Retrospective study of erlotinib in patients with advanced squamous lung cancer

Lung Cancer 77 (2012) 128–133

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Retrospective study of erlotinib in patients with advanced squamous lung cancer Jeng-Sen Tseng a,c , Tsung-Ying Yang a,d , Kun-Chieh Chen a,c , Kuo-Hsuan Hsu c,e , Hsuan-Yu Chen f , Gee-Chen Chang b,c,g,h,∗ a

Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan Institute of Biomedical Sciences, National Chung-Hsing University, Taichung, Taiwan d Institute of Medicine, Chung-Shan Medical University, Taichung, Taiwan e Division of Critical Care and Respiratory Therapy, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan f Institute of Statistical Science, Academia Sinica, Taipei, Taiwan g School of Medicine, China Medical University, Taichung, Taiwan h Comprehensive Cancer Center, Taichung Veterans General Hospital, Taichung, Taiwan b c

a r t i c l e

i n f o

Article history: Received 25 November 2011 Received in revised form 14 February 2012 Accepted 17 February 2012 Keywords: Erlotinib Non-small cell lung cancer Squamous cell carcinoma Epidermal growth factor receptor Epidermal growth factor receptor mutation

a b s t r a c t Background: The effective targeted therapy for lung squamous cell carcinoma (SCC) is needed. The epidermal growth factor receptor (EGFR) mutation rate is low in lung SCC. The aim of this study was to evaluate the status of erlotinib treatment and EGFR mutation in lung SCC patients. Methods: We retrospectively enrolled lung cancer patients with SCC histology and history of erlotinib treatment. The primary objective was to assess overall response rate (ORR) and disease control rate (DCR) and the secondary objective was to assess progression-free survival (PFS) and overall survival (OS). EGFR mutations were assessed in parts of patients using both direct sequencing and protein nucleic acid-locked nucleic acid polymerase chain reaction (PNA-LNA PCR) clamp methods. Results: In total, 92 patients were analyzed (75 men and 17 women, median age 69 years, and 74 current or former smokers). Sixteen patients achieved partial response and 9 had stable disease. The ORR was 17.4% and the DCR was 27.2%. The PFS and OS were longer in patients with disease control than with progressive disease (PFS 7.8 versus 1.3 months and OS 20.7 versus 2.7 months, both p < 0.0001). The 1-year survival rate was 21.7%. In 27 patients with adequate specimens for molecular analysis (including 4 PR and 4 SD), two (7.4%) had EGFR complex mutations. One patient experienced response to erlotinib and the other did not. Conclusions: A significant proportion of lung SCC patients would derive a clinical benefit from erlotinib treatment. The relatively higher response rate than the EGFR mutation rate in present study needs further evaluation. © 2012 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Lung cancer is the leading cause of cancer-related death worldwide [1]. The four major histologic types of lung cancer include adenocarcinoma, squamous cell carcinoma (SCC), large cell carcinoma and small cell carcinoma [2]. Although adenocarcinoma is the

Abbreviations: DC, disease control; DCR, disease control rate; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PNA-LNA PCR, protein nucleic acid-locked nucleic acid polymerase chain reaction; PR, partial response; PD, progressive disease; RECIST, Response Evaluation Criteria in Solid Tumors; SCC, squamous cell carcinoma; SD, stable disease; TKIs, tyrosine kinase inhibitors. ∗ Corresponding author at: Department of Medicine, School of Medicine, National Yang-Ming University, No. 155, Sec. 2, Linong Street, Taipei, 112, Taiwan, ROC. Tel.: +886 4 23592525x3250; fax: +886 4 23552590. E-mail address: [email protected] (G.-C. Chang). 0169-5002/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2012.02.012

