- Email: [email protected]
Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Advanced Squamous Cell Lung Cancer
Original Study
Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Advanced Squamous Cell Lung Cancer Jianlin Xu,1 Tianqing Chu,1 Bo Jin,1 Xue Dong,1 Yuqing Lou,1 Xueyan Zhang,1 Huiming Wang,1 Hua Zhong,1 Chunlei Shi,1 Aiqing Gu,1 Liwen Xiong,1 Yizhuo Zhao,1 Liyan Jiang,1 Jie Zhang,2 Baohui Han1 Abstract The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in squamous cell carcinoma (SCC) and the role of EGFR testing in SCC remain debatable. We retrospectively identified patients with SCC of the lung who had undergone EGFR testing. The EGFR mutation-positive patients had improved overall survival with TKI therapy compared with that of the patients with EGFR wild-type SCC. TKI therapy could be an option for patients with EGFR-mutated SCC. Background: The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in squamous cell carcinoma (SCC) of the lung remains controversial, and the role of EGFR testing in patients with SCC of the lung remains debatable. Patients and Methods: We retrospectively identified patients with stage IIIB or IV SCC of the lung who had undergone EGFR testing at Shanghai Chest Hospital from January 2009 to December 2013. Results: A total of 29 EGFR mutation-positive patients (22 patients had received TKI therapy and 7 had not) and 151 EGFR wild-type patients (27 patients had received TKI therapy and 124 had not) were available for an analysis of efficacy. The EGFR mutation-positive patients had significantly improved overall survival (OS) with EGFR TKI therapy compared with those who had not received EGFR TKIs (18.04 months [95% confidence interval (CI), 13.47-22.61 months] vs 13.18 months [95% CI, 5.22-21.13]; P ¼ .015). Patients with wild-type EGFR did not have an improvement in OS with TKI therapy compared with those who had not received TKIs (14.03 months [95% CI, 11.11-16.9 months] vs. 13.63 months [95% CI, 11.91-15.36]; P ¼ .927). The progression-free survival (PFS) for EGFR mutation-positive and EGFR wild-type patients was 3.94 months (95% CI, 2.73-5.15 months) and 1.94 months (95% CI, 0.89-2.99 months), respectively (P ¼ .004). Conclusion: EGFR TKIs could be an option for the treatment of SCC, and EGFR mutation detection can help to select a subgroup of patients who would have the best response to TKIs. Clinical Lung Cancer, Vol. 17, No. 4, 309-14 ª 2015 Elsevier Inc. All rights reserved. Keywords: EGFR, Mutation, NSCLC, SCC, TKI therapy
Introduction Lung cancer is the most common cause of cancer-related deaths worldwide. Nonesmall-cell lung cancer (NSCLC) constitutes approximately 85% to 90% of all lung cancers.1 Squamous cell cancer (SCC) of the lung is one of the major subtypes of NSCLC 1
Department of Pulmonary Medicine, Department of Pathology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China 2
Submitted: Sep 3, 2015; Revised: Nov 8, 2015; Accepted: Nov 12, 2015; Epub: Dec 1, 2015 Address for correspondence: Baohui Han, PhD, Department of Pathology, Shanghai Chest Hospital, Shanghai Jiaotong University, Huaihai West Road No. 241, Shanghai 230032, China E-mail contact: [email protected]
1525-7304/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cllc.2015.11.009
and accounts for approximately 20% to 30% of cases of NSCLC.2 Our understanding of the development of lung adenocarcinoma (ADC) has greatly improved during the past decade, especially since the discovery of epidermal growth factor receptor (EGFR) mutations and subsequent EGFR-targeted therapies.3-6 Compared with lung ADC, progress in the treatment of advanced SCC of the lung has been modest. Owing to the relatively low frequency of EGFR mutations in SCC,7-9 evidence regarding the efficacy of EGFR tyrosine kinase inhibitors (TKIs) for patients with lung SCC according to EGFR mutation status is limited. In addition, clinical data supporting the efficacy of EGFR TKIs in the treatment of advanced lung SCC are controversial. The Iressa in NSCLC FOR Maintenance (INFORM) and Iressa Survival Evaluation in Lung Cancer (ISEL) studies demonstrated that EGFR TKIs failed to show
