Lee DH Kim SW Suh C Yoon DH Yi EJ and Lee JS Phase II study of erlotinib as a salvage treatment for non-small-cell lung cancer pa-tients after failure of gefitinib treatment Ann Oncol 2008 19 2039-2042

[33] Oh IJ Ban HJ Kim KS and Kim YC Retreatment of gefitinib in patients with non-small-cell lung cancer who previously controlled to gefitinib a single-arm open-label phase II study Lung Cancer 2012 77 121-127

[34] Otsuka K Hata A Takeshita J Okuda C Kaji R Masago K Fujita S and Katakami N EGFR-TKI rechallenge with bevacizumab in EGFR-mutant non-small cell lung cancer Cancer Chemother Pharmacol 2015 76 835-841

[35] Sequist LV Rolfe L and Allen AR Rociletinib in EGFR-Mutated Non-Small-Cell Lung Cancer N Engl J Med 2015 373 578-579

[36] Sim SH Han SW Oh DY Lee SH Kim DW Im SA Chung DH Kim TY Lee JS Kim YW Heo DS and Bang YJ Erlotinib after Gefitinib failure in female never-smoker Asian patients with pul-monary adenocarcinoma Lung Cancer 2009 65 204-207

[37] Vasile E Tibaldi C Chella A and Falcone A Erlotinib after failure of gefitinib in patients with advanced non-small cell lung cancer pre-viously responding to gefitinib J Thorac Oncol 2008 3 912-914

[38] Wong AS Soong R Seah SB Lim SW Chuah KL Nga ME Chin TM and Soo RA Evidence for disease control with erlotinib after gefitinib failure in typical gefitinib-sensitive Asian pa-tients with non-small cell lung cancer J Thorac Oncol 2008 3 400-404

[39] Yoshimura N Okishio K Mitsuoka S Kimura T Kawaguchi T Kobayashi M Hirashima T Daga H Takeda K Hirata K and Kudoh S Prospective assessment of continuation of erlotinib or gefi-tinib in patients with acquired resistance to erlotinib or gefitinib followed by the addition of pemetrexed J Thorac Oncol 2013 8 96-101

[40] Yu S Zhang B Xiang C Shu Y Wu H Huang X Yu Q Yin Y and Guo R Prospective assessment of pemetrexed or pemetrexed plus platinum in combination with gefitinib or erlotinib in pa-tients with acquired resistance to gefitinib or erlotinib a phase II exploratory and prelimi-nary study Clin Lung Cancer 2015 16 121-127

[41] Zhao ZR Wang JF Lin YB Wang F Fu S Zhang SL Su XD Jiang L Zhang YG Shao JY and Long H Mutation abundance affects the efficacy of EGFR tyrosine kinase inhibitor readministra-tion in non-small-cell lung cancer with acquired resistance Med Oncol 2014 31 810

[42] Sandler A Gray R Perry MC Brahmer J Schiller JH Dowlati A Lilenbaum R and John- son DH Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer N Engl J Med 2006 355 2542-2550

[43] Shepherd FA Dancey J Ramlau R Mattson K Gralla R OrsquoRourke M Levitan N Gressot L Vincent M Burkes R Coughlin S Kim Y and Berille J Prospective randomized trial of do- cetaxel versus best supportive care in pa- tients with non-small-cell lung cancer previ-ously treated with platinum-based chemother-apy J Clin Oncol 2000 18 2095-2103

Therapies for advanced lung cancer with acquired resistance

17831 Int J Clin Exp Med 20169(9)17822-17831

[44] Hanna N Shepherd FA Fossella FV Pereira JR De Marinis F von Pawel J Gatzemeier U Tsao TC Pless M Muller T Lim HL Desch C Szondy K Gervais R Shaharyar Manegold C Paul S Paoletti P Einhorn L and Bunn PA Jr Randomized phase III trial of pemetrexed ver-sus docetaxel in patients with non-small-cell lung cancer previously treated with chemo-therapy J Clin Oncol 2004 22 1589-1597

[45] Nishino K Imamura F Morita S Mori M Komuta K Kijima T Namba Y Kumagai T Yamamoto S Tachibana I Nakazawa Y Uchi- da J Minami S Takahashi R Yano Y Okuyama T and Kumanogoh A A retrospective analysis of 335 Japanese lung cancer patients who re-sponded to initial gefitinib treatment Lung Cancer 2013 82 299-304

[46] Uramoto H and Mitsudomi T Which biomarker predicts benefit from EGFR-TKI treatment for patients with lung cancer Br J Cancer 2007 96 857-863

[47] Sequist LV Bell DW Lynch TJ and Haber DA Molecular predictors of response to epidermal growth factor receptor antagonists in non-small-cell lung cancer J Clin Oncol 2007 25 587-595

[48] Lynch TJ Bell DW Sordella R Gurubhagavatula S Okimoto RA Brannigan BW Harris PL Haserlat SM Supko JG Haluska FG Louis DN Christiani DC Settleman J and Haber DA Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib N Engl J Med 2004 350 2129-2139

[49] Shigematsu H Lin L Takahashi T Nomura M Suzuki M Wistuba II Fong KM Lee H Toyooka S Shimizu N Fujisawa T Feng Z Roth JA Herz J Minna JD and Gazdar AF Clinical and bio-logical features associated with epidermal growth factor receptor gene mutations in lung cancers J Natl Cancer Inst 2005 97 339-346

[50] Engelman JA Zejnullahu K Mitsudomi T Song Y Hyland C Park JO Lindeman N Gale CM Zhao X Christensen J Kosaka T Holmes AJ Rogers AM Cappuzzo F Mok T Lee C Johnson BE Cantley LC and Janne PA MET amplifica-tion leads to gefitinib resistance in lung cancer by activating ERBB3 signaling Science 2007 316 1039-1043

[51] Bean J Brennan C Shih JY Riely G Viale A Wang L Chitale D Motoi N Szoke J Broderick S Balak M Chang WC Yu CJ Gazdar A Pass H Rusch V Gerald W Huang SF Yang PC Miller V Ladanyi M Yang CH and Pao W MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib Proc Natl Acad Sci U S A 2007 104 20932-20937

[52] Di Renzo MF Olivero M Ferro S Prat M Bongarzone I Pilotti S Belfiore A Costantino A Vigneri R Pierotti MA et al Overexpression of the c-METHGF receptor gene in human thy-roid carcinomas Oncogene 1992 7 2549-2553

[53] Masuya D Huang C Liu D Nakashima T Kameyama K Haba R Ueno M and Yokomise H The tumour-stromal interaction between in-tratumoral c-Met and stromal hepatocyte growth factor associated with tumour growth and prognosis in non-small-cell lung cancer pa-tients Br J Cancer 2004 90 1555-1562