most frequent histologic type currently, lung SCC still account for 25–30% of all lung cancer cases [3]. Many studies have focused on defining the individualization of non-small cell lung cancer (NSCLC) treatment and several novel anticancer agents have been proved to be active against lung adenocarcinomas [4–7]. By contrast, there was no effective targeted therapy for lung SCC to date. In recent years, the epidermal growth factor receptor (EGFR)targeted therapy has emerged as a novel and effective strategy for lung cancer management. Most studies of EGFR-tyrosine kinase inhibitors (TKIs) focused on patients with specific characteristics (e.g. gender, smoking status and histology) and active EGFR mutations. However, some lung SCC patients could derive a clinical benefit to the EGFR-TKIs in daily practice. In 2006, Achille et al. reported a case of one white male former smoker with advanced lung SCC, who responded to erlotinib [8]. No EGFR mutation was found in the tumor tissue. A phase III study named BR.21, which compared erlotinib with placebo in patients with advanced NSCLC after failure of at least

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one previous chemotherapy regimen, demonstrated female gender, adenocarcinoma, Asian ethnicity and non-smoking history as clinical predictors of better response [7]. Despite the low response rate in male smokers with SCC (3.8% in lung SCC patients), these subgroup patients derived a significant survival benefit from erlotinib treatment [9]. Another phase III study, which evaluated the efficacy of erlotinib as maintenance therapy, also showed the survival benefit in lung SCC patients irrespective of EGFR mutation status [10]. Several studies independently observed the objective responses of erlotinib in lung SCC patients [11–13]. However, the real efficacy of erlotinib in these patients remains unclear due to limited case numbers of these studies. We performed a retrospective cohort study to better understand the efficacy of erlotinib in lung SCC patients. 2. Methods and materials 2.1. Patients This was a retrospective study and the study cohort consisted of patients with advanced lung SCC treated with erlotinib at Taichung Veterans General Hospital, a 1505-bed medical center in Taiwan, from August 2005 to February 2011. We included lung cancer patients with histological or cytological diagnosis of inoperable SCC, history of erlotinib treatment and clinically measurable disease. Patients were excluded if they had only evaluable lesions, other active malignancy, prior history of other EGFR-TKIs treatments, incomplete data records or received other treatments concurrently. All patients received erlotinib at a daily oral dose of 150 mg initially. TNM (tumor, node, and metastases) staging was done according to the 6th edition of the American Joint Committee for Cancer (AJCC) staging system [14]. The study was approved by the institutional review board of Taichung Veterans General Hospital. 2.2. Data records and response evaluation Clinical data for analysis included patients’ age, gender, Eastern Cooperative Oncology Group performance status (ECOG PS), tumor stage, prior chemotherapy regimens, smoking status, pathology diagnosis type and erlotinib treatment history. Chest computed tomographies (CT), including the liver and adrenal glands, and other required image studies for response evaluation were reviewed by two chest physicians. Unidimensional measurements as defined by Response Evaluation Criteria in Solid Tumors (RECIST) were used in this study [15]. The primary objective was to assess the ORR and DCR of erlotinib treatment and the secondary objective was to assess the progression-free survival (PFS) and overall survival (OS). 2.3. EGFR mutation tests Direct sequencing can identify not only the typical sensitizing mutations but also rare and unknown mutations. However, the major limitation is its low sensitivity. Protein nucleic acid-locked nucleic acid polymerase chain reaction (PNA-LNA PCR) clamp has higher sensitivity but it can only detect specific mutation types. The real genetic profile of lung SCC is less understood and low sensitivity of direct sequencing has been questioned in many studies, especially for lung SCC cohort. So, in this study, EGFR mutation analyses were performed using both methods in patients with adequate specimens. Informed consents were obtained. Tumor specimens were procured for EGFR mutation analysis using direct sequencing as previously described [16]. Briefly, DNA was extracted from the tumors using a QIAmp DNA Mini kit (Qiagen,

