Reduced chemotherapy sensitivity in EGFR-mutant lung cancer patient with frontline EGFR tyrosine kinase inhibitor

Lung Cancer 86 (2014) 219–224

Contents lists available at ScienceDirect

Lung Cancer journal homepage: www.elsevier.com/locate/lungcan

Reduced chemotherapy sensitivity in EGFR-mutant lung cancer patient with frontline EGFR tyrosine kinase inhibitor Zhu Zeng a,b,1 , Hong-hong Yan a,1 , Xu-chao Zhang a , Wen-zhao Zhong a , Yan-yan He a , Jin-lin Guan a , Fei-yu Niu a , Zhi Xie a , Yi-sheng Huang a , Chong-rui Xu a , Song Dong a , Yi-long Wu a,∗ a b

Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, China Division of Thoracic Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China

a r t i c l e

i n f o

Article history: Received 27 June 2014 Received in revised form 2 September 2014 Accepted 9 September 2014 Keywords: Epidermal growth factor receptor Tyrosine kinase inhibitors Sensitivity Chemotherapy Non-small-cell lung cancer first-line

a b s t r a c t Objectives: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a standard firstline treatment for EGFR-mutant patients with non-small cell lung cancer (NSCLC). However, it remains unclear whether frontline EGFR TKIs affect subsequent chemo-sensitivity in EGFR-mutant patients. This study compared chemo-sensitivity in patients treated with post-TKI chemotherapy and first-line chemotherapy controls. Materials and methods: This study included 203 EGFR-mutant patients. The study group contained 68 patients treated with chemotherapy after first-line EGFR-TKI and the control group contained 135 patients who received first-line chemotherapy. The response rate (RR), progression-free survival (PFS) and overall survival (OS) were assessed. Results: In study group, the RR of chemotherapy was 13.2% compared with 34.1% in the control group (P = 0.002). The median PFS of chemotherapy in the control group was significantly longer than in the study group (6.9 vs. 3.9 months, P < 0.001), while the RR (76.5% vs. 68.9%, P = 0.259) and PFS (11.0 vs. 10.2 months) of EGFR-TKI were similar between first- and second-line treatment. Cox regression analyses indicated that prior EGFR-TKI treatment had a higher risk for disease progression during chemotherapy treatment [hazard ratio (HR) = 3.06; 95% CI = 2.12–4.42, P < 0.001]. Median overall survival was 31.7 months in the control group and 23.5 months in the study group (P < 0.001). The adjusted HR for death in the study group was 1.91 (95% CI = 1.33–2.76; P < 0.001). Conclusion: In EGFR-mutant patients, frontline EGFR-TKI significantly reduced the sensitivity of subsequent chemotherapy compared with that of TKI-naïve frontline chemotherapy. These findings need to be validated in further randomized trials. © 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction The first-generation small molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib are effective in EGFR-positive advanced non-small-cell lung cancer (NSCLC). Compared with traditional chemotherapy, EGFR-TKIs contributed to longer progression-free survival (PFS) and higher response rate (RR) in EGFR-mutant patients as a firstline treatment [1–6]. But during the course of their disease, disease

relapse or progression is inevitable [7,8], chemotherapy is usually used as the subsequent treatment after EGFR TKI failure [9]. Thus, establishing the efficacy of chemotherapy after EGFR TKI failure is clinically relevant. The clinical concern is that frontline EGFR TKI treatment may influence subsequent chemo-sensitivity in clinical practice. In the absence of randomized data, we designed this retrospective study to assess the sensitivity of chemotherapy after EGFR-TKI failure in EGFR-mutant patients.

2. Materials and methods ∗ Corresponding author at: Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China. Tel.: +86 20 83877855; fax: +86 20 83844620. E-mail addresses: [email protected], [email protected] (Y.-l. Wu). 1 These authors contributed equally to this work. http://dx.doi.org/10.1016/j.lungcan.2014.09.008 0169-5002/© 2014 Elsevier Ireland Ltd. All rights reserved.