[54] Chmielecki J Foo J Oxnard GR Hutchinson K Ohashi K Somwar R Wang L Amato KR Arcila M Sos ML Socci ND Viale A de Stanchina E Ginsberg MS Thomas RK Kris MG Inoue A Ladanyi M Miller VA Michor F and Pao W Optimization of dosing for EGFR-mutant non-small cell lung cancer with evolutionary cancer modeling Sci Transl Med 2011 3 90ra59

[55] Oxnard GR Arcila ME Chmielecki J Ladanyi M Miller VA and Pao W New strategies in over-coming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibi-tors in lung cancer Clin Cancer Res 2011 17 5530-5537

[56] Sequist LV Waltman BA Dias-Santagata D Digumarthy S Turke AB Fidias P Bergethon K Shaw AT Gettinger S Cosper AK Akhavanfard S Heist RS Temel J Christensen JG Wain JC Lynch TJ Vernovsky K Mark EJ Lanuti M Iafrate AJ Mino-Kenudson M and Engelman JA Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibi-tors Sci Transl Med 2011 3 75ra26

[57] Hata A Katakami N Kaji R Fujita S and Imai Y Does T790M disappear Successful gefitinib rechallenge after T790M disappearance in a patient with EGFR-mutant non-small-cell lung cancer J Thorac Oncol 2013 8 e27-29

[58] Cetin K Ettinger DS Hei YJ and OrsquoMalley CD Survival by histologic subtype in stage IV nons-mall cell lung cancer based on data from the Surveillance Epidemiology and End Results Program Clin Epidemiol 2011 3 139-148

Therapies for advanced lung cancer with acquired resistance

1

Table S1 Criteria of the studies

Study [Ref]Criteria

1 2 3 4 5 6 7 8 9 10 11 12 13 14Asahina 2010 [20] Y Y Y Y N N NA N Y NA Y N Y N

Chen 2015 [21] Y Y Y Y N N NA N Y NA Y N Y N

Cho 2007 [22] Y Y Y Y Y N NA N Y NA Y N Y N

Costa 2008 [23] Y Y Y Y N N NA N Y NA Y N Y N

Goldberg 2013 [24] Y Y Y Y N N NA N Y NA Y N Y N

Hata 2011 [25] Y Y Y Y N N NA N Y NA Y N Y N

Janne 2015 [26] Y Y Y Y N N NA Y Y NA Y N Y Y

Johnson 2011 [27] Y Y Y Y N N NA N Y NA Y N Y N

Koizumi 2012 [28] Y Y Y Y Y N NA N Y NA Y N Y N

Kuo 2010 [29] Y Y Y Y N N NA N Y NA Y N Y N

Landi 2014 [30] Y Y Y Y N N NA N Y NA Y N Y N

Lee DH 2008 [31] Y Y Y Y Y N NA N Y NA Y N Y N

Lee 2014 [32] Y Y Y Y N N NA N Y NA Y N Y Y

Oh 2012 [33] Y Y Y Y Y N NA N Y NA Y N Y N

Otsuka 2015 [34] Y Y Y Y N N NA N Y NA Y N Y N

Sequist 2015 [35] Y Y Y Y N N NA N Y NA Y N Y Y

Sim 2009 [36] Y Y Y Y N N NA N Y NA Y N Y N

Vasile 2008 [37] Y Y Y Y N N NA N Y NA Y N Y N

Wong 2008 [38] Y Y Y Y N N NA N Y NA Y N Y N

Yoshimura 2013 [39] Y Y Y Y Y N NA N Y NA Y N Y N

Yu 2015 [40] Y Y Y Y N N NA N Y NA Y N Y N

Zhao 2014 [41] Y Y Y Y N N NA N Y NA Y N Y NCriteria1 Was the research question or objective in this paper clearly stated2 Was the study population clearly specified and defined3 Was the participation rate of eligible persons at least 504 Were all the subjects selected or recruited from the same or similar populations (including the same time period) Were inclusion and exclusion criteria pre-specified and applied uniformly to all participants5 Was a sample size justification power description or variance and effect estimates provided6 For the analyses were the exposure(s) of interest measured prior to the outcome(s) being measured7 Was the timeframe sufficient to reasonably expect to see an association between exposure and outcome8 For exposures that can vary in amount or level did the study examine different levels of the exposure as related to the outcome (eg categories of exposure or exposure measured as continuous variable)9 Were the exposure measures (independent variables) clearly defined valid reliable and implemented consistently across all study participants10 Was the exposure(s) assessed more than once over time11 Were the outcome measures (dependent variables) clearly defined valid reliable and implemented consistently across all study participants12 Were the outcome assessors blinded to the exposure status of participants13 Was loss to follow-up after baseline 20 or less14 Were key potential confounding variables measured and adjusted statistically for their impact on the relationship between exposure(s) and outcome(s)

Therapies for advanced lung cancer with acquired resistance

2

Table S2 Characteristics of the included studies

Study n Treatment Design Age males Smokers Adeno-carcinoma Squamous CC

Exon 19 deletion

Exon 21 L858R T790M

Asahina 2010 16 Re-GEFIERLO Prospective 665 plusmn 7 1875 3125 875 625Chen 2015 55 Re-GEFIERLOICO Prospective 55 plusmn 115 41818 80 96364 36364 41818 36364Cho 2007 21 ERLO Prospective 56 plusmn 85 47619 47619 71429 14286Costa 2008 18 ERLO Retrospective 63 plusmn 9 22222 27778 88889 0 72222 22222Goldberg 2013 74 ERLO-CT Retrospective 58 plusmn 13 17647 29412 58824 32353Hata 2011 125 ERLO Retrospective 64 plusmn 12 392 44 936Janne 2015 222 OSIMER RCT 60 plusmn 125 38739 95946 09009 5045 29279 62162Johnson 2011 21 DASAERLO Prospective 64 plusmn 112 37333 28222 64444 29444 55444Koizumi 2012 20 Re-GEFIERLO Prospective 61 plusmn 10 15 10 100Kuo 2010 67 BSC-CT Retrospective 64 552 478 85 104Landi 2014 96 AFA Retrospective 62 plusmn 14 35417 3125 65625 26042 33Lee DH 2008 23 ERLO Prospective 56 plusmn 8 17391 95652 0Lee 2014 68 Re-GEFIERLO Retrospective 20588 16176 95588 54 46Oh 2012 23 Re-GEFIERLO Prospective 65 plusmn 85 13043 86957 95652 43478Otsuka 2015 24 GEFIERLO + Bevacumab Retrospective 64 plusmn 8 25 29167 100 20833 66667Sequist 2015 63 ROCILE Prospective 60 27 57 32 100Sim 2009 16 ERLO Retrospective 53 plusmn 13 0 0 100 0Vasile 2008 8 ERLO Prospective 70 plusmn 8 50 125 75 0Wong 2008 14 ERLO Retrospective 56 plusmn 82 28571 71429 71429 71429Yoshimura 2013 27 GEFIERLO - Pemetrexed Prospective 67 plusmn 9 22222 96296 37037 5185 40741Yu 2015 42 GEFIERLO - Pemetrexed Prospective 62 plusmn 135 28571 97619 2381Zhao 2014 51 Re-GEFIERLO Retrospective 623 plusmn 11 503 28333 88667Abbreviations AFA Afatinib BSC Best supportive care CT Chemotherapy DASA Dasatinib ERLO Erlotinib GEFI Gefitinib ICO Icotinib OSIMER Osimertinib