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EGFR TKIs for Advanced SCC efficacy in patients with lung SCC compared with placebo.10,11 However, a subgroup analysis of the BR.21 and Sequential Tarceva in Unresectable NSCLC (SATURN) clinical trials showed that treatment with EGFR TKIs was effective in patients with SCC.12,13 A meta-analysis demonstrated that EGFR TKIs exert a modest therapeutic effect compared with placebo in EGFR-unselected patients with advanced SCC of the lung. That meta-analysis and another case report upheld the view that EGFR mutationindependent mechanisms might explain the efficacy of EGFR inhibitors in patients with lung SCC.14,15 However, other studies have suggested that detection of EGFR mutations can help patients with lung SCC receive EGFR TKI therapy and achieve better survival benefits.16,17 The efficacy of EGFR TKIs against lung SCC is still controversial, and the role of EGFR testing in patients with lung SCC remains debatable. In the present study, we summarized the clinical data from patients with local stage IIIB or metastatic stage IV lung SCC who had undergone EGFR testing at the Shanghai Chest Hospital. We then investigated the efficacy of EGFR TKIs in the treatment of patients with EGFR-mutant or EGFR wild-type SCC.
Patients and Methods Patients A retrospective study of patients treated at the Shanghai Chest Hospital from January 2009 to December 2013 was conducted. The institutional review board of the Shanghai Chest Hospital approved the study. The baseline clinical characteristics included age at diagnosis, smoking history, and gender, which were abstracted from the electronic medical records by trained and experienced physicians. NSCLC staging was performed according to the seventh edition of the TNM classification. The inclusion criteria were pathologically confirmed local stage IIIB or metastatic stage IV SCC of the lung (including mixed) and testing for the detection of EGFR mutations.
Test Method for Detection of EGFR Mutations DNA was extracted from 5 serial slices of a 5-mm paraffin section using the DNA FFPE Tissue Kit (Qiagen, Hilden, Germany). The highly sensitive method termed the “Amplification Refractory Mutation System” (ARMS) was used to detect mutations in the EGFR gene using the DxS EGFR mutation test kit, according to the manufacturer’s protocol.18
the median values and 2-sided 95% confidence intervals (CIs) and were analyzed using the Kaplan-Meier method. Statistical significance was defined as P < .05. SPSS software, version 22 (SPSS Inc., Chicago, IL) was used for all statistical analyses.
Results Patient Characteristics Overall, 223 patients with lung SCC underwent EGFR testing. EGFR mutations were detected in 33 patients and included the following: deletion of exon 19 (17 of 33 patients, 51.5%), an L858R point mutation in exon 21 (12 of 33, 36.4%), and 21R831H, G719X, 18S695N þ I706T, and 20P723S mutations. In all, 190 of the 223 patients had wild-type EGFR. Of the 33 EGFR mutation-positive patients, 4 discontinued their treatment at the Shanghai Chest Hospital and could not be followed up (3 patients with an exon 19 deletion and 1 with 20P723S mutation). Of the 190 patients with EGFR wild-type, 38 did not continue to receive therapy at the Shanghai Chest Hospital and could not be followed up. A total of 29 EGFR mutation-positive patients (22 patients received TKI therapy and 7 did not [by patient choice]) and 151 EGFR wild-type patients (27 patients received TKI therapy and 124 did not) were available for an analysis of efficacy. A flow chart of the patients is shown in Figure 1. The demographic data of the 180 patients are listed in Table 1.
