Anticancer Original Research Paper

Risk of interstitial lung disease associated with EGFR-TKIs in advanced non-small-cell lung cancer: a meta-analysis of 24 phase III clinical trials Wei-Xiang Qi, Yuan-Jue Sun, Zan Shen, Yang Yao Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, China Purpose: To assess the risk of interstitial lung disease (ILD) with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) gefitinib, erlotinib, and afatinib. Method: PubMed databases were searched for relevant articles. Statistical analyses were conducted to calculate the summary incidence, odds ratio (OR), and 95% confidence intervals (CIs) by using either random-effects or fixed-effect models. Results: The incidence of all-grade and high-grade (§grade 3) ILD associated with EGFR-TKIs was 1.6% (95% CI, 1.0–2.4%) and 0.9% (95% CI, 0.6%–1.4%), with a mortality of 13.0% (95% CI, 7.6–21.6%). Patients treated with EGFR-TKIs had a significantly increased risk of developing all-grade (OR, 1.74; 95% CI, 1.25– 2.43; P50.001) and high-grade (OR, 4.38; 95% CI, 2.18–8.79; P,0.001) ILD. No significant difference in the risk of ILD was found in sub-group analysis according to EGFR-TKIs, percentage of EGFR mutation, study location, EGFR-TKIs-based regimens, and controlled therapy. Conclusions: Treatment with EGFR-TKIs is associated with a significantly increased risk of developing ILD. Keywords: Non-small-cell lung cancer, Interstitial lung disease, Erlotinib, Gefitinib, Afatinib, Meta-analysis

Introduction Lung cancer continues to be the leading cause of cancer-related mortality not only in the United States but also around the world, with non-small-cell lung cancer (NSCLC) in approximately 85% of cases.1–4 Despite improvements in survival for many other types of cancer in recent years, 5-year survival for patients with NSCLC has remained relatively poor, mainly because by the time a diagnosis is made, NSCLC is often well advanced and the goals of treatment are to extend survival, improve healthrelated quality of life, and reduce disease-related symptoms.5–8 The epidermal growth factor receptor (EGFR) signaling pathway plays a crucial role in regulating tumorigenesis and cell survival and may be important in the development and progression of NSCLC.9,10 As a result, EGFR and its family members have emerged as attractive candidates for anticancer therapy in NSCLC and many other types of cancer. Currently, two reversible EGFR tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and

Correspondence to: Dr. Wei-Xiang Qi, Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600 Yishan Road, Shanghai 200233, China. Email: [email protected]

ß 2014 Edizioni Scientifiche per l’Informazione su Farmaci e Terapia DOI 10.1179/1973947814Y.0000000189

erlotinib, and one irreversible EGFR, human epidermal growth factor receptor (HER) 2, and HER4 inhibitor, afatinib, have been approved for the treatment of EGFR-mutated NSCLC by the US Food and Drug Administration.11–15 In addition, the efficacy of EGFR-TKIs in other malignancies such as advanced pancreatic cancer,16 head and neck cancer,17 and biliary-tract cancer18 has also been investigated, although the clinical benefit from EGFR-TKIs is minimal. Although EGFR-TKIs, gefitinib, erlotinib and afatinib, are well tolerated and the common adverse effects, such as skin rash and diarrhea, are mild in severity and manageable,19–22 interstitial lung disease (ILD) is emerging as a major concern during EGFRTKIs treatment, and several fatal events have been reported since their approval.23–28 The mechanism of EGFR-TKIs-induced ILD has not been fully elucidated. Previous findings demonstrate that EGFR and its family members are usually upregulated early in the response to acute lung injury29,30 and implicated in the repair of pulmonary damage.31,32 Thus, inhibition of EGFR signaling could impair the repair of lung injury and then exacerbate pulmonary injury. An allergic reaction to EGFR-TKIs has also been

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suggested as a possible cause.28 Since ILD associated with EGFR-TKIs could be fatal in many instances, it is important to carefully recognize and document the incidence and risk of ILD with these drugs to perform an early and adequate intervention. We thus conducted this meta-analysis to investigate the overall incidence and risk of ILD associated with EGFRTKIs in patients with advanced NSCLC.

Materials and Methods Data sources We conducted an independent review of citations from PubMed between January 2000 and January 2014. Key words were ‘erlotinib’, ‘Tarceva’, ‘gefitinib’, ‘Iressa’, ‘afatinib’, ‘BIBW 2992’, ‘clinical trials’, ‘interstitial lung disease’ and ‘non-small-cell lung cancer’. The search was limited to prospective phase III clinical trials published in English. We also searched the clinical trial registration website (http://www.ClinicalTrials.gov) to obtain information on the registered prospective clinical trials. Clinical trials that met the following criteria were included: (1) prospective phase III trials involving advanced NSCLC; (2) participants assigned to treatment with EGFR-TKIs (alone or in combination at any dosage or frequency); and (3) available data regarding events or incidence of ILD and sample size.

Data extraction and clinical end point Data extraction was conducted independently by two investigators (WXQ and ZS), and any discrepancy between the reviewers was resolved by consensus. For each study, the following information was extracted: first author’s name, year of publication, number of enrolled subjects, treatment arms, number of patients in treatment and controlled groups, median age, median treatment duration, median progression-free survival, adverse outcomes of interest (ILD), and name and dosage of the EGFR-TKIs agent. The primary goal of our study was to determine the overall incidence and risk of ILD associated with EGFR-TKIs, we did not included trials reporting other pulmonary-related events including pneumonia, acute respiratory failure (ARF), and pneumonitis. For the assignation of TKI-induced ILD, four specific findings were required: (1) progressive dyspnea with or without cough or fever; (2) lack of evidence of infection; (3) radiographic findings consistent with drug-induced ILD, and (4) consistent pathologic findings if available.33 ILD in these trials was reported according to the National Cancer Institute’s common toxicity criteria (version 2 or 3), which had been adopted widely in cancer clinical trials.34 Both versions for adverse events were almost similar in terms of grading the toxicity of a medication leading to ILD. Major differences between the two versions included a particular category for ILD in version 3, which included grade 1–5.