Therapies for advanced lung cancer with acquired resistance

3

Figure S1 Forest graph showing the overall and subgroup-wise effect sizes of the partial remission rate () in the study population

Therapies for advanced lung cancer with acquired resistance

4

Figure S2 Forest graph showing the overall and subgroup-wise effect sizes of the stable disease rate () in the study population

Therapies for advanced lung cancer with acquired resistance

5

Figure S3 Forest graph showing the overall and subgroup-wise effect sizes of the disease control rate () in the study population

Therapies for advanced lung cancer with acquired resistance

17830 Int J Clin Exp Med 20169(9)17822-17831

relapsed non-small cell lung cancer clinical benefit with optimal patient selection Lung Cancer 2011 74 268-273

[26] Janne PA Yang JC Kim DW Planchard D Ohe Y Ramalingam SS Ahn MJ Kim SW Su WC Horn L Haggstrom D Felip E Kim JH Frewer P Cantarini M Brown KH Dickinson PA Ghiorghiu S and Ranson M AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer N Engl J Med 2015 372 1689-1699

[27] Johnson ML Riely GJ Rizvi NA Azzoli CG Kris MG Sima CS Ginsberg MS Pao W and Miller VA Phase II trial of dasatinib for patients with acquired resistance to treatment with the epi-dermal growth factor receptor tyrosine kinase inhibitors erlotinib or gefitinib J Thorac Oncol 2011 6 1128-1131

[28] Koizumi T Agatsuma T Ikegami K Suzuki T Kobayashi T Kanda S Yoshikawa S Kubo K Shiina T Takasuna K Matsuo A Hayasaka M Morikawa M and Ameshima S Prospective study of gefitinib readministration after che-motherapy in patients with advanced non-small-cell lung cancer who previously respond-ed to gefitinib Clin Lung Cancer 2012 13 458-463

[29] Kuo CH Lin SM Lee KY Chung FT Hsieh MH Fang YF Yu CT and Kuo HP Subsequent che-motherapy improves survival outcome in ad-vanced non-small-cell lung cancer with ac-quired tyrosine kinase inhibitor resistance Clin Lung Cancer 2010 11 51-56

[30] Landi L Tiseo M Chiari R Ricciardi S Rossi E Galetta D Novello S Milella M DrsquoIncecco A Minuti G Tibaldi C Salvini J Facchinetti F Haspinger ER Cortinovis D Santo A Banna G Catino A GiajLevra M Crino L de Marinis F and Cappuzzo F Activity of the EGFR-HER2 dual inhibitor afatinib in EGFR-mutant lung cancer patients with acquired resistance to re-versible EGFR tyrosine kinase inhibitors Clin Lung Cancer 2014 15 411-417 e414

[31] Lee Y Kim HY Lee SH Lim KY Lee GK Yun T Han JY Kim HT and Lee JS Clinical signifi-cance of heterogeneity in response to retreat-ment with epidermal growth factor receptor ty-rosine kinase inhibitors in patients with lung cancer acquiring secondary resistance to the drug Clin Lung Cancer 2014 15 145-151

[32] Lee DH Kim SW Suh C Yoon DH Yi EJ and Lee JS Phase II study of erlotinib as a salvage treatment for non-small-cell lung cancer pa-tients after failure of gefitinib treatment Ann Oncol 2008 19 2039-2042

[33] Oh IJ Ban HJ Kim KS and Kim YC Retreatment of gefitinib in patients with non-small-cell lung cancer who previously controlled to gefitinib a single-arm open-label phase II study Lung Cancer 2012 77 121-127

[34] Otsuka K Hata A Takeshita J Okuda C Kaji R Masago K Fujita S and Katakami N EGFR-TKI rechallenge with bevacizumab in EGFR-mutant non-small cell lung cancer Cancer Chemother Pharmacol 2015 76 835-841

[35] Sequist LV Rolfe L and Allen AR Rociletinib in EGFR-Mutated Non-Small-Cell Lung Cancer N Engl J Med 2015 373 578-579

[36] Sim SH Han SW Oh DY Lee SH Kim DW Im SA Chung DH Kim TY Lee JS Kim YW Heo DS and Bang YJ Erlotinib after Gefitinib failure in female never-smoker Asian patients with pul-monary adenocarcinoma Lung Cancer 2009 65 204-207

[37] Vasile E Tibaldi C Chella A and Falcone A Erlotinib after failure of gefitinib in patients with advanced non-small cell lung cancer pre-viously responding to gefitinib J Thorac Oncol 2008 3 912-914

[38] Wong AS Soong R Seah SB Lim SW Chuah KL Nga ME Chin TM and Soo RA Evidence for disease control with erlotinib after gefitinib failure in typical gefitinib-sensitive Asian pa-tients with non-small cell lung cancer J Thorac Oncol 2008 3 400-404

[39] Yoshimura N Okishio K Mitsuoka S Kimura T Kawaguchi T Kobayashi M Hirashima T Daga H Takeda K Hirata K and Kudoh S Prospective assessment of continuation of erlotinib or gefi-tinib in patients with acquired resistance to erlotinib or gefitinib followed by the addition of pemetrexed J Thorac Oncol 2013 8 96-101

[40] Yu S Zhang B Xiang C Shu Y Wu H Huang X Yu Q Yin Y and Guo R Prospective assessment of pemetrexed or pemetrexed plus platinum in combination with gefitinib or erlotinib in pa-tients with acquired resistance to gefitinib or erlotinib a phase II exploratory and prelimi-nary study Clin Lung Cancer 2015 16 121-127

[41] Zhao ZR Wang JF Lin YB Wang F Fu S Zhang SL Su XD Jiang L Zhang YG Shao JY and Long H Mutation abundance affects the efficacy of EGFR tyrosine kinase inhibitor readministra-tion in non-small-cell lung cancer with acquired resistance Med Oncol 2014 31 810

[42] Sandler A Gray R Perry MC Brahmer J Schiller JH Dowlati A Lilenbaum R and John- son DH Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer N Engl J Med 2006 355 2542-2550