2.1. Patients From September 2006 to May 2012, 203 EGFR-mutant inpatients at the Guangdong Lung Cancer Institute (GLCI, Guangzhou, China)

220

Z. Zeng et al. / Lung Cancer 86 (2014) 219–224

were analyzed. The last follow-up occurred on April 26, 2013. The inclusion criteria were (1) pathologically confirmed advanced NSCLC with at least one measurable lesion; (2) activating EGFR mutations consisting of exon 19 deletion or exon 21 point mutation L858R; (3) received chemotherapy as a first-line treatment followed by second-line TKIs or as second-line treatment after gefitinib or erlotinib failure. The treating physician made all treatment strategy decisions. Patients that received salvage therapy with an experiment drug such as afatinib or sorafenib were excluded from the study. Patient’s clinical and treatment information were collected from electronic medical records at GLCI and all tissues used for this study were from the GLCI tissue bank. Informed consent was obtained from each patient for future molecular analyses before any biopsy was performed. This study was approved by the Institutional Review Board of Guangdong General Hospital (GGH, Guangzhou, China).

2.2. Study design According to the sequence of treatment administration, we divided the whole cohort into two groups: a study group consisted of a subset of 68 EGFR-mutant patients treated with first-line EGFR-TKI followed by chemotherapy, a control group included 135 EGFR-mutant patients treated with inverse sequence during the same period of patients in the study group.

2.3. Analysis of EGFR profile Tumor histology and identification were conducted by two independent pathologists to ensure that the specimen contained at least 50% cancer cells before EGFR analysis. DNA was extracted from fresh frozen tissue using the DNeasy Tissue Kit (Qiagen, Valencia, CA. EGFR exons 18–21 were amplified by reverse transcription polymerase chain reaction (RT-PCR), followed by direct sequencing. 2.4. Response evaluation and statistical analysis The response evaluation of chemotherapy was based on the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [10]. RR was defined as either complete response (CR) or partial response (PR). Progression-free survival (PFS) was calculated from the first day of treatment to first radiological evidence of disease progression. The follow up interval were 3 months, CT scan, MRI and bone scan were done for assessment. Overall survival (OS) was defined as the interval from start of first line anti-cancer treatment to the last visit or death. Censored data was defined as data from patients who were alive at the last follow-up visit. Clinical variables, including age at diagnosis of advanced NSCLC, gender, smoking history, Eastern Cooperative Oncology Group (ECOG) status, TNM stage and regimens of chemotherapy were analyzed. Chi-squared (Fisher’s exact test) or Wilcoxon rank-sum tests were used to detect differences in the clinicopathological characteristics and RR. Survival curves were constructed with the

Table 1 Clinical characteristics of patients (N = 203). Variables

Age of diagnosis Median Range Gender Male Female Smoking history Never-smoker Ever-smoker Pathology type ADC SQC Other ECOG status 0–1 2–3 Clinical stage at diagnosis III IV Type of EGFR mutant 19 deletion 21 mutation Regimens of chemotherapy Platinum-based Single-agent Subsequent treatmentc TKI Chemotherapy BSC Otherd

Total (N = 203)

P

Group (%) Study (N = 68)

Control (N = 135)

56.0 28–85

57.5 33–85

55.0 28–84

90 (44.3) 113 (55.7)

27 (39.7) 41 (60.3)

63 (46.7) 72 (53.3)

143 (70.4) 60 (29.6)

51 (75.0) 17 (25.0)

92 (68.1) 43 (31.9)

199 (98.0) 1 (0.5) 3 (1.5)

68 (100.0) 0 (0) 0 (0)

131 (97.0) 1 (0.7) 3 (2.2)

192 (94.6) 11 (5.4)

66 (97.1) 2 (2.9)

126 (93.3) 9 (6.7)

8 (3.9) 195 (96.1)

2 (2.9) 66 (97.1)

6 (4.4) 129 (95.6)

117 (57.6) 86 (42.4)

38 (55.9) 30 (44.1)

79 (58.5) 56 (41.5)

187 (92.1) 16 (7.9)

56 (82.4) 12 (17.6)

131 (97.0) 4 (3.0)

44 (21.7) 63 (31.0) 63 (31.0) 33 (16.3)

18 (26.5) 10 (14.6) 22 (32.4) 18 (26.5)

26 (19.3) 53 (39.2) 41 (30.4) 15 (11.1)

0.432a

0.346b

0.313b

0.192b

0.342b

0.721b

0.720b

<0.001b

0.001b

Abbreviations: ADC, adenocarcinoma; SQC, squamous carcinoma; ECOG status, Eastern Cooperative performance status; EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; BSC, best support care. a Independent-sample T test. b Fisher’s exact test. c Treatment beyond second-line treatment. d Patients with no evidence of disease progression and unknown treatment.