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Statistical analysis For the calculation of incidence, the number of patients with ILD events and the number of patients receiving EGFR-TKIs single agent were extracted from the selected clinical trials; the proportion of patients with EGFR-TKIs and 95% confidence interval (CI) were derived for each study. For the calculation of odds ratio (OR), patients assigned to EGFR-TKIs were compared only with those assigned to control treatment in the same trial. We used the Peto method to calculate OR and 95% CI, because this method provided the best CI coverage and was more powerful and relatively less biased than the fixed- or random-effects analysis when dealing with low-event rates.35 Between-study heterogeneity was estimated using the chi square-based Q statistic.36 Heterogeneity was considered statistically significant when Pheterogeneity,0.1. If heterogeneity existed, data were analyzed using a random-effects model. In the absence of heterogeneity, a fixed-effects model was used. A statistical test with a P value less than 0.05 was considered significant. We also conducted the following pre-specified sub-group analyses: EGFRTKIs (gefitinib vs erlotinib vs afatinib), study location (Asian vs non-Asian), percentage of EGFR mutation (100% vs ,30%) and never-smoked patients in trials (.50% vs #50%), EGFR-TKIs-based regimen (combination vs single agent), and controlled therapy (placebo vs non-placebo). To assess the stability of results, sensitivity analysis was performed by sequential omission of individual studies. Additionally, to test whether effect sizes were moderated by differences in length of treatment, we have carried out metaregressions with difference in median length of experimental treatments (expressed in days) as predictor and OR as dependent variable. The presence of publication bias was evaluated by using the Begg and Egger tests.37,38 All statistical analyses were performed by using Stata version 12.0 software (Stata Corporation, College Station, TX) and Open Meta-Analyst software version 4.16.12 (Tufts University, Medford, MA).

Results Systematic literature search We performed this meta-analysis in accordance with the guidelines of the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statement.39 The literature search yielded 743 abstracts describing the use of gefitinib, erlotinib, and afatinib. A total of 36 phase III randomized controlled trials in patients with advanced NSCLC were carefully reviewed for eligibility: 11 trials did not have an adequate safety profile data listing for ILD due to study drug40–50 and one trial was excluded because all treatment arms received EGFR-TKIs combination therapy.51 Finally, a total of 24 phase III prospective clinical trials14,15,19,20,52–71 were included in the

Qi et al.

ILD associated with EGFR-TKIs

Figure 1 Selection process for prospective clinical trials included in the meta-analysis.

meta-analysis. In total, 15 561 patients were investigated in these trials. The selection process is summarized in Fig. 1. The 24 prospective clinical trials were published in 2004–2014. Sample size was in the range of 135 to 1692 patients, with 17 trials including .300 patients each. The median age of study participants was in the range of 55–64 years (some studies only reported the mean age). Table 1 reports the study and patient characteristics for the included trials.

Incidence of ILD A total of 5265 patients from 18 treatment arms received EGFR-TKIs single agent were available for all-grade ILD analysis. The incidence of all-grade ILD ranged between 0% and 5.7%. Based on data from 5265 patients, the overall incidence of all-grade ILD was 1.6% (95% CI, 1.0–2.4%) according to the random-effects model (Fig. 2A). High-grade ILD (§grade 3) was associated with increased morbidity and could result in dose modification or treatment interruption. A total of 3093 patients prescribed EGFR-TKIs single agent from 14 treatment arms were included for analysis. The incidence of highgrade ILD ranged from 0% to 2.6%. And the overall incidence of high-grade ILD was 0.9% (95% CI, 0.6– 1.4%) according to the fixed-effects model (Fig. 2B). Interstitial lung disease could be fatal in many instance, meta-analysis showed that the mortality was 13.0% (95% CI, 7.6–21.6%) among patients with EGFR-TKIs-associated ILD. We also performed

sub-group analysis to investigate the rate difference among gefitinib, erlotinib, and afatinib according to study locations. The incidence of all-grade ILD associated with gefitinib in Asian and non-Asian countries was 3.1% (95% CI, 1.7–5.6%) and 1.9% (95% CI, 0.9–4.1%), respectively. And the incidence of all-grade ILD associated with erlotinib in nonAsian countries was 0.9% (95% CI, 0.2–1.7%). Although only one phase III trial of erlotinib was included in our study for calculating incidence of ILD, none of ILD event was reported in that trials.57 In addition, the incidence of all-grade ILD associated with afatinib in Asian and non-Asian countries was 0.4% (95% CI, 0.1–2.9%) and 0.6% (95% CI, 0.2– 5.0%), respectively. There was significant difference in incidences of all-grade ILD between gefitinib and erlotinib in Asian countries (P50.04) but not in nonAsian countries (P50.13). Significant differences were also observed between gefitinib and afatinib in Asian countries (P50.012) but not for non-Asian countries (P50.14). As for high-grade ILD, the incidence of ILD associated with gefitinib in Asian and non-Asian countries was 0.9% (95% CI, 0.5– 1.7%) and 2.1% (95% CI, 0.8–5.6%), respectively. The incidence of high-grade ILD associated with erlotinib in non-Asian countries was 0.5% (95% CI, 0.2–1.4%), and none of ILD event was reported in trial located in Asian countries.57 Additionally, the incidence of high-grade ILD associated with afatinib in Asian countries was 0.4% (95% CI, 0.1–2.9%), and none of

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Maemondo et al., 2010

Lee et al., 2010

Mok et al., 2009

1466

1692

1037

1093

Kim et al., 2008

Thatcher et al., 2005

Herbst et al., 2004

Giaccone et al., 2004

490

1059

Herbst et al., 2005

Maruyama et al., 2008

1172

636

Gatzemeier et al., 2007

Herbst et al., 2011

165

451

Authors, year

Zhou et al., 2011

Patients enrolled

Erlotinib 150 mg/dayzGEMzplatinum PlacebozGEMzplatinum Erlotinib 150 mg/dayzBev PlacebozBev Erlotinib 150 mg/dayzsunitinib Erlotinib 150 mg/dayzplacebo Erlotinib 150 mg/day Chemotherapy Erlotinib 150 mg/day GEMzCBP Erlotinib 150 mg/dayzBev Erlotinib 150 mg/dayzplacebo Erlotinib 150 mg/day zGEMzDDP placebozGEMzDDP Erlotinib 150 mg/dayzCBPzPTX PlacebozCBPzPTX Gefitinib 250 mg/day Placebo Gefitinib 250 mg/day Pemetrexed Gefitinib 250 mg/day GEMzDDP Gefitinib 250 mg/day after 3 cycles chemotherapy Platinum-doublet chemotherapy Gefitinib 250 mg/day DDPz DOC Gefitinib 250 mg/day CBPzPTX Gefitinib 250 mg/day DOC Gefitinib 250 mg/day CBPzPTX Gefitinib 250 mg/day DOC Gefitinib 250 mg/day DOC Gefitinib 250 mg/day Placebo Gefitinib 500 mg/dayzCBPzPTX Gefitinib 250 mg/dayzCBPzPTX PlacebozCBPzPTX Gefitinib 500 mg/dayzDDPzGEM Gefitinib 250 mg/dayzDDPzGEM