[43] Shepherd FA Dancey J Ramlau R Mattson K Gralla R OrsquoRourke M Levitan N Gressot L Vincent M Burkes R Coughlin S Kim Y and Berille J Prospective randomized trial of do- cetaxel versus best supportive care in pa- tients with non-small-cell lung cancer previ-ously treated with platinum-based chemother-apy J Clin Oncol 2000 18 2095-2103

Therapies for advanced lung cancer with acquired resistance

17831 Int J Clin Exp Med 20169(9)17822-17831

[44] Hanna N Shepherd FA Fossella FV Pereira JR De Marinis F von Pawel J Gatzemeier U Tsao TC Pless M Muller T Lim HL Desch C Szondy K Gervais R Shaharyar Manegold C Paul S Paoletti P Einhorn L and Bunn PA Jr Randomized phase III trial of pemetrexed ver-sus docetaxel in patients with non-small-cell lung cancer previously treated with chemo-therapy J Clin Oncol 2004 22 1589-1597

[45] Nishino K Imamura F Morita S Mori M Komuta K Kijima T Namba Y Kumagai T Yamamoto S Tachibana I Nakazawa Y Uchi- da J Minami S Takahashi R Yano Y Okuyama T and Kumanogoh A A retrospective analysis of 335 Japanese lung cancer patients who re-sponded to initial gefitinib treatment Lung Cancer 2013 82 299-304

[46] Uramoto H and Mitsudomi T Which biomarker predicts benefit from EGFR-TKI treatment for patients with lung cancer Br J Cancer 2007 96 857-863

[47] Sequist LV Bell DW Lynch TJ and Haber DA Molecular predictors of response to epidermal growth factor receptor antagonists in non-small-cell lung cancer J Clin Oncol 2007 25 587-595

[48] Lynch TJ Bell DW Sordella R Gurubhagavatula S Okimoto RA Brannigan BW Harris PL Haserlat SM Supko JG Haluska FG Louis DN Christiani DC Settleman J and Haber DA Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib N Engl J Med 2004 350 2129-2139

[49] Shigematsu H Lin L Takahashi T Nomura M Suzuki M Wistuba II Fong KM Lee H Toyooka S Shimizu N Fujisawa T Feng Z Roth JA Herz J Minna JD and Gazdar AF Clinical and bio-logical features associated with epidermal growth factor receptor gene mutations in lung cancers J Natl Cancer Inst 2005 97 339-346

[50] Engelman JA Zejnullahu K Mitsudomi T Song Y Hyland C Park JO Lindeman N Gale CM Zhao X Christensen J Kosaka T Holmes AJ Rogers AM Cappuzzo F Mok T Lee C Johnson BE Cantley LC and Janne PA MET amplifica-tion leads to gefitinib resistance in lung cancer by activating ERBB3 signaling Science 2007 316 1039-1043

[51] Bean J Brennan C Shih JY Riely G Viale A Wang L Chitale D Motoi N Szoke J Broderick S Balak M Chang WC Yu CJ Gazdar A Pass H Rusch V Gerald W Huang SF Yang PC Miller V Ladanyi M Yang CH and Pao W MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib Proc Natl Acad Sci U S A 2007 104 20932-20937

[52] Di Renzo MF Olivero M Ferro S Prat M Bongarzone I Pilotti S Belfiore A Costantino A Vigneri R Pierotti MA et al Overexpression of the c-METHGF receptor gene in human thy-roid carcinomas Oncogene 1992 7 2549-2553

[53] Masuya D Huang C Liu D Nakashima T Kameyama K Haba R Ueno M and Yokomise H The tumour-stromal interaction between in-tratumoral c-Met and stromal hepatocyte growth factor associated with tumour growth and prognosis in non-small-cell lung cancer pa-tients Br J Cancer 2004 90 1555-1562

[54] Chmielecki J Foo J Oxnard GR Hutchinson K Ohashi K Somwar R Wang L Amato KR Arcila M Sos ML Socci ND Viale A de Stanchina E Ginsberg MS Thomas RK Kris MG Inoue A Ladanyi M Miller VA Michor F and Pao W Optimization of dosing for EGFR-mutant non-small cell lung cancer with evolutionary cancer modeling Sci Transl Med 2011 3 90ra59

[55] Oxnard GR Arcila ME Chmielecki J Ladanyi M Miller VA and Pao W New strategies in over-coming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibi-tors in lung cancer Clin Cancer Res 2011 17 5530-5537

[56] Sequist LV Waltman BA Dias-Santagata D Digumarthy S Turke AB Fidias P Bergethon K Shaw AT Gettinger S Cosper AK Akhavanfard S Heist RS Temel J Christensen JG Wain JC Lynch TJ Vernovsky K Mark EJ Lanuti M Iafrate AJ Mino-Kenudson M and Engelman JA Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibi-tors Sci Transl Med 2011 3 75ra26

[57] Hata A Katakami N Kaji R Fujita S and Imai Y Does T790M disappear Successful gefitinib rechallenge after T790M disappearance in a patient with EGFR-mutant non-small-cell lung cancer J Thorac Oncol 2013 8 e27-29

[58] Cetin K Ettinger DS Hei YJ and OrsquoMalley CD Survival by histologic subtype in stage IV nons-mall cell lung cancer based on data from the Surveillance Epidemiology and End Results Program Clin Epidemiol 2011 3 139-148