Z. Zeng et al. / Lung Cancer 86 (2014) 219–224

221

Table 2 Efficacy of chemotherapy and EGFR-TKIs. RR (%)

DCR (%)

PFS (months)

OS (months)

Chemotherapy in 1st line (N = 135) Chemotherapy in 2nd line (N = 68) P value

34.1 13.2 0.002a

86.7 55.9 <0.001a

6.9 3.9 <0.001b

31.7 23.5 <0.001b

EGFR TKIs in 1st line (N = 68) EGFR TKIs in 2nd line (N = 135) P value

76.5 68.9 0.259a

97.1 93.3 0.268a

11.0 10.2 0.670b

23.5 31.7 <0.001b

Abbreviations: RR, complete response and partial response; DCR, RR and stable disease, PFS, progression-free survival; OS, overall survival; EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; 1st, first; 2nd, second. a Pearson Chi-square test or Fisher’s exact test. b Logistic regression.

Kaplan–Meier method and differences analyzed by the log-rank test. A Cox regression model was used to calculate hazard ratio (HR) and its 95% confidence interval (CI), while a logistic regression model was used to assess the independent predictive factors for RR. All analysis was done with SPSS 13.0 software (IBM, Armonk, NY, US). P values < 0.05 was considered statistical significance, all P values are based on two-tailed analysis. 3. Results

who received platinum-based chemotherapy, median PFS was 6.9 months (95% CI = 5.96–7.84) in study group and 4.3 months (95% CI = 2.77–5.83, P < 0.001) in control group. Clinical characteristics, including gender, smoking history, pathological type, ECOG status, clinical stage, regimens of chemotherapy (platinum-based or single-agent) and mutation types of EGFR were correlated to PFS. Multivariate Cox regression analysis indicated that frontline EGFRTKI treatment (HR = 3.06; 95% CI = 2.12–4.42, P < 0.001) had a higher risk of disease progression.

3.1. Clinical characteristics

3.4. Efficacy of EGFR-TKI treatment

Baseline characteristics of the 203 patients were similar between the groups (Table 1). All patients were of Chinese ethnicity. Among the 203 patients, 98.0% were diagnosed with adenocarcinoma. Most patients received platinum-based chemotherapy; 7.9% received single agent chemotherapy due to poor ECOG status or advanced age. All patients received EGFR-TKIs during their treatment course, including 113 patients who received gefitinib and 90 patients who received erlotinib. The distribution of these two types of TKIs was similar between the study and control groups (P = 0.080).

We evaluated the efficacy of EGFR-TKIs in 68 patients who received EGFR-TKI as a first-line therapy and 135 patients who received EGFR-TKI as second-line treatment after first-line chemotherapy. The median PFS of EGFR-TKI as a first-line therapy was 11.0 months (95% CI = 8.99–11.41), compared with 10.2 months in the second-line setting (P = 0.670) (Fig. 1B). All of the 203 were available for chemotherapy response evaluation (Table 2). The response rate of TKI was similar if given as a first- or second-line treatment (P = 0.259), calculated as 76.5% for chemotherapy-naïve patients in the study group and 68.9% for chemotherapy-refractory patients in the control group.

3.2. Chemotherapy response 3.5. Treatment and overall survival Among the 203 patients, all patients were available for chemotherapy response evaluation (Table 2). There was a statistically significant difference in the RR of the study group compared with that of the control group (13.2% vs. 34.1%, P = 0.002). In the subgroup of patients who received platinum-based chemotherapy (n = 187), RR was 14.3% in study group and 34.4% in control group (P = 0.005). Clinical characteristics, including gender, smoking history, pathological type, ECOG status, clinical disease stage at diagnosis, EGFR mutation type, and chemotherapy agents, were analyzed in a logistic regression model to evaluate the predictive value of each factor to RR. Multivariate logistic regression analysis indicated that previous TKI treatment (odds ratio [OR] = 3.386; 95% CI = 1.53–7.50, P = 0.003) and advanced clinical stage (OR = 4.821; 95% CI = 1.05–22.05) were independent negative predictive factors of response to chemotherapy. The overall disease control rate (DCR, RR and stable disease) was 76.4% (155/203 patients), which corresponded to a DCR of 55.9% in the study group and 86.7% in the control group (P < 0.001).