Efficacy and Survival Comparisons For the EGFR mutation-positive patients, treatment with EGFR TKIs (n ¼ 22) led to significantly improved OS compared with treatment without EGFR TKIs (n ¼ 7; 18.04 months [95% CI, 13.47-22.61 months] and 13.18 months [95% CI, 5.22-21.13 months], respectively; P ¼ .015; Figure 2A). EGFR wild-type patients did not experience an improvement in OS from TKI therapy (n ¼ 27) compared with those (n ¼ 124) who did not receive TKI therapy (14.03 months [95% CI, 11.11-16.95 months] vs. 13.63 months [95% CI, 11.91-15.36 months]; P ¼ .927; Figure 2B).
Figure 1 Flow Diagram of Patients Studied
Clinical Assessments The clinical follow-up protocol included physical examination, an imaging examination, and routine laboratory tests, performed every 4 weeks. The objective tumor responses included complete response, partial response, stable disease, and progressive disease using the Response Evaluation Criteria in Solid Tumors, version 1.1.19 PFS was determined from the date of initiation of EGFR TKI therapy until the date of the first documented progression or the last follow-up visit. OS was measured from the date of diagnosis until the date of death or the last follow-up visit, whichever occurred first.
Statistical Analysis
310
-
For descriptive purposes, the demographic and clinical data were summarized as the median and range for the continuous variables; categorical variables were expressed and summarized using absolute numbers and percentages. The survival results were summarized as
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Abbreviations: EGFR ¼ Epidermal Growth Factor Receptor; mutþ ¼ Mutation Positive; mut- ¼ Mutation Negative; SCC ¼ Squamous Cell Carcinoma; TKI ¼ Tyrosine Kinase Inhibitor.
Jianlin Xu et al Table 1 Demographic Data (n [ 180) EGFR Mutation-Positive (n [ 29) Characteristic
EGFR TKI Therapy (n [ 22)
No EGFR TKI Therapy (n [ 7)
EGFR Mutation-Negative (n [ 151) EGFR TKI Therapy (n [ 27)
No EGFR TKI Therapy (n [ 124)
Age (year) Median
64
65
61
65
Range
36-71
46-77
45-81
36-85
16 (72.7)
5 (71.4)
24 (89.9)
115 (92.7)
6 (27.3)
2 (28.6)
3 (11.1)
9 (7.3)
Former smoker
2 (9.1)
1 (14.3)
4 (14.8)
14 (11.3)
Current smoker
10 (45.5)
4 (57.1)
17 (63.0)
91 (73.4)
Never smoker
10 (45.5)
2 (28.6)
6 (22.2)
19 (15.3)
Gender Male Female Smoking status
Stage IIIB
2 (9.1)
1 (14.3)
2 (7.4)
9 (7.3)
IV
20 (90.9)
6 (85.7)
25 (92.6)
115 (92.7)
1
21 (95.5)
7 (100.0)
25 (92.6)
112 (90.3)
>1
1 (4.5)
2 (7.4)
12 (9.7)
NA
NA
ECOG PS 0 (0.0)
Mutation status Exon 19 deletion
10 (45.5)
4 (57.1)
L858R in exon 21
10 (45.5)
2 (28.6)
2 (9.1)
1 (14.3)
Other Chemotherapy None
1 (4.5)
1 (14.3)
2 (7.4)
18 (14.5)
First line
8 (36.4)
2 (28.6)
8 (29.6)
41 (33.1)
13 (59.1)
4 (57.1)
17 (63.0)
65 (52.4)
Second line or more EGFR TKI
NA
NA
Erlotinib
11 (50.0)
13 (48.1)
Gefitinib
7 (31.8)
8 (29.6)
Icotinib
4 (18.2)
6 (22.2)
Data presented as n (%). Abbreviations: ECOG ¼ Eastern Cooperative Oncology Group; EGFR ¼ epidermal growth factor receptor; NA ¼ not applicable; PS ¼ performance status; TKI ¼ tyrosine kinase inhibitor.
