Comparative survival analysis of the treatment options for TKI resistant advanced non-small cell ...

Int J Clin Exp Med 2016;9(9):17822-17831 www.ijcem.com /ISSN:1940-5901/IJCEM0033064

Original Article Comparative 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 eligibility 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 patients’ data) were used in this meta-analysis. Two major mutations, exon 19 deletion and exon 21 L858R, were found in 54.4 ± 15.7% and 35.4 ± 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 4.28 [95% CI: 3.09, 5.46] months after any treatment. In the EGFR-TKI resistant NSCLC patients, overall survival after any treatment was 12.24 [10.38, 14.09] months. Partial response rate, stable disease rate, and disease control rate to any therapy in the present study were 28.52 [20.58, 36.47]%, 33.88 [26.09, 41.68]% and 59 [47.14, 70.85]%, respectively. With approximately 60% disease control rate, overall chemotherapeutic interventions to advanced NSCLC patients with acquired mutations is associated with 4.3 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 resistance, mutation, survival

Introduction Lung cancer is the leading cause of cancerrelated mortality that accounts for approximately 27% of deaths due to cancer [1] with nearly 1.4-1.6 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-superior in efficacy over chemotherapy and therefore are the mainstay treatment for NSCLC with EGFR mutations [4, 5]. Activating muta-

tions in the tyrosine kinase domain of EGFR (deletion in exon 19/L858R substitution in exon 21 etc) are the main determinants of the response to EGFR-TKI therapy which significantly improves the overall response rate and progression-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 control 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 discovered for the development of acquired resistance to EGFR-TKIs, of which T790M missense

Therapies for advanced lung cancer with acquired resistance mutation leading to the incorporation of methionine instead of threonine in the ATP binding site causing a conformational change, mesenchymal-epithelial transition factor (MET) protooncogene amplification, and changes in histological 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 (6.67 versus 4.7 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 effective treatment for NSCLC patients upon development 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 Systematic reviews and Meta-Analysis (PRSIMA) guidelines [19]. Literature search strategy A comprehensive search strategy was adapted in order to acquire the relevant research articles from different electronic databases including PubMed/Medline, Embase, OVID SP, Google Scholar, and ClinicalTrials.gov. Important keywords and MeSH terms used for the literature search were: Non-small cell lung cancer (NSCLC), epidermal growth factor receptor

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(EGFR) tyrosine kinase inhibitor (TKI), acquired resistance, gefitinib, erlotinib, dasatinib, afatinib, rociletinib, osimertinib, chemotherapy, treatment, therapy, mutation, survival, remission, response rate, and disease control. These key terms were used in different logical combinations. Same search strategy was used for each database. Identified title and abstracts were reviewed by 3 authors (a, b, c) independently to screen for articles that met eligibility criteria. The search was restricted to research articles published before April 2016 in English language. Additional research articles 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 advanced NSCLC patients with acquired resistance to a EGFR-TKI drug. Studies were excluded if involved: a) cell culture or physiological evaluations, b) genetic techniques, c) case reports, and d) those which did not report efficacy and/ or 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 remission (PR) rate, stable disease (SD) rate, response rate (RR) and disease control rate (DCR). Data and analyses Information regarding the study endpoints and outcomes, type and dosage of the drug/s, and clinical/pathological/demographic characteristics were obtained from identified research articles and organized in datasheets. To achieve 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 effect 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,

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Figure 1. A flowchart of the study screening and selection process.

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 including the number of patients in a study, age, gender, smoking, histological type (percent patients with adenocarcinoma/squamous cell carcinoma), and mutation (percent patients with exon 19 deletion/exon 21 L858R). Restricted maximum likelihood method was used for the metaregression analyses. Between-study variance was tested with tau2 and the percentage of between-study heterogeneity was assessed with I-squared (I2) index. A p value of less than 0.1 was considered to show a significant relationship.

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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 assessment of publication bias, Begg’s funnel plot and Egger’s 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 patients’ data were used for the meta-

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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.

analyses. These studies were either retrospective or prospective in design. The quality of these studies was adequate (Table S1). A significant publication bias was identified upon assessment with funnel plot asymmetry and trim and fill method (Figure 2A-D). Important characteristics of the included studies are presented in Table S2. Average age (mean ± standard deviation) of the patients was 61.32 ± 10.2 years and 31 ± 14% of the patients were female. Patients who ever smoked constituted 26 ± 18% of this population. Histologically, 90.6 ± 9.2% of the patients had adenocarcinoma and 4 ± 4% harboured squamous cell carcinoma. Two major mutants (exon 19 deletion and exon 21 L858R) prevailed in 54.4 ± 15.7% and 35.4 ± 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, overall PFS with 95% confidence interval (CI) was 4.28 [3.09, 5.46] months after the treatment.