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Valencia, CA) following the manufacturer’s protocols. The tyrosine kinase domain of the EGFR coding sequence, exons 18, 19, 20, 21, was amplified by polymerase chain reaction and sequenced bidirectionally with an ABI Prism 3730 DNA Analyzer following standard protocol. The details of PNA-LNA PCR clamp methods and the design of PCR primers were followed by Nagai et al. [17]. The real-time amplification monitoring for the PNA-LNA PCR clamp was done using Smart Cycler (Cepheid, Sunnyvale, CA) to detect mutations on tyrosine kinase domain of the EGFR coding sequence, exons 18, 19, 20 and 21. 2.4. Statistical methods Univariate analysis by Fisher’s exact test was conducted on ORR and DCR to evaluate the effects of clinical factors relating to patient and disease characteristics and previous treatments. Multivariate analyses using logistic regression model with stepwise selection method were performed for ORR and DCR. The Kaplan–Meier method was used to estimate PFS and OS. Differences in survival time between disease control status and lines of therapy were analyzed using the log-rank test. Multivariate analyses using Cox proportional hazard model with stepwise selection method were performed for PFS and OS. All statistical tests were done with SAS version.9.1 software (SAS Institute Inc). Two-tailed tests and p values <0.05 for significance were used. 3. Results 3.1. Patient characteristics There were total 108 patients with advanced lung SCC and history of erlotinib treatment in our hospital during this period. Eleven patients were excluded due to incomplete data records or without measurable lesions. Another 5 patients were excluded because of receiving other treatments concurrently (2 cytotoxic chemotherapies, 2 radiotherapies and 1 sunitinib). The remaining 92 patients were enrolled for analysis of erlotinib efficacy. The baseline characteristics are shown in Table 1. The median age was 69 years (range: Table 1 Baseline demographic and clinical characteristics. Characteristics Number of patients Age, yrs, median (range) Gender, n (%) Male Female ECOG PS, n (%) 0 1 2 3 4 Stage, n (%) Stage IIIB Stage IV Prior chemotherapy, n (%) 0 1 2 or more Smoking status, n (%) NS C/FS Diagnosed by, n (%) Histology Cytology

92 69 (35–89) 75 (81.5) 17 (18.5) 6 (6.5) 39 (42.4) 27 (29.3) 16 (17.4) 4 (4.3) 9 (9.8) 83 (90.2) 9 (9.8) 20 (21.7) 63 (68.5) 18 (19.6) 74 (80.4) 68 (73.9) 24 (26.1)

ECOG PS, Eastern Cooperative Oncology Group performance status; NS, nonsmoker; C/FS, current or former smoker.

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Table 2 Best response to erlotinib in patients with lung squamous cell carcinoma. Best response

n (%)

Complete response (CR) Partial response (PR)a Overall response rate (ORR = CR + PR) Stable disease (SD)b Disease control rate (DCR = CR + PR + SD) Progressive disease (PD)

0 (0) 16 (17.4) 16 (17.4)

a b

9 (9.8) 25 (27.2) 67 (72.8)

3 patients are still under erlotinib treatment without PD. 1 patients is still under erlotinib treatment without PD.

35–89 years) and 75 patients (81.5%) were male. Seventy-four patients (80.4%) were current or former smokers and majority of our patients (90.2%) had received at least one previous chemotherapy regimen. Eighty-three patients (90.2%) had metastatic lung cancer and 45 patients (48.9%) had ECOG PS 0-1 at baseline. 3.2. Efficacy The results of best tumor response are shown in Table 2. Sixteen patients achieved PR and 9 had SD. No patient achieved complete response. The ORR and DCR were 17.4% and 27.2% respectively. At the end of data cutoff, 4 patients (3 PR and 1 SD; total 4.3%) had not experienced progression at the last observation and their data were therefore censored. The ORR and DCR for each line of therapy are shown in Supplementary Table 1. Results of univariate analysis for ORR and DCR are shown in Table 3. No factor correlated significantly with ORR and DCR, but we observed the trends of higher response rate in female and nonsmokers (p = 0.069 and 0.077 respectively). In multivariate logistic regression model for ORR analysis, female patients (odds ratio 0.26, 95% CI 0.07–0.89; p = 0.032) were more likely to experience response. For DCR analysis, no covariate reached the significant level to entry to the model. Survival data were followed up until the end of July 2011. The outcome and best response analysis are shown in Table 4. The median PFS of all patients was 1.7 (95% CI 1.4–2.0) months. The median PFS of patients with PR, SD and PD were 9.7 (95% CI 4.6–20.0), 6.3 (95% CI 4.1–10.3) and 1.3 (95% CI 0.9–1.6) months respectively. Patients with disease control (DC) had median PFS as 7.8 (95% CI 5.4–11.6) months. Kaplan–Meier curve of PFS is shown in Fig. 1. The PFS was significantly longer in patients with