On April 22, 2013, 68.5% (139/203) patients had died. At the end of the last follow-up, thirty-three patients (16.3%) with no evidence of disease progression or unknown treatment. A total of 107 patients received TKIs or chemotherapy in subsequent treatment (Table 1). The median OS was 27.9 months (95% CI = 25.22–30.58) in all study subjects. The OS was significantly longer in the control group (median OS = 31.7 months, 95% CI = 27.21–36.19) compared with that in study group (median OS = 23.5 months; 95% CI = 19.29–27.70, P < 0.001) (Fig. 2). Clinical variables were analyzed using the multivariate Cox regression model, and results indicated that frontline EGFR-TKI treatment (HR = 1.91; 95% CI = 1.33–2.76, P < 0.001), as well as ECOG status (HR = 1.93; 95% CI = 1.01–3.70, P = 0.047) were independent prognostic factors of OS. The median survival beyond second-line, which was calculated by OS and PFS, was 14.6 months in the control group compared with only 8.6 months in the study group (Fig. 3). 4. Discussion

3.3. Progression-free survival of chemotherapy All of the patients were available for survival analysis. Median progression-free survival (PFS) was 6.0 months (95% CI = 5.34–6.66) for the whole cohort. Patients in the control group experienced a median PFS of 6.9 months (95% CI = 6.01–7.79) compared with only 3.9 months (95% CI = 2.51–5.30, P < 0.001) in patients that received chemotherapy after TKI failure (Fig. 1A). Among patients

In this study, we aimed at assessing the sensitivity of chemotherapy after EGFR-TKI failure and compared the RR and PFS of chemotherapy in TKI-naïve and -refractory patients. Our work demonstrated that frontline EGFR-TKI treatment yielded a significantly decreased RR and shorter PFS in patients who received subsequent chemotherapy when compared to those that received first-line chemotherapy. We also evaluated the influence of

222

Z. Zeng et al. / Lung Cancer 86 (2014) 219–224

Fig. 1. Progression-free survival of chemotherapy (A) and EGFR-TKI treatment (B) in the study and control groups.

Fig. 2. Overall survival in the study and control groups.

first-line chemotherapy on subsequent EGFR-TKI treatment, finding that the RR and PFS of EGFR-TKI were similar in chemotherapy-naïve and -refractory patients. Thus, we predict that first-line TKI treatment may lead to a significantly reduced efficacy of subsequent chemotherapy, while TKI treatment after chemotherapy would not reduce the efficacy (Fig. 3).

Fig. 3. Clinical course of EGFR mutant patients receiving first-line EGFR-TKIs or second-line EGFR-TKI. a Calculated by OS and PFS.

Randomized trials have demonstrated improvement RR and PFS over platinum-based combination chemotherapy, but none of them have shown a prolonged OS [1,3–6,11]. TORCH [A Study of Tarceva or Chemotherapy for the Treatment of Advanced NonSmall-Cell Lung Cancer], a phase III randomized clinical trial that compared first-line EGFR-TKI followed by chemotherapy with first-line chemotherapy followed by second-line EGFR-TKI [12] in an unselected Caucasian population indicated that the RR of chemotherapy was not influenced by preceding EGFR-TKI treatment and first-line erlotinib followed by cisplatin–gemcitabine was inferior in terms of OS compared with the first-line chemotherapy. However, these findings were affected by the limited proportion of EGFR mutation patients in unselected Caucasian population, and could not represent the EGFR mutant patients at largely. To our knowledge, this is the first study examining the influence of frontline EGFR TKI on the sensitivity of chemotherapy. In our study, the RR of first-line chemotherapy was 34.1% and the median PFS was 6.9 months, which is similar to historical controls [13], suggesting that our data were reliable. The RR and median PFS in our study group were inferior to the control group, as well as historical controls [13]. Furthermore, to address whether the observed differences in RR and PFS between groups could be confounded by the unbalanced chemotherapy regimens distribution, we examined RR and PFS in the subset of patients who received platinum-base double agent chemotherapy. We observed a similar result: the PFS and RR of control group were superior to study group. Multivariate Cox regression analysis revealed that prior EGFR-TKIs treatment was an independent risk factor for disease progression and lack of response to chemotherapy. These findings suggest that frontline EGFR-TKIs treatment did influence the efficacy of subsequent chemotherapy in EGFR mutant patients in clinical practice. This TKI-related change of subsequent chemotherapy sensitivity may be partially explained by multidrug resistance, in which the cancer cell becomes resistant to a variety of structurally unrelated drugs [14]. TKI may induce biological effects that lead to chemotherapy resistance. Our previous study in cell lines found that exposure to paclitaxel resulted in increased pEGFR and greater anti-VEGF activity. This increase in phosphorylation was inhibited by subsequent exposure to gefitinib, whereas prior exposure to gefitinib reduced this inhibition [15]. The T790M mutation, along with c-Met gene amplification, accounts for more than 50% of acquired EGFR-TKI resistance in EGFR mutant patients [16], and both mechanisms can promote increased signaling though the PI3K/Akt pathway [16], while the PI3K/Akt pathway also affects the sensitivity of cisplatin [17]. Hence, EGFR-TKI resistance mechanisms that arise in frontline treatment may contribute to reduced