A total of 49 patients were treated with EGFR TKIs. The PFS for EGFR mutation-positive patients and EGFR wild-type patients was 3.94 months (95% CI, 2.73-5.15 months) and 1.94 months (95% CI, 0.89-2.99 months), respectively (P ¼ .004; Figure 3). Of the 22 EGFR mutation positive-patients, 7 achieved a partial response and 11 achieved stable disease from EGFR TKI treatment. Of the 27 EGFR wild-type patients, none achieved a partial response, although 15 had stable disease from EGFR TKI treatment (Table 2).
Discussion Patients with ADC with sensitizing EGFR mutations can survive > 30 months from the onset of TKI therapy. However, evidence of the efficacy of EGFR TKIs for SCC according to EGFR mutation status is lacking. A retrospective study that focused on the assessment of erlotinib in the treatment of patients with lung SCC demonstrated a survival benefit20; however, most of these patients did not undergo testing to determine their EGFR
mutation status. In the present study, we summarized the clinical data from patients with lung SCC who had undergone EGFR testing. The results demonstrated that EGFR TKIs might be an option for the treatment of SCC. EGFR mutation detection helped to select a subgroup of patients who exhibited the best response to TKIs. In the present study, EGFR mutation-positive patients experienced a significantly improved OS from TKI therapy, but EGFR wild-type patients did not. These results were consistent with those of previous clinical trials. The OPTIMAL research study21 demonstrated that erlotinib was associated with survival benefits for patients with EGFR mutations, irrespective of the histologic type. The Tarceva Italian Lung Optimization Trial (TAILOR) study22 demonstrated that OS for EGFR wild-type patients with a SCC histologic type did not differ between the erlotinib-treated group and the control group. Thus, EGFR TKIs might be an option for EGFR mutation-positive patients but not for EGFR wildtype patients. The survival benefits for EGFR mutation-positive
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EGFR TKIs for Advanced SCC Figure 2 Kaplan-Meier Plots of Overall Survival (OS) of (A) Epidermal Growth Factor Receptor (EGFR) MutationPositive Patients and (B) EGFR Wild-Type Patients Stratified by Receipt of EGFR Tyrosine Kinase Inhibitor (TKI) Therapy
Table 2 Best Response to EGFR TKIs in Patients With Lung Squamous Cell Carcinoma EGFR Mutation Best Response CR PR SD PD ORR (CR þ PR) DCR (CR þ PR þ SD)
Yes (n [ 22) 0 7 11 6 7 18
(0) (31.8) (50.0) (27.3) (31.8) (81.8)
No (n [ 27) 0 0 15 12 0 15
(0) (0) (55.6) (44.4) (0) (55.6)
Data presented as n (%). Abbreviations: CR ¼ complete response; DCR ¼ disease control rate; EGFR ¼ epidermal growth factor receptor; ORR ¼ overall response rate; PD ¼ progressive disease; PR ¼ partial response; SD ¼ stable disease; TKIs ¼ tyrosine kinase inhibitors.
patients and the poor survival of EGFR wild-type patients suggests the importance of using EGFR mutation detection to guide the treatment of patients with SCC of the lung. To confirm the predictive value of EGFR mutation status for the benefit of EGFR TKI treatment in SCC of lung, we also compared the PFS and tumor response to EGFR TKI therapy between patients with EGFR mutations and those with wild-type EGFR. The results showed that the median PFS (3.94 months) was significantly longer for patients with EGFR mutations than that (1.94 months)
Figure 3 Kaplan-Meier Plots of Progression-Free Survival (PFS) for Patients Receiving Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) Therapy
312
-
Abbreviation: mutþ ¼ Mutation Positive.