Fig. 1. Kaplan–Meier plot showing progression-free survival (DC, disease control; PD, progressive disease).

DC than in those with PD (p < 0.0001). The median OS of all patients was 4.4 (95% CI 2.8–7.1) months (14.1% censored). The median OS of patients with PR, SD and PD were 20.7 (95% CI 5.3), 15.3 (95% CI 5.2–31.1) and 2.7 (95% CI 1.8–3.6) months respectively. Patients with DC had median OS as 20.7 (95% CI 10.8–26.4) months. The OS was significantly longer in patients with DC than with PD (p < 0.0001). Kaplan–Meier curves of PFS and OS for each line of therapy are showed in Supplementary Figs. 2 and 3. The 1-year survival rate was 21.7%. In multivariate Cox proportional hazard model for PFS analysis, no covariate reached the significant level to entry to the model. For OS analysis, patients with ECOG PS 0-1 (HR 0.50, 95% CI 0.32–0.79; p = 0.003) and non-smokers (HR 0.53, 95% CI 0.30–0.96; p = 0.036) were more likely to experience a longer OS. 3.3. EGFR mutation analysis Twenty-seven patients had adequate specimens for EGFR mutation analysis. The median age was 73 years (range: 43–85 years) and 20 patients (74.1%) were male. Twenty-two patients (81.5%) were current or former smokers and all patients had received at least one previous chemotherapy regimen. Eleven (40.7%) samples were surgical specimens. Among the 27 patients, 4 achieved PR and 4 had SD in response to erlotinib. No EGFR mutation was detected using direct sequencing. EGFR mutations were identified in 2 of 27 patients (7.4%) using PNA-LNA PCR clamp and both of them

Table 3 Univariate analysis of response rate and disease control rate. Characteristics Gender Male Female Age (yr) <65 65 ECOG PS 0–1 2 Smoking NS C/FS Previous CT 0–1 2 Stage IIIB IV

Patient no.

Response rate (%)

75 17

13.3 35.3

33 59

24.2 13.6

45 47

22.2 12.8

18 74

33.3 13.5

29 63

27.6 12.7

9 83

12.2 16.9

p

Disease control rate (%)

0.069

p 0.225

24.0 41.2 0.253

1.00 27.3 27.1

0.278

0.485 31.1 23.4

0.077

0.244 38.9 24.3

0.136

0.618 31.0 25.4

0.653

1.000 22.2 27.7

ECOG PS, Eastern Cooperative Oncology Group performance status; NS, nonsmoker; C/FS, current or former smoker; CT, chemotherapy.

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Table 4 Outcome and best response analysis. Best Response

Median PFS (m)a (95% CI)

Median OS (m)b (95% CI)

PR SD DC PD

9.7 (4.6–20.0) 6.3 (4.1–10.3) 7.8 (5.4–11.6) 1.3 (0.9–1.6)

20.7 (5.3) 15.3 (5.2–31.1) 20.7 (10.8–26.4) 2.7 (1.8–3.6)

Total

1.7 (1.4–2.0)

4.4 (2.8–7.1)

1-year survival rate (%)b – – – – 21.7

PFS, progression-free survival; OS, overall survival; PR, partial response; SD, stable disease; DC, disease control; PD, progressive disease. a 4 patients are still under erlotinib treatment without PD. b 13 patients are still alive.

disclosed complex mutations (Supplementary Fig. 1). One patient had L858R and exon 19 deletion and achieved PR in response to erlotinib. The other patient had L858R and T790M and had progressive disease after erlotinib treatment.