Treatment aim 59 57.3 64 64 61 61 63.44 64.15 57 59 64.8 65 61 60 63 63 55 55 58 64 57 56.5 62 63 64 64 NR NR 57 58 57 57 NR NR 61 60 62 61 62 61 63 61 59

Median age (years)

Table 1 Baseline characteristics of 24 phase III trials in the meta-analysis (n515 561)

50 48 18 17 20 18.8 66 72 72 69 10 11 NR NR 8.2 13.4 53 55 NR NR 100 100 32.3 30 70.9 66.3 65.8 57.9 36.6 45.6 93.8 93.6 29 35.7 20.2 20.5 22 22 NR NR NR NR NR

Never smoked (%) 22 21 NR NR 5.8 6.3 100 100 100 100 11 6 NR NR NR NR 27 26.3 23.5 25.4 16.3 10.7 NR NR 100 100 100 100 NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR

EGFR mutation (%) NR NR 2.8 2.6 2.8 2.8 8.2 2.8 13.0 2.4 NR NR NR NR 4.6 5.3 4.9 2.4 NR NR NR NR 2.3 2.8 5.5 2.1 10.3 2.8 NR NR 5.6 4.1 1.9 2.1 4.4 3 2.9 2.7 3.3 4.3 4.6 3.2 5

Treatment duration (months) 7.6 6 4.8 3.7 3.6 2 9.4 5.2 13.1 4.6 3.4 1.7 5.5 5.7 5.1 4.9 4.8 2.6 9 3 5.8 6.4 NR NR 9.2 6.3 10.8 5.4 3.3 3.4 5.7 5.8 2 2 2.2 2.7 3 2.6 4.6 5.3 5 5.5 5.8

Median PFS/TTP (months) 18.3 15.2 14.4 13.3 9 8.5 19.3 19.5 NR NR 9.3 9.2 10.0 10.3 10.6 10.5 18.7 16.9 22.2 18.9 22.3 22.9 NR NR NR NR 30.5 23.6 NR NR 18.6 17.3 11.5 14 7.6 8 5.6 5.1 8.7 9.8 9.9 9.9 9.9

Median OS (months) 226 222 367 368 473 477 84 82 83 72 313 313 580 589 539 540 147 148 68 67 159 150 300 298 87 88 114 113 81 76 607 589 244 239 729 715 1129 563 342 342 341 358 362

No. for analysis

NR NR 2 0 2 0 0 0 0 0 2 2 1 0 5 1 1 0 1 0 2 0 4 2 1 0 3 0 1 0 3 1 3 0 NR NR NR NR NR NR NR NR NR

High-grade ILD events

Qi et al. ILD associated with EGFR-TKIs

345

585

Sequist et al., 2013

Miller et al., 2012

PFS: progression-free survival; TTP: time-to-progression; OS: overall survival; ILD: interstitial lung disease; GEM: gemcitabine; DOC: docetaxel; Bev: bevacizumab; DDP: cisplatin; PTX: paclitaxel; CBP: carboplatin; NR: not reported.

NR 1 0 NR NR 0 0 355 239 113 229 111 390 195 10.9 NR NR 16.6 14.8 10.8 12 6 11 5.6 11.1 6.9 3.3 1.1 5.3 13.3 NR 11 NR NR NR NR 74.8 81.1 67.4 70.4 63 62 61 58 58 61.5 61 58 59 Wu et al., 2014

PlacebozDDPzGEM Afatinib 40 mg/day GEMzDDP Afatinib 40 mg/day PemetrexedzDDP Afatinib 50 mg/day Placebo 364

Authors, year

Treatment aim Patients enrolled Table 1 Continued

NR 100 100 100 100 15.9 17.4

Median PFS/TTP (months) Median age (years)

Never smoked (%)

EGFR mutation (%)

Treatment duration (months)

Median OS (months)

No. for analysis

High-grade ILD events

Qi et al.

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ILD event was reported in trial located in non-Asian countries.

Odds ratio of ILD A meta-analysis of the OR for all-grade ILD attributable to EGFR-TKIs compared with controls was performed on 22 randomized controlled trials. The overall OR for all-grade ILD was 1.74 (95% CI, 1.25–2.43; P50.001; Fig. 3A), according to the fixedeffects model. As for high-grade ILD, 14 RCTs were available for analysis. The combined OR also demonstrated that EGFR-TKIs significantly increased the risk of developing ILD (OR, 4.38; 95% CI, 2.18–8.79; P,0.001; Fig. 3B), using a fixed-effects model. We also did sensitivity analysis to examine the stability and reliability of pooled ORs by sequential omission of individual studies. The results indicated that the significance estimate of pooled ORs was not significantly influenced by omitting any single study (Fig. 4).

Risk of ILD According to Pre-specified Subgroups The ORs of ILD might be different between gefitinib, erlotinib, and afatinib, and we thus performed subgroup analysis according to EGFR-TKIs. Our combined results demonstrated that the use of gefitinib significantly increased the risk of developing all-grade ILD (OR, 1.76; 95% CI, 1.22–2.54; P50.003) but not for erlotinib (OR, 1.41; 95% CI, 0.61–3.28; P50.42) and afatinib (OR, 4.43; 95% CI, 0.54–36.06; P50.16). Similarly, treatment with gefitinib (OR, 4.23; 95% CI, 1.83–9.78; P,0.001) and erlotinib (OR, 4.77; 95% CI, 1.29–17.66; P50.019) significantly increased the risk of developing high-grade ILD, but not for afatinib (OR, 4.36; 95% CI, 0.066–290.30; P50.49). However, OR of all-grade (P50.50) and high-grade ILD (P50.99) did not significantly varied among these three EGFR-TKIs. The ORs of ILD might also vary between patients with or without EGFR mutation because of a longer duration of exposure to EGFRTKIs for patients with EGFR mutation. Our result showed that EGFR-TKIs significantly increased the risk of all-grade (OR, 4.87; 95% CI, 1.67–14.25; P50.004) and high-grade (OR, 6.77; 95% CI, 1.14– 40.2; P50.035) ILD in patients with advanced NSCLC with EGFR mutation, while a non-significantly increased risk of ILD was observed in trials of patients with less than 30% EGFR mutation (Table 2). Additionally, a meta-regression was carried out to test whether the OR of ILD varied as function of difference in length of the experimental. Results indicated that the OR of ILD did not significantly associate with treatment duration of EGFR-TKIs (allgrade ILD: beta50.35, P50.38; high-grade ILD: beta51.50, P50.062; Fig. 5). We then conducted sub-group analysis according to percentage of never-smoked patients in trials