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for patients with wild-type EGFR. Similarly, Fang et al,16 in a retrospective study, demonstrated that the PFS of EGFR-mutated patients and EGFR wild-type patients was 3.9 and 1.9 months, respectively. Hata et al17 reported that the median PFS of the EGFR-mutated and EGFR wild-type SCC patients was 1.4 and 1.8 months, respectively. However, the overall response rate (25.0% vs. 9.1%) and OS (14.6 vs. 11.0 months) have shown that EGFRTKIs seem to be more effective against EGFR-mutated SCC. A pooled analysis of 15 published reports analyzed the data from 27 patients with EGFR-mutated lung SCC who had received gefitinib therapy and reported that 8 of these 27 patients demonstrated a response to gefitinib.23 In that study, 7 of the 27 EGFR mutationpositive patients demonstrated a response to EGFR TKIs. However, none of the 27 EGFR wild-type patients with lung SCC achieved a response to EGFR TKIs. Precision EGFR detection can also help to select patients with EGFR-mutated SCC for EGFR TKI therapy to achieve the best efficacy. The EGFR mutation status should be considered in the prediction of clinical benefits from EGFR TKIs.24 Considering the importance of the classification of lung SCC using molecular diagnostics, experts have recommended that selected SCC tumors (from patients with minimal or remote smoking history) should be strongly considered for testing.25 Previously, the INFORM and ISEL studies demonstrated that EGFR TKIs failed to show efficacy in patients with lung SCC compared with placebo.10,11 This could be explained in part by the low frequency of EGFR mutations in lung SCC. In the present study, 223 patients underwent EGFR testing, and 33 patients were found to harbor EGFR mutations. According to previous studies, the EGFR mutation rate in SCC varies in different ethnicities, ranging from 1% to 15%.7,26,27 Most of these studies detected the EGFR gene mutation using direct DNA sequencing. In the present study, we used the ARMS method, which has a sensitivity much greater than that of DNA sequencing.28 The frequency of EGFR mutations in the present study was similar to that of our prospective multicenter study (IGNITE study), which showed that in an Asian population with lung SCC, the EGFR mutation frequency was 10%.29 We should also note the inferior efficacy of EGFR TKIs in patients with lung SCC compared with patients with ADC. In the present study, the PFS and OS for EGFR mutation-positive patients with SCC of the lung was 3.94 and 18.04 months, respectively, far
Jianlin Xu et al shorter than the PFS and OS for patients with ADC, who were treated with EGFR TKIs in a previous clinical trial.23 The reason for the inferior efficacy of EGFR TKIs in patients with lung SCC is not clear. It was reported that the alterations in the PI3K/RTK/RAS signaling pathway that are associated with smoking might be one of the most important reasons for the inferior efficacy.30,31 Recently, Soria et al32 reported that the second-generation EGFR TKI afatinib was associated with improved PFS and OS compared with the first-generation EGFR TKI erlotinib in EGFR-unselected patients with SCC. The reason for the superior efficacy of afatinib compared with erlotinib in patients with lung SCC warrants additional investigation. Moreover, as first- or second-line therapy for EGFR mutation-positive patients with lung SCC, whether chemotherapy or EGFR TKIs will provide better survival benefits should also be determined. In the present study, most patients received TKIs as second- or third-line therapy, which could explain, in part, the relatively short PFS (3.94 months). In the future, a clinical trial might be necessary to make a direct comparison between the effectiveness of TKIs and chemotherapy in this population. The results of the present study should be interpreted with the consideration of several limitations. First, the major limitation of the present study was its retrospective nature. Second, the small sample size in each cohort might have affected the statistical analysis. Furthermore, the present study might have included patients with tumors of mixed histologic features. Roggli et al33 addressed histologic heterogeneity in a comprehensive study of 27 patients with SCC, of whom, 4 (15%) had an ADC component. Some experts have suggested that most EGFR-mutated non-ADC patients had mixed ADC histologic features, and the sensitivity of EGFR TKIs in these patients might depend on the proportion of EGFR-mutated ADC components in the whole tumor.9,17 The diagnostic criteria in the World Health Organization classification of lung carcinomas34 require examination of the entire tumor. However, in “real-world” situations, the classification of most lung carcinomas is performed using small diagnostic biopsy or cytology type samples. Owing to the difficulty and complexity of pathologic diagnoses, especially those from small biopsy samples, it is impractical to determine whether all cases of lung SCC have an ADC component.