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Treatment with EGFR-TKI in combination with chemotherapy was associated with maximum PFS (5.35 [3.18, 7.51] months) followed by the treatment with an alternative EGFR-TKI alone (4.22 [2.51, 5.93] months and retreatment with the same EGFR-TKI (3.86 [2.27, 5.44] months (Figure 3). In the EGFR-TKI resistant NSCLC patients, overall survival after any treatment was 12.24 [10.38, 14.09] months (Figure 4). There were no statistically significant differences between the subgroups in progressionfree survival or overall survival (Figures 3, 4). Partial response rate, stable disease rate, and disease control rate to any therapy in the present study were 28.52 [20.58, 36.47]%, 33.88 [26.09, 41.68]% and 59 [47.14, 70.85]%, respectively. Subgroup meta-analyses of these variables are presented in Figures S1, S2, S3. In the metaregression analyses, only the percentage of patients with adenocarcinoma was significantly inversely associated with the overall survival (coefficient: -339 [-0.717, 0.04]; P=0.074). None of any other independent vari-

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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 ± represents T790M mutation positive/negative patient groups.

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 effective treatment for NSCLC patients with acquired resistance to EGFR-TKI, as observed in the present meta-analysis, any regimen including 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 4.3 months of progression-free survival with no statistically significant between group differences. Addition of the bevacizumab (vascular endothelial growth factor monoclonal antibody) to palliative platinum-based chemotherapy achi17826

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 secondline therapies such as docetaxel or pemetrexed, 2-year survival is achieved in a very few patients [43, 44]. Introduction of EGFR-TKIs such as gefitinib and erlotinib improved the outcomes when compared to conventional platinum-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 anticancer 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 adenocarcinoma patients with mutations in the Int J Clin Exp Med 2016;9(9):17822-17831

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

EGFR gene exhibit a partial response upon EGFR-TKI such as erlotinib or gefitinib treatment [6]. In addition to T790M mutation [10, 11], resistance to TKIs has also been shown to manifest through MET which is a transmembrane receptor that binds to the ligand hepatocyte growth factor/scatter factor (HGF) with high affinity. Interaction of MET with avian v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (ERBB3) causes sustained activation of the phosphatidylinositol 3’-kinase-serine/threonine kinase Akt (PI3K/AKT) signalling pathway bypassing EGFR inhibition. The MET amplification has been reported to be a mechanism of EGFR-TKI resistance in 22% of cases independent of T790M status [50-52] and abnormal MET activation is associated with poor NSCLC prognosis [53]. Based on the indolent nature of T790M-positive cells and rapid growth potential of T790M17827

negative cells [54, 55], it is postulated that EGFR-TKI-free interval can repopulate T790Mnegative cells because of the withdrawal of the mutagenic pressure resulting in more cells to respond to EGFR-TKI re-challenge [34]. Although negative T790M status of the tumour cells is considered predictive of EGFR-TKI rechallenge [56, 57], in the present metaregression analyses, T790M prevalence data were inadequate to study this phenomenon and an attempt with 6 studies data revealed no significant association between percentage of patients with T790M mutations and PFS. Nevertheless, 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 relationship between the incidence of adenocarcinoma and overall survival is observed. Better survival is reported in patients with bronchioalveolar adenocarcinoma than in patients with large cell tumours [58]. Since approximately

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Therapies for advanced lung cancer with acquired resistance 90% of patients included in this meta-analysis had adenocarcinoma, more data will be required 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 1.5 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 survival was analysed. Thus, it will be necessary to have some more well-designed studies before using combinational treatments as such regimens 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.

[2]

[3] [4]

Conclusion With approximately 60% disease control rate, overall chemotherapeutic interventions to advanced NSCLC patients with acquired resistance is associated with less than 5 months of progression-free survival and approximately 1 year of overall survival. Partial response rate and stable disease rate are found to be 28.52 [20.58, 36.47]% and 33.88 [26.09, 41.68]%, respectively. Acknowledgements

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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 Natural Science Foundation of Jilin Province (No. 20150101151JC). Disclosure of conflict of interest

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None. Address correspondence to: Ke Wang, Department of Respiratory Medicine, The Second Affiliated Hospital of Jilin University, No. 218 Ziqiang Street, Nanguan District, Changchun 130041, Jilin, China. E-mail: [email protected]

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Therapies for advanced lung cancer with acquired resistance [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 versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. 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, Uchida J, Minami S, Takahashi R, Yano Y, Okuyama T and Kumanogoh A. A retrospective analysis of 335 Japanese lung cancer patients who responded 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 nonsmall-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 biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 2005; 97: 339346. [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 amplification 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: 2093220937.