4. Discussion EGFR-TKIs have been proved to be active against EGFR mutant NSCLC. Many studies therefore focused on patients with characteristics associated with the presence of active mutations, especially those with adenocarcinoma histology [4,18,19]. The frequency of EGFR mutations is much lower in lung SCC patients, ranging from 0 to 5% in various reports [20–24]. Study with largest cohort was conducted by Miyamae et al. [21], and EGFR mutations were detected in 3.4% among 87 lung SCC specimens using SmartAmp2 and PNA-enriched sequencing methods. In our unpublished data, we retrospectively obtained 247 lung SCC samples (including 27 in the present study) for EGFR mutation analysis (median age 70 years, 91.5% males and 88.7% current or former smokers). Majority of these samples (86.6%) were surgical specimens. EGFR mutation was detected in 6 of the 247 patients (2.4%) using direct sequencing (2 with exon 19 deletion and 4 with L858R), yielding results similar to those of Miyamae et al.’s study. In the present study, PNA-LNA PCR clamp had detected 2 patients with EGFR complex mutations and yielded a 7.4% (2/27) mutation rate. The patient harboring L858R and exon 19 deletion experienced response and the other patient with L858R and T790M did not. According to previous reports, the non-adenocarcinoma histology and the presence of T790M mutation may account for the lower efficacy of erlobinib [25,26]. The ORR of our study was 17.4%, which was much higher than the reported EGFR mutation rates. We searched for studies that have reported the ORR of erlotinib in East Asian lung SCC patients. Studies that focused on efficacy of erlotinib after gefitinib failure were excluded. The results are summarized in Supplementary Table 2 [11–13,27,28]. We found 5 studies with total 81 patients. Pooled analysis showed an ORR of 16.0%, which was similar to that of our results. Furthermore, in the present study, there were 3 patients who did not harbor EGFR mutations achieved PR in response to erlotinib. Despite the tight association of EGFR mutations with the responsiveness of EGFR-TKIs in lung adenocarcinomas, the relatively high ORR of erlotinib in lung SCC patients could not be solely explained by the EGFR status. The sensitivity of EGFR mutation tests has been suspected to be one of the possible reasons for the responses to EGFR-TKIs in patients without detectable EGFR mutations [28,29]. However, both Miyamae et al.’s study [21] and our study used the sensitive methods to detect EGFR mutations. According to the Catalogue of Somatic Mutations in Cancer (COSMIC) (v54) database, the frequency of EGFR mutations is 5.1% in 2458 lung SCC samples [30]. It might be less likely to explain the relative high ORR only by the sensitivity of detection methods.