Therapies for advanced lung cancer with acquired resistance

1

Table S1 Criteria of the studies

Study [Ref]Criteria

1 2 3 4 5 6 7 8 9 10 11 12 13 14Asahina 2010 [20] Y Y Y Y N N NA N Y NA Y N Y N

Chen 2015 [21] Y Y Y Y N N NA N Y NA Y N Y N

Cho 2007 [22] Y Y Y Y Y N NA N Y NA Y N Y N

Costa 2008 [23] Y Y Y Y N N NA N Y NA Y N Y N

Goldberg 2013 [24] Y Y Y Y N N NA N Y NA Y N Y N

Hata 2011 [25] Y Y Y Y N N NA N Y NA Y N Y N

Janne 2015 [26] Y Y Y Y N N NA Y Y NA Y N Y Y

Johnson 2011 [27] Y Y Y Y N N NA N Y NA Y N Y N

Koizumi 2012 [28] Y Y Y Y Y N NA N Y NA Y N Y N

Kuo 2010 [29] Y Y Y Y N N NA N Y NA Y N Y N

Landi 2014 [30] Y Y Y Y N N NA N Y NA Y N Y N

Lee DH 2008 [31] Y Y Y Y Y N NA N Y NA Y N Y N

Lee 2014 [32] Y Y Y Y N N NA N Y NA Y N Y Y

Oh 2012 [33] Y Y Y Y Y N NA N Y NA Y N Y N

Otsuka 2015 [34] Y Y Y Y N N NA N Y NA Y N Y N

Sequist 2015 [35] Y Y Y Y N N NA N Y NA Y N Y Y

Sim 2009 [36] Y Y Y Y N N NA N Y NA Y N Y N

Vasile 2008 [37] Y Y Y Y N N NA N Y NA Y N Y N

Wong 2008 [38] Y Y Y Y N N NA N Y NA Y N Y N

Yoshimura 2013 [39] Y Y Y Y Y N NA N Y NA Y N Y N

Yu 2015 [40] Y Y Y Y N N NA N Y NA Y N Y N

Zhao 2014 [41] Y Y Y Y N N NA N Y NA Y N Y NCriteria1 Was the research question or objective in this paper clearly stated2 Was the study population clearly specified and defined3 Was the participation rate of eligible persons at least 504 Were all the subjects selected or recruited from the same or similar populations (including the same time period) Were inclusion and exclusion criteria pre-specified and applied uniformly to all participants5 Was a sample size justification power description or variance and effect estimates provided6 For the analyses were the exposure(s) of interest measured prior to the outcome(s) being measured7 Was the timeframe sufficient to reasonably expect to see an association between exposure and outcome8 For exposures that can vary in amount or level did the study examine different levels of the exposure as related to the outcome (eg categories of exposure or exposure measured as continuous variable)9 Were the exposure measures (independent variables) clearly defined valid reliable and implemented consistently across all study participants10 Was the exposure(s) assessed more than once over time11 Were the outcome measures (dependent variables) clearly defined valid reliable and implemented consistently across all study participants12 Were the outcome assessors blinded to the exposure status of participants13 Was loss to follow-up after baseline 20 or less14 Were key potential confounding variables measured and adjusted statistically for their impact on the relationship between exposure(s) and outcome(s)

Therapies for advanced lung cancer with acquired resistance

2

Table S2 Characteristics of the included studies

Study n Treatment Design Age males Smokers Adeno-carcinoma Squamous CC

Exon 19 deletion

Exon 21 L858R T790M

Asahina 2010 16 Re-GEFIERLO Prospective 665 plusmn 7 1875 3125 875 625Chen 2015 55 Re-GEFIERLOICO Prospective 55 plusmn 115 41818 80 96364 36364 41818 36364Cho 2007 21 ERLO Prospective 56 plusmn 85 47619 47619 71429 14286Costa 2008 18 ERLO Retrospective 63 plusmn 9 22222 27778 88889 0 72222 22222Goldberg 2013 74 ERLO-CT Retrospective 58 plusmn 13 17647 29412 58824 32353Hata 2011 125 ERLO Retrospective 64 plusmn 12 392 44 936Janne 2015 222 OSIMER RCT 60 plusmn 125 38739 95946 09009 5045 29279 62162Johnson 2011 21 DASAERLO Prospective 64 plusmn 112 37333 28222 64444 29444 55444Koizumi 2012 20 Re-GEFIERLO Prospective 61 plusmn 10 15 10 100Kuo 2010 67 BSC-CT Retrospective 64 552 478 85 104Landi 2014 96 AFA Retrospective 62 plusmn 14 35417 3125 65625 26042 33Lee DH 2008 23 ERLO Prospective 56 plusmn 8 17391 95652 0Lee 2014 68 Re-GEFIERLO Retrospective 20588 16176 95588 54 46Oh 2012 23 Re-GEFIERLO Prospective 65 plusmn 85 13043 86957 95652 43478Otsuka 2015 24 GEFIERLO + Bevacumab Retrospective 64 plusmn 8 25 29167 100 20833 66667Sequist 2015 63 ROCILE Prospective 60 27 57 32 100Sim 2009 16 ERLO Retrospective 53 plusmn 13 0 0 100 0Vasile 2008 8 ERLO Prospective 70 plusmn 8 50 125 75 0Wong 2008 14 ERLO Retrospective 56 plusmn 82 28571 71429 71429 71429Yoshimura 2013 27 GEFIERLO - Pemetrexed Prospective 67 plusmn 9 22222 96296 37037 5185 40741Yu 2015 42 GEFIERLO - Pemetrexed Prospective 62 plusmn 135 28571 97619 2381Zhao 2014 51 Re-GEFIERLO Retrospective 623 plusmn 11 503 28333 88667Abbreviations AFA Afatinib BSC Best supportive care CT Chemotherapy DASA Dasatinib ERLO Erlotinib GEFI Gefitinib ICO Icotinib OSIMER Osimertinib

Therapies for advanced lung cancer with acquired resistance

3

Figure S1 Forest graph showing the overall and subgroup-wise effect sizes of the partial remission rate () in the study population

Therapies for advanced lung cancer with acquired resistance

4

Figure S2 Forest graph showing the overall and subgroup-wise effect sizes of the stable disease rate () in the study population

Therapies for advanced lung cancer with acquired resistance

5

Figure S3 Forest graph showing the overall and subgroup-wise effect sizes of the disease control rate () in the study population

Therapies for advanced lung cancer with acquired resistance

17831 Int J Clin Exp Med 20169(9)17822-17831

[44] Hanna N Shepherd FA Fossella FV Pereira JR De Marinis F von Pawel J Gatzemeier U Tsao TC Pless M Muller T Lim HL Desch C Szondy K Gervais R Shaharyar Manegold C Paul S Paoletti P Einhorn L and Bunn PA Jr Randomized phase III trial of pemetrexed ver-sus docetaxel in patients with non-small-cell lung cancer previously treated with chemo-therapy J Clin Oncol 2004 22 1589-1597

[45] Nishino K Imamura F Morita S Mori M Komuta K Kijima T Namba Y Kumagai T Yamamoto S Tachibana I Nakazawa Y Uchi- da J Minami S Takahashi R Yano Y Okuyama T and Kumanogoh A A retrospective analysis of 335 Japanese lung cancer patients who re-sponded to initial gefitinib treatment Lung Cancer 2013 82 299-304

[46] Uramoto H and Mitsudomi T Which biomarker predicts benefit from EGFR-TKI treatment for patients with lung cancer Br J Cancer 2007 96 857-863

[47] Sequist LV Bell DW Lynch TJ and Haber DA Molecular predictors of response to epidermal growth factor receptor antagonists in non-small-cell lung cancer J Clin Oncol 2007 25 587-595

[48] Lynch TJ Bell DW Sordella R Gurubhagavatula S Okimoto RA Brannigan BW Harris PL Haserlat SM Supko JG Haluska FG Louis DN Christiani DC Settleman J and Haber DA Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib N Engl J Med 2004 350 2129-2139