Conclusion The survival benefits for EGFR mutation-positive patients with SCC suggest that TKI therapy might be an option for the treatment of this population. Considering the different efficacy of EGFR TKIs in EGFR mutation-positive patients and EGFR wild-type patients, precision EGFR mutation detection should be used to help guide the treatment of patients with SCC.
Clinical Practice Points EGFR mutation-positive patients with SCC experienced survival
benefits from EGFR TKI therapy. EGFR wild-type patients with SCC failed to experience survival
benefits from EGFR TKI therapy. EGFR TKIs might also be an option for the treatment of SCC. EGFR gene mutation status has a predictive role in the treatment
of SCC.
Acknowledgments This work was supported by Key Projects of the Biomedicine Department, Science and Technology Commission of Shanghai Municipality (Project No. 11411951200). The funders played no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. We acknowledge support from the Department of Pathology, Shanghai Chest Hospital. We also thank Bo Jin, Tianqing Chu, Huiming Wang, Hua Zhong, Chunlei Shi, Aiqing Gu, Liwen Xiong, and Yizhuo Zhao for their provision of study materials or patients for the present study.
Disclosure The authors have stated that they have no conflicts of interest.
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EGFR TKIs for Advanced SCC 22. Garassino MC, Martelli O, Broggini M, et al. Erlotinib versus docetaxel as secondline treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. Lancet Oncol 2013; 14: 981-8. 23. Shukuya T, Takahashi T, Kaira R, et al. Efficacy of gefitinib for nonadenocarcinoma non-small-cell lung cancer patients harboring epidermal growth factor receptor mutations: a pooled analysis of published reports. Cancer Sci 2011; 102:1032-7. 24. Park SH, Ha SY, Lee JI, et al. Epidermal growth factor receptor mutations and the clinical outcome in male smokers with squamous cell carcinoma of lung. J Korean Med Sci 2009; 24:448-52. 25. Kerr KM, Bubendorf L, Edelman MJ, et al. Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer. Ann Oncol 2014; 25:1681-90. 26. Kenmotsu H, Serizawa M, Koh Y, et al. Prospective genetic profiling of squamous cell lung cancer and adenosquamous carcinoma in Japanese patients by multitarget assays. BMC Cancer 2014; 14:786. 27. Rekhtman N, Paik PK, Arcila ME, et al. Clarifying the spectrum of driver oncogene mutations in biomarker-verified squamous carcinoma of lung: lack of EGFR/KRAS and presence of PIK3CA/AKT1 mutations. Clin Cancer Res 2012; 18:1167-76.
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28. Liu Y, Liu B, Li XY, et al. A comparison of ARMS and direct sequencing for EGFR mutation analysis and tyrosine kinase inhibitors treatment prediction in body fluid samples of non-small-cell lung cancer patients. J Exp Clin Cancer Res 2011; 30:111. 29. Han B, Tjulandin S, Hagiwara K, et al. Determining the prevalence of EGFR mutations in Asian and Russian patients with advanced non-small-cell lung cancer (ANSCLC) of adenocarcinoma (ADC) and non-ADC histology: IGNITE study. Ann Oncol 2015; 26(suppl 1):i29-30. 30. Hirsch FR, Herbst RS, Gandara DR. EGFR tyrosine kinase inhibitors in squamous cell lung cancer. Lancet Oncol 2015; 16:872-3. 31. Perez-Moreno P, Brambilla E, Thomas R, et al. Squamous cell carcinoma of the lung: molecular subtypes and therapeutic opportunities. Clin Cancer Res 2012; 18: 2443-51. 32. Soria JC, Felip E, Cobo M, et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol 2015; 16:897-907. 33. Roggli VL, Vollmer RT, Greenberg SD, et al. Lung cancer heterogeneity: a blinded and randomized study of 100 consecutive cases. Hum Pathol 1985; 16:569-79. 34. Travis WD, Brambilla E, Muller-Hermelink HK, et al. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: IARC Press; 2004.
Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Advanced Squamous Cell Lung Cancer Jianlin Xu,1 Tianqing Chu,1 Bo Jin,1 Xue Dong,1 Yuqing Lou,1 Xueyan Zhang,1 Huiming Wang,1 Hua Zhong,1 Chunlei Shi,1 Aiqing Gu,1 Liwen Xiong,1 Yizhuo Zhao,1 Liyan Jiang,1 Jie Zhang,2 Baohui Han1 Abstract The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in squamous cell carcinoma (SCC) and the role of EGFR testing in SCC remain debatable. We retrospectively identified patients with SCC of the lung who had undergone EGFR testing. The EGFR mutation-positive patients had improved overall survival with TKI therapy compared with that of the patients with EGFR wild-type SCC. TKI therapy could be an option for patients with EGFR-mutated SCC. Background: The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in squamous cell carcinoma (SCC) of the lung remains controversial, and the role of EGFR testing in patients with SCC of the lung remains debatable. Patients and Methods: We retrospectively identified patients with stage IIIB or IV SCC of the lung who had undergone EGFR testing at Shanghai Chest Hospital from January 2009 to December 2013. Results: A total of 29 EGFR mutation-positive patients (22 patients had received TKI therapy and 7 had not) and 151 EGFR wild-type patients (27 patients had received TKI therapy and 124 had not) were available for an analysis of efficacy. The EGFR mutation-positive patients had significantly improved overall survival (OS) with EGFR TKI therapy compared with those who had not received EGFR TKIs (18.04 months [95% confidence interval (CI), 13.47-22.61 months] vs 13.18 months [95% CI, 5.22-21.13]; P ¼ .015). Patients with wild-type EGFR did not have an improvement in OS with TKI therapy compared with those who had not received TKIs (14.03 months [95% CI, 11.11-16.9 months] vs. 13.63 months [95% CI, 11.91-15.36]; P ¼ .927). The progression-free survival (PFS) for EGFR mutation-positive and EGFR wild-type patients was 3.94 months (95% CI, 2.73-5.15 months) and 1.94 months (95% CI, 0.89-2.99 months), respectively (P ¼ .004). Conclusion: EGFR TKIs could be an option for the treatment of SCC, and EGFR mutation detection can help to select a subgroup of patients who would have the best response to TKIs. Clinical Lung Cancer, Vol. 17, No. 4, 309-14 ª 2015 Elsevier Inc. All rights reserved. Keywords: EGFR, Mutation, NSCLC, SCC, TKI therapy
Introduction Lung cancer is the most common cause of cancer-related deaths worldwide. Nonesmall-cell lung cancer (NSCLC) constitutes approximately 85% to 90% of all lung cancers.1 Squamous cell cancer (SCC) of the lung is one of the major subtypes of NSCLC 1
Department of Pulmonary Medicine, Department of Pathology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China 2
Submitted: Sep 3, 2015; Revised: Nov 8, 2015; Accepted: Nov 12, 2015; Epub: Dec 1, 2015 Address for correspondence: Baohui Han, PhD, Department of Pathology, Shanghai Chest Hospital, Shanghai Jiaotong University, Huaihai West Road No. 241, Shanghai 230032, China E-mail contact: [email protected]
1525-7304/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cllc.2015.11.009
and accounts for approximately 20% to 30% of cases of NSCLC.2 Our understanding of the development of lung adenocarcinoma (ADC) has greatly improved during the past decade, especially since the discovery of epidermal growth factor receptor (EGFR) mutations and subsequent EGFR-targeted therapies.3-6 Compared with lung ADC, progress in the treatment of advanced SCC of the lung has been modest. Owing to the relatively low frequency of EGFR mutations in SCC,7-9 evidence regarding the efficacy of EGFR tyrosine kinase inhibitors (TKIs) for patients with lung SCC according to EGFR mutation status is limited. In addition, clinical data supporting the efficacy of EGFR TKIs in the treatment of advanced lung SCC are controversial. The Iressa in NSCLC FOR Maintenance (INFORM) and Iressa Survival Evaluation in Lung Cancer (ISEL) studies demonstrated that EGFR TKIs failed to show