The EGFR mutations seem to be evenly distributed in the lung tumors. Recently, Hsu et al. showed that the central and peripheral parts of 45 microdissected lung tumors had identical EGFR mutation status [31]. In the study by Yatabe et al., identical EGFR mutations were also found throughout individual lung tumors in a trans-sectional analysis and no discordant mutation patterns were detected among paired primary and metastatic site samples [32]. These results suggested that neither sizes nor locations of tumor sampling could account for the responses to erlotinib in patients without detectable EGFR mutations. Another possibility is that erlotinib might target additional pathways other than the EGFR mutations. Although several studies independently observed the responses to erlotinib after gefitinib failure in NSCLC patients [33,34], it is still doubtful that erlotinib and gefitinib provide equal benefits. However, maximal tolerated dose of erlotinib might explain a SD, but not a PR, because some patients with lung SCC were also sensitive to gefitinib. In 2004, Kozuki et al. reported the efficacy of gefitinib in patients with lung SCC [35]. Three of 12 patients (25%, 95% CI 9–43%) with lung SCC achieved PR. Furthermore, objective responses to erlotinib have been observed in patients with advanced NSCLC who do not possess active EGFR mutations [8,28]. As both EGFR-TKIs, erlotinib and gefitinib, had effects on lung SCC patients, there might be additional mechanisms other than activating EGFR mutations. Both the BR.21 and TRUST trials disclosed a significantly higher response rate in NSCLC patients with Asian ethnicity [7,36] and the ORR of our study was higher than expected from the BR.21 trial. An ethic difference of responses to erlotinib might also exist in lung SCC subgroup. The median OS of present study was significantly longer in patients with better ECOG PS and non-smokers. These results are compatible with a recent published study, which showed that performance status and smoking status are independent prognostic factors for survival in NSCLC [37]. The median OS was 4.4 months, which was shorter than that of BR.21 and TRUST trials (6.7 and 7.9 months respectively) [7,38]. However, our cohort consisted exclusively of lung SCC patients and a significant proportion of our patients had poor performance status and received erlotinib as salvage treatment. The median PFS of the present study was 1.7 months, which was similar to that of Perng et al.’s study (2 months in SCC subgroup) [12]. In our study, 18 patients (19.6%) were never smokers. Majority of them were female. As in the review article by Sun et al., 25% of lung cancer patients are not attributable to smoking and there is high proportion of never smokers in Asian women with lung cancer [39]. In the Japanese cohort reported by Kawaguchi et al., 36.2% of female lung SCC patients were never smokers (n = 991) [37]. Several risk factors, such as environmental tobacco smoke, cooking oil vapors and wood or coal burning, are reported to be associated with lung cancer in never smokers [39,40], which exposures are also common in Taiwanese women. Due to the retrospective nature of the present study, it is difficult to evaluate these factors contributing to our cohort.

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There are three major limitations of this study. First, this is a retrospective study. Although data were collected retrospectively, we tried to ensure the validity of patients’ characteristics and excluded patients with confounding factors that may lead to incorrect response evaluation. Second, the study cohort was heterogeneous regarding performance status and lines of therapy. This might explain partly, why 1-year survival and DCR are lower than expected from clinical studies in second line treatments. Third, there were only 27 patients with adequate specimens for EGFR mutation analysis. However, we used both direct sequencing and PNA-LNA PCR clamp methods for EGFR mutation analysis and the results disclosed the discrepancy between the ORR and EGFR mutation rate in lung SCC patients. There are only few treatment options for patients with advanced lung SCC beyond standard platinum doublet chemotherapy. Several studies try to investigate the effectiveness of combination therapies, such as docetaxel and intermittent erlotinib. Preliminary results of a phase II randomized trial, which investigated docetaxel and intermittent erlotinib versus erlotinib as second line therapy for patients with advanced NSCLC (n = 32), showed median PFS 2.3 and 3.1 months and DCR 25% and 50% in each group. Majority of these patients were male (90.6%), smokers (93.7%) and nonadenocarcinoma (71%) [41]. Another study on the same topic with similar design is also ongoing [42]. Final results of these studies may provide us another aspect on lung SCC management. 5. Conclusion In conclusion, a significant proportion of lung SCC patients would derive a clinical benefit from erlotinib treatment. Here, we showed that overall response rate of erlotinib in lung SCC patients was much higher than the frequency of EGFR mutations. The major limitation of the present study is its retrospective nature. Prospective studies with larger cohort should be conducted to verify the efficacy of erlotinib in lung SCC patients and to define the underlying mechanisms. Conflict of interest statement

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14] [15]

[16]

We have no conflict of interest to disclose. [17]

Funding None. [18]

Acknowledgment We would like to acknowledge for the statistical assistance provided by Kuang-Hsi Chang, MS, Biostatistics Task Force of Taichung Veterans General Hospital, Taichung, Taiwan.

[19]

Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.lungcan.2012.02.012.

[20]

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