[49] Shigematsu H Lin L Takahashi T Nomura M Suzuki M Wistuba II Fong KM Lee H Toyooka S Shimizu N Fujisawa T Feng Z Roth JA Herz J Minna JD and Gazdar AF Clinical and bio-logical features associated with epidermal growth factor receptor gene mutations in lung cancers J Natl Cancer Inst 2005 97 339-346

[50] Engelman JA Zejnullahu K Mitsudomi T Song Y Hyland C Park JO Lindeman N Gale CM Zhao X Christensen J Kosaka T Holmes AJ Rogers AM Cappuzzo F Mok T Lee C Johnson BE Cantley LC and Janne PA MET amplifica-tion leads to gefitinib resistance in lung cancer by activating ERBB3 signaling Science 2007 316 1039-1043

[51] Bean J Brennan C Shih JY Riely G Viale A Wang L Chitale D Motoi N Szoke J Broderick S Balak M Chang WC Yu CJ Gazdar A Pass H Rusch V Gerald W Huang SF Yang PC Miller V Ladanyi M Yang CH and Pao W MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib Proc Natl Acad Sci U S A 2007 104 20932-20937

[52] Di Renzo MF Olivero M Ferro S Prat M Bongarzone I Pilotti S Belfiore A Costantino A Vigneri R Pierotti MA et al Overexpression of the c-METHGF receptor gene in human thy-roid carcinomas Oncogene 1992 7 2549-2553

[53] Masuya D Huang C Liu D Nakashima T Kameyama K Haba R Ueno M and Yokomise H The tumour-stromal interaction between in-tratumoral c-Met and stromal hepatocyte growth factor associated with tumour growth and prognosis in non-small-cell lung cancer pa-tients Br J Cancer 2004 90 1555-1562

[54] Chmielecki J Foo J Oxnard GR Hutchinson K Ohashi K Somwar R Wang L Amato KR Arcila M Sos ML Socci ND Viale A de Stanchina E Ginsberg MS Thomas RK Kris MG Inoue A Ladanyi M Miller VA Michor F and Pao W Optimization of dosing for EGFR-mutant non-small cell lung cancer with evolutionary cancer modeling Sci Transl Med 2011 3 90ra59

[55] Oxnard GR Arcila ME Chmielecki J Ladanyi M Miller VA and Pao W New strategies in over-coming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibi-tors in lung cancer Clin Cancer Res 2011 17 5530-5537

[56] Sequist LV Waltman BA Dias-Santagata D Digumarthy S Turke AB Fidias P Bergethon K Shaw AT Gettinger S Cosper AK Akhavanfard S Heist RS Temel J Christensen JG Wain JC Lynch TJ Vernovsky K Mark EJ Lanuti M Iafrate AJ Mino-Kenudson M and Engelman JA Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibi-tors Sci Transl Med 2011 3 75ra26

[57] Hata A Katakami N Kaji R Fujita S and Imai Y Does T790M disappear Successful gefitinib rechallenge after T790M disappearance in a patient with EGFR-mutant non-small-cell lung cancer J Thorac Oncol 2013 8 e27-29

[58] Cetin K Ettinger DS Hei YJ and OrsquoMalley CD Survival by histologic subtype in stage IV nons-mall cell lung cancer based on data from the Surveillance Epidemiology and End Results Program Clin Epidemiol 2011 3 139-148

Therapies for advanced lung cancer with acquired resistance

1

Table S1 Criteria of the studies

Study [Ref]Criteria

1 2 3 4 5 6 7 8 9 10 11 12 13 14Asahina 2010 [20] Y Y Y Y N N NA N Y NA Y N Y N

Chen 2015 [21] Y Y Y Y N N NA N Y NA Y N Y N

Cho 2007 [22] Y Y Y Y Y N NA N Y NA Y N Y N

Costa 2008 [23] Y Y Y Y N N NA N Y NA Y N Y N

Goldberg 2013 [24] Y Y Y Y N N NA N Y NA Y N Y N

Hata 2011 [25] Y Y Y Y N N NA N Y NA Y N Y N

Janne 2015 [26] Y Y Y Y N N NA Y Y NA Y N Y Y

Johnson 2011 [27] Y Y Y Y N N NA N Y NA Y N Y N

Koizumi 2012 [28] Y Y Y Y Y N NA N Y NA Y N Y N

Kuo 2010 [29] Y Y Y Y N N NA N Y NA Y N Y N

Landi 2014 [30] Y Y Y Y N N NA N Y NA Y N Y N

Lee DH 2008 [31] Y Y Y Y Y N NA N Y NA Y N Y N

Lee 2014 [32] Y Y Y Y N N NA N Y NA Y N Y Y

Oh 2012 [33] Y Y Y Y Y N NA N Y NA Y N Y N

Otsuka 2015 [34] Y Y Y Y N N NA N Y NA Y N Y N

Sequist 2015 [35] Y Y Y Y N N NA N Y NA Y N Y Y

Sim 2009 [36] Y Y Y Y N N NA N Y NA Y N Y N

Vasile 2008 [37] Y Y Y Y N N NA N Y NA Y N Y N

Wong 2008 [38] Y Y Y Y N N NA N Y NA Y N Y N

Yoshimura 2013 [39] Y Y Y Y Y N NA N Y NA Y N Y N

Yu 2015 [40] Y Y Y Y N N NA N Y NA Y N Y N

Zhao 2014 [41] Y Y Y Y N N NA N Y NA Y N Y NCriteria1 Was the research question or objective in this paper clearly stated2 Was the study population clearly specified and defined3 Was the participation rate of eligible persons at least 504 Were all the subjects selected or recruited from the same or similar populations (including the same time period) Were inclusion and exclusion criteria pre-specified and applied uniformly to all participants5 Was a sample size justification power description or variance and effect estimates provided6 For the analyses were the exposure(s) of interest measured prior to the outcome(s) being measured7 Was the timeframe sufficient to reasonably expect to see an association between exposure and outcome8 For exposures that can vary in amount or level did the study examine different levels of the exposure as related to the outcome (eg categories of exposure or exposure measured as continuous variable)9 Were the exposure measures (independent variables) clearly defined valid reliable and implemented consistently across all study participants10 Was the exposure(s) assessed more than once over time11 Were the outcome measures (dependent variables) clearly defined valid reliable and implemented consistently across all study participants12 Were the outcome assessors blinded to the exposure status of participants13 Was loss to follow-up after baseline 20 or less14 Were key potential confounding variables measured and adjusted statistically for their impact on the relationship between exposure(s) and outcome(s)