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Figure 2 Incidence of ILD associated with EGFR-TKIs: all-grade ILD (A); high-grade ILD (B).

Figure 3 Odds ratio of ILD associated with EGFR-TKIs versus control: all-grade ILD (A); high-grade ILD (B).

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Figure 4 Meta-analysis of ILD associated with EGFR-TKIs versus control: ‘leave-one-out’ sensitivity analysis: all-grade ILD (A); high-grade ILD (B).

(.50% vs #50%). Our results showed that there was a significantly higher risk of developing all-grade ILD in trials with more never-smoked patients compared to trials with less never-smoked patients (OR 2.89 vs 1.48, P50.044), but not for high-grade ILD (OR 5.00 vs 3.79, P50.35). As previous studies had showed that the incidence of ILD was higher in Asians than in Non-Asians,72–75 we then performed sub-group analysis according to countries and found that the OR of all-grade and high-grade ILD was comparable between Asian and non-Asian countries (all-grade: 1.83 vs 1.66; high-grade: 3.76 vs 5.47). Again, the difference in risk of ILD between Asian and nonAsian countries was not statistically significant (allgrade: P50.39, high-grade: P50.30). To determine whether the types of concurrent therapy with EGFRTKIs may alter the risk of ILD, we performed a subgroup risk analysis stratified according to EGFRTKIs-based regimens. The OR of all-grade ILD for EGFR-TKIs monotherapy was 1.83 (95% CI, 1.25– 2.68; P50.002) versus 1.49 (95% CI, 0.75–2.93; P50.25) for combination therapy, whereas the ORs of high-grade ILD for EGFR-TKIs monotherapy was 4.23 (95% CI, 1.86–9.63; P,0.001) versus 4.77 (95% CI, 1.29–17.66; P50.019) for combination therapy. This difference in risk of developing ILD with EGFR-TKIs among these therapeutic classes was not statistically significant (all grade: P50.30,

high grade: P50.43). Finally, we also did sub-group analysis according to controlled therapy, and the combined results showed that the use of EGFR-TKIs was associated with a significantly increased risk of all-grade (OR, 1.86; 95% CI, 1.31–2.65; P,0.001) and high-grade ILD (OR, 4.31; 95% CI, 2.12–8.73; P,0.001) in comparison with non-placebo. While a non-significantly increased risk of ILD associated with EGFR-TKIs was observed in comparison with placebo (Table 2). This difference in risk of all-grade and high-grade ILD with EGFR-TKIs among these therapeutic classes was not statistically significant (all-grade: P50.16, high-grade: P50.39).

Publication Bias No evidence of publication bias was detected for the OR of all-grade and high-grade ILD in this study by Egger’s test (OR of all-grade: P50.44; OR of highgrade: P50.48).

Discussion The recent introduction of EGFR-TKIs, like erlotinib, gefitinib and afatinib, has opened up a new array of effective and relatively safe drugs for the treatment of patients with advanced NSCLC. However, ILD has emerged as a rare but potentially fatal adverse event associated with these drugs. Although ILD associated with gefitinib has been reported with a variation in the incidences ranging from 3.5 to 5.0%

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83/4988 13/1960 4/858

13/836 3/831 84/6139

32/2139 50/3615 18/2052

44/2238 56/5568

75/4690 25/3116

12/1666 88/6140

6 4 12

10 8 4

11 11

16 6

3 19

100/7806

EGFR-TKIs

12 7 3

22

Studies, n

6/906 40/5118

35/3619 11/2405

23/2056 23/3968

9/1661 29/3021 8/1342

1/579 2/632 43/4813

37/3666 9/1939 0/419

46/6024

Control

1.04 (0.39–2.78) 1.86 (1.31–2.65)

1.83 (1.25–2.68) 1.49 (0.75–2.93)

1.83 (1.13–2.98) 1.66 (1.05–2.63)

2.89 (1.55–5.38) 1.48 (0.94–2.32) 1.25 (0.56–2.82)

4.87 (1.67–14.25) 1.48 (0.26–8.54) 1.56 (1.09–2.24)

1.76 (1.22–2.54) 1.41 (0.61–3.28) 4.43 (0.54–36.06)

1.74 (1.25–2.43)

OR (95% CI)a

0.94 ,0.001

0.002 0.25

0.0015 0.029

,0.001 0.091 0.59

0.004 0.66 0.014

0.003 0.42 0.16

0.001

P value

2 14

13 3

9 7

8 6 2

5 3 8

9 5 2

16

Studies, n

1/390 27/3552

20/2603 8/1486

16/1928 12/2161

11/1520 15/1921 2/648

5/607 2/605 21/2877

19/1807 8/1653 1/629

28/4089

EGFR-TKIs

0/343 4/3374

3/2230 1/1487

3/1752 1/1965

1/1355 3/1716 0/646

0/468 0/410 4/2839

3/1768 1/1641 0/308

4/3717

Control

High-grade ILD, n/total, n

7.44 (0.15–374.94) 4.31 (2.12–8.73)

4.23 (1.86–9.63) 4.77 (1.29–17.66)

3.76 (1.52–9.28) 5.47 (1.84–16.27)

5.00 (1.60–15.64) 3.79 (1.50–9.57) 7.32 (0.46–117.17)

6.77 (1.14–40.2) 7.36 (0.46–117.67) 3.86 (1.76–8.47)