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Therapies for advanced lung cancer with acquired resistance Table S1. Criteria of the studies Study [Ref.]

Criteria* 1

2

3

4

5

6

7

8

9

10

11

12

13

14

Asahina 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

N

*Criteria 1. Was the research question or objective in this paper clearly stated? 2. Was the study population clearly specified and defined? 3. Was the participation rate of eligible persons at least 50%? 4. 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 participants? 5. Was a sample size justification, power description, or variance and effect estimates provided? 6. For the analyses, were the exposure(s) of interest measured prior to the outcome(s) being measured? 7. Was the timeframe sufficient to reasonably expect to see an association between exposure and outcome? 8. For exposures that can vary in amount or level, did the study examine different levels of the exposure as related to the outcome (e.g., 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 participants? 10. Was the exposure(s) assessed more than once over time? 11. Were the outcome measures (dependent variables) clearly defined, valid, reliable, and implemented consistently across all study participants? 12. Were the outcome assessors blinded to the exposure status of participants? 13. Was loss to follow-up after baseline 20% or less? 14. Were key potential confounding variables measured and adjusted statistically for their impact on the relationship between exposure(s) and outcome(s)?

1

Therapies for advanced lung cancer with acquired resistance Table S2. Characteristics of the included studies Study

n

Treatment

Design

Age

% males

% Smokers

% Adeno-carcinoma

% Squamous % Exon 19 % Exon 21 % T790M CC deletion L858R

Asahina 2010

16

Re-GEFI/ERLO

Prospective

66.5 ± 7

18.75

31.25

87.5

6.25

Chen 2015

55

Re-GEFI/ERLO/ICO

Prospective

55 ± 11.5

41.818

80

96.364

3.6364

Cho 2007

21

ERLO

Prospective

56 ± 8.5

47.619

47.619

71.429

14.286

Costa 2008

18

ERLO

Retrospective

63 ± 9

22.222

27.778

88.889

0

Goldberg 2013

74

ERLO-CT

Retrospective

58 ± 13

17.647

29.412

Hata 2011

125

ERLO

Retrospective

64 ± 12

39.2

44

Janne 2015

222

OSIMER

RCT

60 ± 12.5

38.739

21

DASA/ERLO

Prospective

64 ± 11.2

37.333

95.946

0.9009

Koizumi 2012

20

Re-GEFI/ERLO

Prospective

61 ± 10

15

10

100

Kuo 2010

67

BSC-CT

Retrospective

64

55.2

47.8

85

Landi 2014

96

AFA

Retrospective

62 ± 14

35.417

3.125

Lee DH 2008

23

ERLO

Prospective

56 ± 8

Lee 2014

68

Re-GEFI/ERLO

Retrospective

Oh 2012

23

Re-GEFI/ERLO

Prospective

Otsuka 2015

24

GEFI/ERLO + Bevacumab

Sequist 2015

63

ROCILE

Sim 2009

16

ERLO

Vasile 2008

8

ERLO

Prospective

70 ± 8

50

12.5

75

0

Wong 2008

14

ERLO

Retrospective

56 ± 8.2

28.571

7.1429

71.429

7.1429

Yoshimura 2013

27

GEFI/ERLO - Pemetrexed

Prospective

67 ± 9

22.222

96.296

3.7037

Yu 2015

42

GEFI/ERLO - Pemetrexed

Prospective

62 ± 13.5

28.571

97.619

2.381

Zhao 2014

51

Re-GEFI/ERLO

Retrospective

62.3 ± 11

50.3

28.222

95.652

20.588

16.176

95.588

65 ± 8.5

13.043

8.6957

95.652

Retrospective

64 ± 8

25

29.167

100

Prospective

60

27

Retrospective

53 ± 13

0

0

28.333

72.222

22.222

58.824

32.353

100

50.45

29.279

62.162

64.444

29.444

55.444

65.625

26.042

33

54

46

20.833

66.667

57

32

51.85

40.741

10.4 0 4.3478

0

88.667

Abbreviations: AFA, Afatinib, BSC, Best supportive care; CT, Chemotherapy, DASA, Dasatinib; ERLO, Erlotinib; GEFI, Gefitinib; ICO, Icotinib; OSIMER, Osimertinib.

2

36.364

93.6

Johnson 2011

17.391

41.818

100

Therapies for advanced lung cancer with acquired resistance

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

3

Therapies for advanced lung cancer with acquired resistance

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

4

Therapies for advanced lung cancer with acquired resistance

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

5