Therapies for advanced lung cancer with acquired resistance

2

Table S2 Characteristics of the included studies

Study n Treatment Design Age males Smokers Adeno-carcinoma Squamous CC

Exon 19 deletion

Exon 21 L858R T790M

Asahina 2010 16 Re-GEFIERLO Prospective 665 plusmn 7 1875 3125 875 625Chen 2015 55 Re-GEFIERLOICO Prospective 55 plusmn 115 41818 80 96364 36364 41818 36364Cho 2007 21 ERLO Prospective 56 plusmn 85 47619 47619 71429 14286Costa 2008 18 ERLO Retrospective 63 plusmn 9 22222 27778 88889 0 72222 22222Goldberg 2013 74 ERLO-CT Retrospective 58 plusmn 13 17647 29412 58824 32353Hata 2011 125 ERLO Retrospective 64 plusmn 12 392 44 936Janne 2015 222 OSIMER RCT 60 plusmn 125 38739 95946 09009 5045 29279 62162Johnson 2011 21 DASAERLO Prospective 64 plusmn 112 37333 28222 64444 29444 55444Koizumi 2012 20 Re-GEFIERLO Prospective 61 plusmn 10 15 10 100Kuo 2010 67 BSC-CT Retrospective 64 552 478 85 104Landi 2014 96 AFA Retrospective 62 plusmn 14 35417 3125 65625 26042 33Lee DH 2008 23 ERLO Prospective 56 plusmn 8 17391 95652 0Lee 2014 68 Re-GEFIERLO Retrospective 20588 16176 95588 54 46Oh 2012 23 Re-GEFIERLO Prospective 65 plusmn 85 13043 86957 95652 43478Otsuka 2015 24 GEFIERLO + Bevacumab Retrospective 64 plusmn 8 25 29167 100 20833 66667Sequist 2015 63 ROCILE Prospective 60 27 57 32 100Sim 2009 16 ERLO Retrospective 53 plusmn 13 0 0 100 0Vasile 2008 8 ERLO Prospective 70 plusmn 8 50 125 75 0Wong 2008 14 ERLO Retrospective 56 plusmn 82 28571 71429 71429 71429Yoshimura 2013 27 GEFIERLO - Pemetrexed Prospective 67 plusmn 9 22222 96296 37037 5185 40741Yu 2015 42 GEFIERLO - Pemetrexed Prospective 62 plusmn 135 28571 97619 2381Zhao 2014 51 Re-GEFIERLO Retrospective 623 plusmn 11 503 28333 88667Abbreviations AFA Afatinib BSC Best supportive care CT Chemotherapy DASA Dasatinib ERLO Erlotinib GEFI Gefitinib ICO Icotinib OSIMER Osimertinib

Therapies for advanced lung cancer with acquired resistance

3

Figure S1 Forest graph showing the overall and subgroup-wise effect sizes of the partial remission rate () in the study population

Therapies for advanced lung cancer with acquired resistance

4

Figure S2 Forest graph showing the overall and subgroup-wise effect sizes of the stable disease rate () in the study population

Therapies for advanced lung cancer with acquired resistance

5

Figure S3 Forest graph showing the overall and subgroup-wise effect sizes of the disease control rate () in the study population

Therapies for advanced lung cancer with acquired resistance

1

Table S1 Criteria of the studies

Study [Ref]Criteria

1 2 3 4 5 6 7 8 9 10 11 12 13 14Asahina 2010 [20] Y Y Y Y N N NA N Y NA Y N Y N

Chen 2015 [21] Y Y Y Y N N NA N Y NA Y N Y N

Cho 2007 [22] Y Y Y Y Y N NA N Y NA Y N Y N

Costa 2008 [23] Y Y Y Y N N NA N Y NA Y N Y N

Goldberg 2013 [24] Y Y Y Y N N NA N Y NA Y N Y N

Hata 2011 [25] Y Y Y Y N N NA N Y NA Y N Y N

Janne 2015 [26] Y Y Y Y N N NA Y Y NA Y N Y Y

Johnson 2011 [27] Y Y Y Y N N NA N Y NA Y N Y N

Koizumi 2012 [28] Y Y Y Y Y N NA N Y NA Y N Y N

Kuo 2010 [29] Y Y Y Y N N NA N Y NA Y N Y N

Landi 2014 [30] Y Y Y Y N N NA N Y NA Y N Y N

Lee DH 2008 [31] Y Y Y Y Y N NA N Y NA Y N Y N

Lee 2014 [32] Y Y Y Y N N NA N Y NA Y N Y Y

Oh 2012 [33] Y Y Y Y Y N NA N Y NA Y N Y N

Otsuka 2015 [34] Y Y Y Y N N NA N Y NA Y N Y N

Sequist 2015 [35] Y Y Y Y N N NA N Y NA Y N Y Y

Sim 2009 [36] Y Y Y Y N N NA N Y NA Y N Y N

Vasile 2008 [37] Y Y Y Y N N NA N Y NA Y N Y N

Wong 2008 [38] Y Y Y Y N N NA N Y NA Y N Y N

Yoshimura 2013 [39] Y Y Y Y Y N NA N Y NA Y N Y N

Yu 2015 [40] Y Y Y Y N N NA N Y NA Y N Y N

Zhao 2014 [41] Y Y Y Y N N NA N Y NA Y N Y NCriteria1 Was the research question or objective in this paper clearly stated2 Was the study population clearly specified and defined3 Was the participation rate of eligible persons at least 504 Were all the subjects selected or recruited from the same or similar populations (including the same time period) Were inclusion and exclusion criteria pre-specified and applied uniformly to all participants5 Was a sample size justification power description or variance and effect estimates provided6 For the analyses were the exposure(s) of interest measured prior to the outcome(s) being measured7 Was the timeframe sufficient to reasonably expect to see an association between exposure and outcome8 For exposures that can vary in amount or level did the study examine different levels of the exposure as related to the outcome (eg categories of exposure or exposure measured as continuous variable)9 Were the exposure measures (independent variables) clearly defined valid reliable and implemented consistently across all study participants10 Was the exposure(s) assessed more than once over time11 Were the outcome measures (dependent variables) clearly defined valid reliable and implemented consistently across all study participants12 Were the outcome assessors blinded to the exposure status of participants13 Was loss to follow-up after baseline 20 or less14 Were key potential confounding variables measured and adjusted statistically for their impact on the relationship between exposure(s) and outcome(s)