4.23 (1.83–9.78) 4.77 (1.29–17.66) 4.36 (0.066–290.30)

4.38 (2.18–8.79)

OR (95% CI)b

0.32 ,0.001

,0.001 0.019

0.004 0.002

0.006 0.005 0.16

0.035 0.16 ,0.001

,0.001 0.019 0.49

,0.001

P value

ILD: interstitial lung disease; OR: odds ratio. a P50.50 for variation in ORs by EGFR-TKIs; P50.13 for variation in ORs by percentage of EGFR mutation; P50.044 for variation in ORs by percentage of never-smoked patients; P50.39 for variation in ORs by study locations; P50.30 for variation in ORs by EGFR-TKIs regimens; P50.16 for variation in ORs by controlled therapy. b P50.99 for variation in ORs by EGFR-TKIs; P50.48 for variation in ORs by percentage of EGFR mutation; P50.35 for variation in ORs by percentage of never smoked patients; P50.30 for variation in ORs by study locations; P50.43 for variation in ORs by EGFR-TKIs regimens; P50.39 for variation in ORs by controlled therapy.

Overall EGFR-TKIs Gefitinib Erlotinib Afatinib EGFR mutation 100% ,30% Not reported Never smoked .50% #50% Not reported Study location Asian Non-Asian EGFR-TKIs-based regimens EGFR-TKIs monotherapy Combinations Controlled therapy Placebo Non-placebo

Groups

All-grade ILD, n/total, n

Table 2 Odds ratio of ILD with EGFR-TKIs according to prescribed sub-groups

Qi et al. ILD associated with EGFR-TKIs

Qi et al.

Figure 5 Meta-regression analysis of trends between treatment duration and odds ratio of ILD: symbols: each study is represented by a circle, the diameter of which is proportional to its statistical weight; all-grade ILD (A); high-grade ILD (B).

in several retrospective studies.73,75,76 However, there has been no systematic attempt to synthesize these data, and the overall incidence and risk of ILD with EGFR-TKIs have yet to be defined. As EGFR-TKIs are increasingly used in the routine treatment of patients with advanced NSCLC, and in many other types of tumors, it is of particular importance to determine the overall incidence and risk of ILD associated with these drugs. Our study includes a total of 15 561 patients with advanced NSCLC from 24 phase III clinical trials, which show that the overall incidence of all-grade and high-grade ILD associated with EGFR-TKIs is 1.6% (95% CI: 1.0–2.4%) and 0.9% (95% CI: 0.6–1.4%), which is lower than that previous reported.73,75,76 Possible explanation for this finding is that these previous studies are retrospective review of one or two published phase III trials, which might increase the potential bias. While our study includes all prospective phase III clinical trials with data on ILD associated with EGFR-TKIs by using metaanalysis, we could thus achieve more stable estimates of ILD incidence rate. In addition, our study finds that patients treated with EGFR-TKIs have a significantly increased risk of developing all-grade and high-grade ILD compared with controls. Similar results are also observed in sub-group analysis based on EGFR-TKIs, percentage of EGFR mutation and percentage of never smoker in trials, study location, EGFR-TKIs-based regimens, and controlled therapy, although the risk does not increase in phase II trials (Table 2). Since ILD associated with EGFR-TKIs could be fatal in many instances, we also investigate the outcome of ILD in patients with advanced NSCLC. Our study shows that the mortality is 13.0% (95% CI, 7.6–21.6%) among patients who have ILD associated with EGFR-TKIs treatment. This study will help physicians and patients to

ILD associated with EGFR-TKIs

understand the incidence and risk of ILD with EGFR-TKIs therapy. As EGFR-TKIs is used extensively in treatment of patients with advanced NSCLC and in clinical trials, it will be particularly important to recognize symptoms indicating ILD and intervene promptly to reduce morbidity and fatality. The etiology and molecular mechanism of EGFRTKI-induced ILD are not clearly understood. EGFR inhibitors may interfere with both the damage and repair pathways of pulmonary tissue. Epidermal growth factor (EGF) is secreted into bronchial surface fluid.77 EGFR inhibition by erlotinib and gefitinib may thus impair EGF-induced repair by pneumocytes.78 Furthermore, the increased lung damage as a result of EGFR inhibition has been recently confirmed in an animal model, Harad et al.79 found that gefitinib use upregulated expression of genes involved in neutrophil sequestration, acute inflammation and airway remodelling, while EGFR inhibition with gefitinib prolonged pulmonary inflammation and potentiated acute lung injury. Another study suggested that gefitinib therapy may augment any underlying pulmonary fibrosis via a decrease in EGFR phosphorylation, based on a coincident decrease in regenerative epithelial proliferation in a murine model.80 However, cetuximab, a recombinant monoclonal antibody against human EGFR, also inhibits EGFR tyrosine kinase activation but its associated pulmonary toxicity is extremely rare.81 As a result, more studies are still needed to address this issue. Identifying patients at high risk of ILD will be an important initial step in reducing the risk of occurrence. Careful assessment of the patient’s history should include a history of smoking, preexisting interstitial pneumonia, reduced normal lung, age, and complications of cardiovascular diseases.75 Currently, there are no specific guidelines for the treatment of EGFR-TKIs-induced ILD because there is a lack of controlled studies addressing the subject. The packet insert recommends permanently discontinuing EGFR-TKIs in patients with ILD.11,13 When ILD is suspected clinically, EGFR-TKIs are always discontinued immediately, and early administration of high-dose glucocorticoids generally presents curative effects.82 Treatment of EGFR-TKI-induced ILD is largely supportive, including supplemental oxygen, empirical antibiotics, and mechanical ventilation. Due to the fear of recurrence of ILD, physicians are hesitant to rechallenge patients with EGFRTKIs. This may hamper the use of EGFR-TKI in patients with specific EGFR mutations; for them, the treatment effect of EGFR-TKI is expected to continue for up to 8 or 9 months.83 As a result, further studies are recommended to investigate the rechallenge of EGFR-TKIs in selected patients who have recovered from ILD.