Z. Zeng et al. / Lung Cancer 86 (2014) 219–224

subsequent chemo-sensitivity compared with that in TKI-naïve patients. In the current study, patients in the control arm had a significantly longer overall survival than those in the study arm (P < 0.001). Furthermore, the survival beyond second-line was longer in control group than study group (Fig. 3). This maybe partially attributable to different influence of first line treatment on subsequent anti-cancer therapy or the shrinking PFS of chemotherapy after frontline EGFR-TKI treatment. However, we noted that there were several limitations in this retrospective study may influence overall survival. The most important of which is that this non-randomized study with unmatched populations and unbalanced subsequent treatment. Since patients enrolled in study group was treated chemotherapy in EGFR-TKI failure setting, some EGFR mutant patients who manifested a more indolent disease course show no evidence of disease progression on EGFR-TKI treatment might not be enrolled in the study for the absence of post-TKI chemotherapy. Hence, survival differences between study group and control group can be difficult to interpret because of confounding by the potential bias in patient selection. Furthermore, assessment of overall survival can be difficult to interpret because of confounding by the unbalanced subsequent treatments. At the end of last follow up, a higher proportion of patients in control group (58.5% vs. 41.1%) were known have received systematic anti-cancer treatment after disease progression on second-line treatment, which may contribute to an imbalance favoring the control group. Although subgroup analysis and multivariate Cox regression model were performed to minimize the bias, further studies are needed to validate the differences we observed in OS. This question will be addressed in ENSURE study. ENSURE is a randomized phase III study which compared erlotinib with platinum-based chemotherapy as first-line treatment for NSCLC patients harboring EGFR mutation, patients can crossover to the other group when progressive disease is documented. OS is the second endpoint of the study. It is also interesting to consider how first-line chemotherapy might affect subsequent EGFR-TKI therapy. Rosell et al. [2] conducted a phase II study that determined that the RR and PFS of EGFR-TKI given as first- or second-line treatment were similar in patients with EGFR mutations. The response rates were 73.5% and 67.4% for first-line and second-line EGFR-TKI, respectively. The median PFS was 14.0 months for first-line EGFR-TKI compared with 13.0 months for chemotherapy-refractory patients that received TKI as a second-line treatment (P = 0.62). Our result is consistent with the observation of Rosell et al., suggesting that second-line EGFR-TKI could maintain the anti-cancer effects similar first-line therapy. However, the phase III trial NEJ002 reported a conflicting result [6], whereby the response rate of EGFR-TKI decreased from 73.3% with first-line treatment to 58.5% in second-line treatment. However, the discordant results among clinical trial warrant further investigation from comparative, randomized clinical trials. Given that the sequence of administration may affect the subsequent treatment strategy, patients who received EGFR TKI as first-line may lose the opportunity to receive chemotherapy due to the poor personal status after EGFR TKI failure, and eventually affect the survival outcome [18]. It is arguable whether EGFR-TKI should be given as a first- or second-line treatment for patients with activating EGFR mutations since overall survival was not different with either treatment regimen [19]. However, considering the lower toxicity, higher efficacy and better tolerance by patients with poor performance status, patients received first-line EGFR TKI had better health-related quality of life (QoL) [4–6,20]. Hence, first-line EGFR TKI is a standard treatment for EGFR mutant patients, though the PFS prolongation did not translate into OS benefit. Recently, the phase III trial FASTACT-2 demonstrated that the intercalated chemotherapy and erlotinib significantly prolonged both PFS and