Therapies for advanced lung cancer with acquired resistance

2

Table S2 Characteristics of the included studies

Study n Treatment Design Age males Smokers Adeno-carcinoma Squamous CC

Exon 19 deletion

Exon 21 L858R T790M

Asahina 2010 16 Re-GEFIERLO Prospective 665 plusmn 7 1875 3125 875 625Chen 2015 55 Re-GEFIERLOICO Prospective 55 plusmn 115 41818 80 96364 36364 41818 36364Cho 2007 21 ERLO Prospective 56 plusmn 85 47619 47619 71429 14286Costa 2008 18 ERLO Retrospective 63 plusmn 9 22222 27778 88889 0 72222 22222Goldberg 2013 74 ERLO-CT Retrospective 58 plusmn 13 17647 29412 58824 32353Hata 2011 125 ERLO Retrospective 64 plusmn 12 392 44 936Janne 2015 222 OSIMER RCT 60 plusmn 125 38739 95946 09009 5045 29279 62162Johnson 2011 21 DASAERLO Prospective 64 plusmn 112 37333 28222 64444 29444 55444Koizumi 2012 20 Re-GEFIERLO Prospective 61 plusmn 10 15 10 100Kuo 2010 67 BSC-CT Retrospective 64 552 478 85 104Landi 2014 96 AFA Retrospective 62 plusmn 14 35417 3125 65625 26042 33Lee DH 2008 23 ERLO Prospective 56 plusmn 8 17391 95652 0Lee 2014 68 Re-GEFIERLO Retrospective 20588 16176 95588 54 46Oh 2012 23 Re-GEFIERLO Prospective 65 plusmn 85 13043 86957 95652 43478Otsuka 2015 24 GEFIERLO + Bevacumab Retrospective 64 plusmn 8 25 29167 100 20833 66667Sequist 2015 63 ROCILE Prospective 60 27 57 32 100Sim 2009 16 ERLO Retrospective 53 plusmn 13 0 0 100 0Vasile 2008 8 ERLO Prospective 70 plusmn 8 50 125 75 0Wong 2008 14 ERLO Retrospective 56 plusmn 82 28571 71429 71429 71429Yoshimura 2013 27 GEFIERLO - Pemetrexed Prospective 67 plusmn 9 22222 96296 37037 5185 40741Yu 2015 42 GEFIERLO - Pemetrexed Prospective 62 plusmn 135 28571 97619 2381Zhao 2014 51 Re-GEFIERLO Retrospective 623 plusmn 11 503 28333 88667Abbreviations AFA Afatinib BSC Best supportive care CT Chemotherapy DASA Dasatinib ERLO Erlotinib GEFI Gefitinib ICO Icotinib OSIMER Osimertinib

Therapies for advanced lung cancer with acquired resistance

3

Figure S1 Forest graph showing the overall and subgroup-wise effect sizes of the partial remission rate () in the study population

Therapies for advanced lung cancer with acquired resistance

4

Figure S2 Forest graph showing the overall and subgroup-wise effect sizes of the stable disease rate () in the study population

Therapies for advanced lung cancer with acquired resistance

5

Figure S3 Forest graph showing the overall and subgroup-wise effect sizes of the disease control rate () in the study population

Therapies for advanced lung cancer with acquired resistance

2

Table S2 Characteristics of the included studies

Study n Treatment Design Age males Smokers Adeno-carcinoma Squamous CC

Exon 19 deletion

Exon 21 L858R T790M

Asahina 2010 16 Re-GEFIERLO Prospective 665 plusmn 7 1875 3125 875 625Chen 2015 55 Re-GEFIERLOICO Prospective 55 plusmn 115 41818 80 96364 36364 41818 36364Cho 2007 21 ERLO Prospective 56 plusmn 85 47619 47619 71429 14286Costa 2008 18 ERLO Retrospective 63 plusmn 9 22222 27778 88889 0 72222 22222Goldberg 2013 74 ERLO-CT Retrospective 58 plusmn 13 17647 29412 58824 32353Hata 2011 125 ERLO Retrospective 64 plusmn 12 392 44 936Janne 2015 222 OSIMER RCT 60 plusmn 125 38739 95946 09009 5045 29279 62162Johnson 2011 21 DASAERLO Prospective 64 plusmn 112 37333 28222 64444 29444 55444Koizumi 2012 20 Re-GEFIERLO Prospective 61 plusmn 10 15 10 100Kuo 2010 67 BSC-CT Retrospective 64 552 478 85 104Landi 2014 96 AFA Retrospective 62 plusmn 14 35417 3125 65625 26042 33Lee DH 2008 23 ERLO Prospective 56 plusmn 8 17391 95652 0Lee 2014 68 Re-GEFIERLO Retrospective 20588 16176 95588 54 46Oh 2012 23 Re-GEFIERLO Prospective 65 plusmn 85 13043 86957 95652 43478Otsuka 2015 24 GEFIERLO + Bevacumab Retrospective 64 plusmn 8 25 29167 100 20833 66667Sequist 2015 63 ROCILE Prospective 60 27 57 32 100Sim 2009 16 ERLO Retrospective 53 plusmn 13 0 0 100 0Vasile 2008 8 ERLO Prospective 70 plusmn 8 50 125 75 0Wong 2008 14 ERLO Retrospective 56 plusmn 82 28571 71429 71429 71429Yoshimura 2013 27 GEFIERLO - Pemetrexed Prospective 67 plusmn 9 22222 96296 37037 5185 40741Yu 2015 42 GEFIERLO - Pemetrexed Prospective 62 plusmn 135 28571 97619 2381Zhao 2014 51 Re-GEFIERLO Retrospective 623 plusmn 11 503 28333 88667Abbreviations AFA Afatinib BSC Best supportive care CT Chemotherapy DASA Dasatinib ERLO Erlotinib GEFI Gefitinib ICO Icotinib OSIMER Osimertinib

Therapies for advanced lung cancer with acquired resistance

3

Figure S1 Forest graph showing the overall and subgroup-wise effect sizes of the partial remission rate () in the study population

Therapies for advanced lung cancer with acquired resistance

4

Figure S2 Forest graph showing the overall and subgroup-wise effect sizes of the stable disease rate () in the study population

Therapies for advanced lung cancer with acquired resistance

5

Figure S3 Forest graph showing the overall and subgroup-wise effect sizes of the disease control rate () in the study population

Therapies for advanced lung cancer with acquired resistance

3

Figure S1 Forest graph showing the overall and subgroup-wise effect sizes of the partial remission rate () in the study population

Therapies for advanced lung cancer with acquired resistance

4

Figure S2 Forest graph showing the overall and subgroup-wise effect sizes of the stable disease rate () in the study population

Therapies for advanced lung cancer with acquired resistance

5

Figure S3 Forest graph showing the overall and subgroup-wise effect sizes of the disease control rate () in the study population

Therapies for advanced lung cancer with acquired resistance

4

Figure S2 Forest graph showing the overall and subgroup-wise effect sizes of the stable disease rate () in the study population

Therapies for advanced lung cancer with acquired resistance

5

Figure S3 Forest graph showing the overall and subgroup-wise effect sizes of the disease control rate () in the study population

Therapies for advanced lung cancer with acquired resistance

5

Figure S3 Forest graph showing the overall and subgroup-wise effect sizes of the disease control rate () in the study population