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Our study has several limitations. First, these studies are conducted at various institutions by different investigators internationally and may have potential bias in reporting incidences of ILD. In particular, the frequency of ILD is underreported in clinical trials. Second, ILD is not a single disease, assessment of ILD in patients with advanced NSCLC is challenging because of confounding factors such as heart failure, pulmonary lymphangitis, infectious pulmonary diseases, pneumonia, or disease progression within the lungs. Also, the National Cancer Institute’s common toxicity criteria grading system for ILD has its own limitations. No term specific for ILD is listed in NCI common terminology criteria for adverse events (CTCAE) version 2.0 or 3.0. In addition, our study only includes trials reporting incidence of ILD and excludes trials reporting other pulmonary related adverse events such as pneumonia, ARF, and pneumonitis, whereas patients with a history of ILD are commonly excluded for participating in clinical trials with EGFR-TKIs. All these factors contribute the heterogeneity of the incidence of ILD events among the included studies, which makes the interpretation of meta-analysis a little problematic. Third, our study includes a mixed population of patients treated with EGFR-TKIsbased combination therapy or EGFR-TKIs alone, and concomitant chemotherapy such as gemcitabine and docetaxel could also induce pulmonary toxicity and may contribute to the ILD toxicity observed with EGFR-TKIs. Therefore, different treatment design might be another source of heterogeneity. Fourth, all these studies exclude patients with poor renal, hematological, and hepatic functions, and are performed mostly at major academic centers and research institutions; the analysis of these studies may not apply to patients with organ dysfunctions and in the community, and the overall incidences of ILD from this study may be overestimated. Finally, this is a meta-analysis at the study level; therefore, some risk factors at the patient level, such as history of previous ILD, pre-existing pulmonary fibrosis and performance status, cannot be assessed properly and incorporated into the analysis.

Conclusion In conclusion, our study has demonstrated that the use of EGFR-TKIs is associated with a substantial risk of developing ILD in patients with advanced NSCLC. Clinicians should have a high suspicion for the diagnosis of pulmonary toxicity when respiratory symptoms appear in patients receiving EGFR-TKIs treatment. Further investigation is necessary to establish if concomitant use of corticoids and EGFR-TKIs can lower the incidence of ILD associated with the EGFR-TKIs.

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Disclaimer Statements Contributors W-XQ and YY designed research; WXQ, ZS, and S-YJ conducted research; W-XQ and SZ analyzed data; W-XQ wrote the draft; all authors read, reviewed and approved the final manuscript. WXQ had primary responsibility for final content. Funding None Conflicts of interest The authors have declared no conflicts of interest. Ethics approval None required, meta-analysis.

References 1 Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55(2):74–108. 2 Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60(5):277–300. 3 Govindan R, Page N, Morgensztern D, Read W, Tierney R, Vlahiotis A, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol. 2006;24(28):4539–44. 4 Youlden DR, Cramb SM, Baade PD. The International Epidemiology of Lung Cancer: geographical distribution and secular trends. J Thorac Oncol. 2008;3(8):819–31. 5 Azzoli CG, Baker S Jr., Temin S, Pao W, Aliff T, Brahmer J, et al. American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol. 2009;27(36):6251–66. 6 Goetti R, Leschka S, Baumuller S, Plass A, Wieser M, Desbiolles L, et al. Low dose high-pitch spiral acquisition 128-slice dual-source computed tomography for the evaluation of coronary artery bypass graft patency. Invest Radiol. 2010;45(6):324–30. 7 Spiro SG, Silvestri GA. One hundred years of lung cancer. Am J Respir Crit Care Med. 2005;172(5):523–9. 8 Qi WX, Wang Q, Jiang YL, Sun YJ, Tang LN, He AN, et al. Overall survival benefits for combining targeted therapy as second-line treatment for advanced non-small-cell-lung cancer: a meta-analysis of published data. PLoS One. 2013;8(2):e55637. 9 Lee CK, Brown C, Gralla RJ, Hirsh V, Thongprasert S, Tsai CM, et al. Impact of EGFR inhibitor in non-small cell lung cancer on progression-free and overall survival: a metaanalysis. J Natl Cancer Inst. 2013;105(9):595–605. 10 Scaltriti M, Baselga J. The epidermal growth factor receptor pathway: a model for targeted therapy. Clin Cancer Res. 2006;12(18):5268–72. 11 Cohen MH, Williams GA, Sridhara R, Chen G, McGuinn WD Jr., Morse D, et al. United States Food and Drug Administration Drug Approval summary: Gefitinib (ZD1839; Iressa) tablets. Clin Cancer Res. 2004;10(4):1212–8. 12 Cohen MH, Johnson JR, Chattopadhyay S, Tang S, Justice R, Sridhara R, et al. Approval summary: erlotinib maintenance therapy of advanced/metastatic non-small cell lung cancer (NSCLC). Oncologist. 2010;15(12):1344–51. 13 Cohen MH, Johnson JR, Chen YF, Sridhara R, Pazdur R. FDA drug approval summary: erlotinib (Tarceva) tablets. Oncologist. 2005;10(7):461–6. 14 Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15(2):213–22. 15 Sequist LV, Yang JC, Yamamoto N, O’Byrne K, Hirsh V, Mok T, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31(27):3327–34. 16 Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25(15):1960–6. 17 Martins RG, Parvathaneni U, Bauman JE, Sharma AK, Raez LE, Papagikos MA, et al. Cisplatin and radiotherapy with or without erlotinib in locally advanced squamous cell carcinoma

Qi et al.