223

OS of patients with EGFR mutations [21]. This is the first trial to show prolonged OS of EGFR mutant patients, indicating that intercalated chemotherapy combined with TKI might have minimized the negative interaction of these anti-cancer treatments and be an alternative approach in EGFR-mutant patients. 5. Conclusion In summary, we retrospectively found that frontline EGFRTKI treatment may lead to a decreased objective response rate and shorter progression-free survival of subsequent chemotherapy in EGFR-mutant patients. For EGFR mutant patients, the influence of EGFR-TKI on subsequent chemotherapy will be critical in establishing the sequence and timing of EGFR-TKI vs conventional chemotherapy in the management of advanced NSCLC, we are looking forward to more data from randomized trial to validate our findings. Conflict of interest statement Yi-Long Wu has received honorarium from Roche, Eli Lilly, AstraZeneca, Pfizer and Sanofi. For the remaining authors none were declared. Funding This work did not receive any funding. Acknowledgements The authors thank Zhi-hong Chen and Jian Su for the careful laboratory data analysis. She-juan An, Jian-guang Chen and Shiliang Chen for the clinical information collection. References [1] 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;361:947–57. [2] Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009;361:958–67. [3] Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13:239–46. [4] 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 mutationpositive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011;12:735–42. [5] 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;11:121–8. [6] 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;362:2380–8. [7] Costa DB, Kobayashi S, Tenen DG, Huberman MS. Pooled analysis of the prospective trials of gefitinib monotherapy for EGFR-mutant non-small cell lung cancers. Lung Cancer 2007;58:95–103. [8] Jackman D, Pao W, Riely GJ, Engelman JA, Kris MG, Jänne PA, et al. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol 2010;28:357–60. [9] Ettinger DS, Akerley W, Bepler G, Blum MG, Chang A, Cheney RT, et al. Nonsmall cell lung cancer. J Natl Compr Canc Netw 2010;8:740–801. [10] Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205–16. [11] Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT, et al. First-SIGNAL: firstline single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol 2012;30:1122–8.

224

Z. Zeng et al. / Lung Cancer 86 (2014) 219–224

[12] Gridelli C, Ciardiello F, Gallo C, Feld R, Butts C, Gebbia V, et al. First-line erlotinib followed by second-line cisplatin-gemcitabine chemotherapy in advanced non-small-cell lung cancer: the TORCH randomized trial. J Clin Oncol 2012;30:3002–11. [13] Ardizzoni A, Boni L, Tiseo M, Fossella FV, Schiller JH, Paesmans M, et al. Cisplatinversus carboplatin-based chemotherapy in first-line treatment of advanced non-small-cell lung cancer: an individual patient data meta-analysis. J Natl Cancer Inst 2007;99:847–57. [14] Gillet JP, Gottesman MM. Mechanisms of multidrug resistance in cancer. Methods Mol Biol 2010;596:47–76. [15] Cheng H, An SJ, Zhang XC, Dong S, Zhang YF, Chen ZH, et al. In vitro sequencedependent synergism between paclitaxel and gefitinib in human lung cancer cell lines. Cancer Chemother Pharmacol 2011;67:637–46. [16] Brugger W, Thomas M. EGFR-TKI resistant non-small cell lung cancer (NSCLC): new developments and implications for future treatment. Lung Cancer 2012;77:2–8. [17] Chin TM, Quinlan MP, Singh A, Sequist LV, Lynch TJ, Haber DA, et al. Reduced Erlotinib sensitivity of epidermal growth factor receptor-mutant non-small cell

[18]

[19]

[20]

[21]

lung cancer following cisplatin exposure: a cell culture model of second-line erlotinib treatment. Clin Cancer Res 2008;14:6867–76. Zhou CC, Wu YL, Liu XQ, Wang CL, Chen GY, Ji FF, et al. Overall survival results from OPTIMAL (CTONG0802), a phase III trial of erlotinib versus carboplatin plus gemcitabine as first-line treatment for Chinese patients with EGFR mutation-positive advanced non-small cell lung cancer. J Clin Oncol 2012;30 [suppl; abstr 7520]. Mok T, Yang JJ, Lam KC. Treating patients with EGFR-sensitizing mutations: first line or second line – is there a difference? J Clin Oncol 2013;31: 1081–8. Thongprasert S, Duffield E, Saijo N, Wu YL, Yang JC, Chu DT, et al. Health-related quality-of-life in a randomized phase III first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients from Asia with advanced NSCLC (IPASS). J Thorac Oncol 2011;6:1872–80. 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;14:777–86.