18

19

20

21 22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

of the head and neck: a randomized phase II trial. J Clin Oncol. 2013;31(11):1415–21. Lee J, Park SH, Chang HM, Kim JS, Choi HJ, Lee MA, et al. Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2012;13(2):181–8. Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, Sandler A, et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2005;23(25):5892–9. Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial-INTACT 2. J Clin Oncol. 2004;22(5):785–94. Cersosimo RJ. Gefitinib: an adverse effects profile. Expert Opin Drug Saf. 2006;5(3):469–79. Qi WX, Tang LN, He AN, Yao Y, Shen Z. Incidence and risk of treatment-related mortality in cancer patients treated with EGFR-TKIs: A meta-analysis of 22 phase III randomized controlled trials. Respir Med. 2013;107(8):1280–3. Nasrallah H, Bar-Sela G, Haim N. Fatal interstitial lung disease associated with gemcitabine and erlotinib therapy for lung cancer. Med Oncol. 2012;29(1):212–4. Um SJ, Lee SK, Yang DK, Son C, Roh MS, Kim KN, et al. Fatal interstitial lung disease after erlotinib administration in a patient with radiation fibrosis. Clin Respir J. 2009;3(3):181–4. Lind JS, Smit EF, Grunberg K, Senan S, Lagerwaard FJ. Fatal interstitial lung disease after erlotinib for non-small cell lung cancer. J Thorac Oncol. 2008;3(9):1050–3. Makris D, Scherpereel A, Copin MC, Colin G, Brun L, Lafitte JJ, et al. Fatal interstitial lung disease associated with oral erlotinib therapy for lung cancer. BMC Cancer. 2007;7:150. Tammaro KA, Baldwin PD, Lundberg AS. Interstitial lung disease following erlotinib (Tarceva) in a patient who previously tolerated gefitinib (Iressa). J Oncol Pharm Pract. 2005;11(3):127–30. Aoe K, Hiraki A, Murakami T, Maeda T, Umemori Y, Katayama H, et al. Sudden onset of interstitial lung disease induced by gefitinib in a lung cancer patient with multiple drug allergy. Anticancer Res. 2005;25(1B):415–8. Madtes DK, Busby HK, Strandjord TP, Clark JG. Expression of transforming growth factor-alpha and epidermal growth factor receptor is increased following bleomycin-induced lung injury in rats. Am J Respir Cell Mol Biol. 1994;11(5):540–51. Madtes DK, Rubenfeld G, Klima LD, Milberg JA, Steinberg KP, Martin TR, et al. Elevated transforming growth factoralpha levels in bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 1998;158(2):424–30. Hardie WD, Prows DR, Leikauf GD, Korfhagen TR. Attenuation of acute lung injury in transgenic mice expressing human transforming growth factor-alpha. Am J Physiol. 1999;277(5 Pt 1):L1045–50. Hardie WD, Prows DR, Piljan-Gentle A, Dunlavy MR, Wesselkamper SC, Leikauf GD, et al. Dose-related protection from nickel-induced lung injury in transgenic mice expressing human transforming growth factor-alpha. Am J Respir Cell Mol Biol. 2002;26(4):430–7. Min JH, Lee HY, Lim H, Ahn MJ, Park K, Chung MP, et al. Drug-induced interstitial lung disease in tyrosine kinase inhibitor therapy for non-small cell lung cancer: a review on current insight. Cancer Chemother Pharmacol. 2011;68(5): 1099–109. NCI, Cancer Therapy Evaluation Program. CTC v 2.0 and common terminology criteria for adverse events criteria V3.0 (CTCAE). 2010 Feb 25 [cited 2013 Jan Available from: http:// ctepcancergov/protocolDevelopment/electronic_applications/ctchtm Sweeting MJ, Sutton AJ, Lambert PC. What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med. 2004;23(9):1351–75. Zintzaras E, Ioannidis JP. Heterogeneity testing in metaanalysis of genome searches. Genet Epidemiol. 2005;28(2): 123–37. Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis. 1985;27(5):335–71. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50(4): 1088–101.

ILD associated with EGFR-TKIs

39 Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and metaanalyses: the PRISMA statement. PLoS Med. 2009;6(7): e1000097. 40 Shi Y, Zhang L, Liu X, Zhou C, Zhang L, Zhang S, et al. Icotinib versus gefitinib in previously treated advanced nonsmall-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial. Lancet Oncol. 2013;14(10):953–61. 41 Karampeazis A, Voutsina A, Souglakos J, Kentepozidis N, Giassas S, Christofillakis C, et al. Pemetrexed versus erlotinib in pretreated patients with advanced non-small cell lung cancer: A Hellenic Oncology Research Group (HORG) randomized phase 3 study. Cancer. 2013;119(15):2754–64. 42 Goss GD, O’Callaghan C, Lorimer I, Tsao MS, Masters GA, Jett J, et al. Gefitinib versus placebo in completely resected nonsmall-cell lung cancer: results of the NCIC CTG BR19 study. J Clin Oncol. 2013;31(27):3320–6. 43 Garassino MC, Martelli O, Broggini M, Farina G, Veronese S, Rulli E, et al. Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. Lancet Oncol. 2013;14(10):981–8. 44 Perol M, Chouaid C, Perol D, Barlesi F, Gervais R, Westeel V, et al. Randomized, phase III study of gemcitabine or erlotinib maintenance therapy versus observation, with predefined second-line treatment, after cisplatin-gemcitabine induction chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2012;30(28):3516–24. 45 Lee SM, Khan I, Upadhyay S, Lewanski C, Falk S, Skailes G, et al. First-line erlotinib in patients with advanced non-smallcell lung cancer unsuitable for chemotherapy (TOPICAL): a double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2012;13(11):1161–70. 46 Ciuleanu T, Stelmakh L, Cicenas S, Miliauskas S, Grigorescu AC, Hillenbach C, et al. Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study. Lancet Oncol. 2012;13(3):300–8. 47 Natale RB, Thongprasert S, Greco FA, Thomas M, Tsai CM, Sunpaweravong P, et al. Phase III trial of vandetanib compared with erlotinib in patients with previously treated advanced nonsmall-cell lung cancer. J Clin Oncol. 2011;29(8):1059–66. 48 Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczesna A, Juhasz E, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebocontrolled phase 3 study. Lancet Oncol. 2010;11(6):521–9. 49 Kelly K, Chansky K, Gaspar LE, Albain KS, Jett J, Ung YC, et al. Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol. 2008;26(15):2450–6. 50 Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al. Erlotinib in previously treated nonsmall-cell lung cancer. N Engl J Med. 2005;353(2):123–32. 51 Gridelli C, Ciardiello F, Gallo C, Feld R, Butts C, Gebbia V, et al. First-line erlotinib followed by second-line cisplatingemcitabine chemotherapy in advanced non-small-cell lung cancer: the TORCH randomized trial. J Clin Oncol. 2012; 30(24):3002–11. 52 Wu YL, Lee JS, Thongprasert S, Yu CJ, Zhang L, Ladrera G, et al. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. Lancet Oncol. 2013;14(8):777–86. 53 Zhang L, Ma S, Song X, Han B, Cheng Y, Huang C, et al. Gefitinib versus placebo as maintenance therapy in patients with locally advanced or metastatic non-small-cell lung cancer (INFORM; C-TONG 0804): a multicentre, double-blind randomised phase 3 trial. Lancet Oncol. 2012;13(5):466–75. 54 Sun JM, Lee KH, Kim SW, Lee DH, Min YJ, Yun HJ, et al. Gefitinib versus pemetrexed as second-line treatment in patients with nonsmall cell lung cancer previously treated with platinum-based chemotherapy (KCSG-LU08-01): An openlabel, phase 3 trial. Cancer. 2012;118(24):6234–42. 55 Scagliotti GV, Krzakowski M, Szczesna A, Strausz J, Makhson A, Reck M, et al. Sunitinib plus erlotinib versus placebo plus erlotinib in patients with previously treated advanced nonsmall-cell lung cancer: a phase III trial. J Clin Oncol. 2012;30(17):2070–8.

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0

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Qi et al.

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56 Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. Erlotinib versus standard chemotherapy as firstline treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239–46. 57 Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-smallcell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12(8):735–42. 58 Herbst RS, Ansari R, Bustin F, Flynn P, Hart L, Otterson GA, et al. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial. Lancet. 2011;377(9780): 1846–54. 59 Takeda K, Hida T, Sato T, Ando M, Seto T, Satouchi M, et al. Randomized phase III trial of platinum-doublet chemotherapy followed by gefitinib compared with continued platinumdoublet chemotherapy in Japanese patients with advanced non-small-cell lung cancer: results of a west Japan thoracic oncology group trial (WJTOG0203). J Clin Oncol. 2010; 28(5):753–60. 60 Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11(2):121–8. 61 Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362(25): 2380–8. 62 Lee DH, Park K, Kim JH, Lee JS, Shin SW, Kang JH, et al. Randomized Phase III trial of gefitinib versus docetaxel in nonsmall cell lung cancer patients who have previously received platinum-based chemotherapy. Clin Cancer Res. 2010;16(4): 1307–14. 63 Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947–57. 64 Maruyama R, Nishiwaki Y, Tamura T, Yamamoto N, Tsuboi M, Nakagawa K, et al. Phase III study, V-15-32, of gefitinib versus docetaxel in previously treated Japanese patients with non-small-cell lung cancer. J Clin Oncol. 2008;26(26):4244–52. 65 Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, et al. Gefitinib versus docetaxel in previously treated non-smallcell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008;372(9652):1809–18. 66 Gatzemeier U, Pluzanska A, Szczesna A, Kaukel E, Roubec J, De Rosa F, et al. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol. 2007;25(12):1545–52. 67 Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-smallcell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet. 2005;366(9496):1527–37. 68 Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial-INTACT 1. J Clin Oncol. 2004;22(5):777–84. 69 Johnson BE, Kabbinavar F, Fehrenbacher L, Hainsworth J, Kasubhai S, Kressel B, et al. ATLAS: randomized, double-blind,

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placebo-controlled, phase IIIB trial comparing bevacizumab therapy with or without erlotinib, after completion of chemotherapy, with bevacizumab for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol. 2013;31(31): 3926–34. Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT, et al. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol. 2012;30(10):1122–8. Miller VA, Hirsh V, Cadranel J, Chen YM, Park K, Kim SW, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUXLung 1): a phase 2b/3 randomised trial. Lancet Oncol. 2012;13(5):528–38. Chang SC, Chang CY, Chang SJ, Yuan MK, Lai YC, Liu YC, et al. Gefitinib-related interstitial lung disease in Taiwanese patients with non-small-cell lung cancer. Clin Lung cancer. 2013;14(1):55–61. Akamatsu H, Inoue A, Mitsudomi T, Kobayashi K, Nakagawa K, Mori K, et al. Interstitial lung disease associated with gefitinib in Japanese patients with EGFR-mutated non-smallcell lung cancer: combined analysis of two Phase III trials (NEJ 002 and WJTOG 3405). Jpn J Clin Oncol. 2013;43(6):664–8. Hotta K, Kiura K, Takigawa N, Yoshioka H, Harita S, Kuyama S, et al. Comparison of the incidence and pattern of interstitial lung disease during erlotinib and gefitinib treatment in Japanese Patients with non-small cell lung cancer: the Okayama Lung Cancer Study Group experience. J Thorac Oncol. 2010;5(2):179–84. Kudoh S, Kato H, Nishiwaki Y, Fukuoka M, Nakata K, Ichinose Y, et al. Interstitial lung disease in Japanese patients with lung cancer: a cohort and nested case-control study. Am J Respir Crit Care Med. 2008;177(12):1348–57. Ando M, Okamoto I, Yamamoto N, Takeda K, Tamura K, Seto T, et al. Predictive factors for interstitial lung disease, antitumor response, and survival in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol. 2006;24(16):2549– 56. Aida S, Tamai S, Sekiguchi S, Shimizu N. Distribution of epidermal growth factor and epidermal growth factor receptor in human lung: immunohistochemical and immunoelectronmicroscopic studies. Respiration. 1994;61(3):161–6. Higenbottam T, Kuwano K, Nemery B, Fujita Y. Understanding the mechanisms of drug-associated interstitial lung disease. Br J Cancer. 2004;91(Suppl 2):S31–7. Harada C, Kawaguchi T, Ogata-Suetsugu S, Yamada M, Hamada N, Maeyama T, et al. EGFR tyrosine kinase inhibition worsens acute lung injury in mice with repairing airway epithelium. Am J Respir Crit Care Med. 2011;183(6): 743–51. Suzuki H, Aoshiba K, Yokohori N, Nagai A. Epidermal growth factor receptor tyrosine kinase inhibition augments a murine model of pulmonary fibrosis. Cancer Res. 2003;63(16): 5054–9. Hoag JB, Azizi A, Doherty TJ, Lu J, Willis RE, Lund ME. Association of cetuximab with adverse pulmonary events in cancer patients: a comprehensive review. J Exp Clin Cancer Res. 2009;28:113. Zhang Y, Yang H, Zhao M, He J. Successful treatment of gefitinib-induced acute interstitial pneumonitis with corticosteroid and non-invasive BIPAP-ventilation. J Thorac Dis. 2012;4(3):316–9. Yang CH, Yu CJ, Shih JY, Chang YC, Hu FC, Tsai MC, et al. Specific EGFR mutations predict treatment outcome of stage IIIB/IV patients with chemotherapy-naive non-small-cell lung cancer receiving first-line gefitinib monotherapy. J Clin Oncol. 2008;26(16):2745–53.