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EGFR TKIs for Advanced SCC efficacy in patients with lung SCC compared with placebo.10,11 However, a subgroup analysis of the BR.21 and Sequential Tarceva in Unresectable NSCLC (SATURN) clinical trials showed that treatment with EGFR TKIs was effective in patients with SCC.12,13 A meta-analysis demonstrated that EGFR TKIs exert a modest therapeutic effect compared with placebo in EGFR-unselected patients with advanced SCC of the lung. That meta-analysis and another case report upheld the view that EGFR mutationindependent mechanisms might explain the efficacy of EGFR inhibitors in patients with lung SCC.14,15 However, other studies have suggested that detection of EGFR mutations can help patients with lung SCC receive EGFR TKI therapy and achieve better survival benefits.16,17 The efficacy of EGFR TKIs against lung SCC is still controversial, and the role of EGFR testing in patients with lung SCC remains debatable. In the present study, we summarized the clinical data from patients with local stage IIIB or metastatic stage IV lung SCC who had undergone EGFR testing at the Shanghai Chest Hospital. We then investigated the efficacy of EGFR TKIs in the treatment of patients with EGFR-mutant or EGFR wild-type SCC.
Patients and Methods Patients A retrospective study of patients treated at the Shanghai Chest Hospital from January 2009 to December 2013 was conducted. The institutional review board of the Shanghai Chest Hospital approved the study. The baseline clinical characteristics included age at diagnosis, smoking history, and gender, which were abstracted from the electronic medical records by trained and experienced physicians. NSCLC staging was performed according to the seventh edition of the TNM classification. The inclusion criteria were pathologically confirmed local stage IIIB or metastatic stage IV SCC of the lung (including mixed) and testing for the detection of EGFR mutations.
Test Method for Detection of EGFR Mutations DNA was extracted from 5 serial slices of a 5-mm paraffin section using the DNA FFPE Tissue Kit (Qiagen, Hilden, Germany). The highly sensitive method termed the “Amplification Refractory Mutation System” (ARMS) was used to detect mutations in the EGFR gene using the DxS EGFR mutation test kit, according to the manufacturer’s protocol.18
the median values and 2-sided 95% confidence intervals (CIs) and were analyzed using the Kaplan-Meier method. Statistical significance was defined as P < .05. SPSS software, version 22 (SPSS Inc., Chicago, IL) was used for all statistical analyses.
Results Patient Characteristics Overall, 223 patients with lung SCC underwent EGFR testing. EGFR mutations were detected in 33 patients and included the following: deletion of exon 19 (17 of 33 patients, 51.5%), an L858R point mutation in exon 21 (12 of 33, 36.4%), and 21R831H, G719X, 18S695N þ I706T, and 20P723S mutations. In all, 190 of the 223 patients had wild-type EGFR. Of the 33 EGFR mutation-positive patients, 4 discontinued their treatment at the Shanghai Chest Hospital and could not be followed up (3 patients with an exon 19 deletion and 1 with 20P723S mutation). Of the 190 patients with EGFR wild-type, 38 did not continue to receive therapy at the Shanghai Chest Hospital and could not be followed up. A total of 29 EGFR mutation-positive patients (22 patients received TKI therapy and 7 did not [by patient choice]) and 151 EGFR wild-type patients (27 patients received TKI therapy and 124 did not) were available for an analysis of efficacy. A flow chart of the patients is shown in Figure 1. The demographic data of the 180 patients are listed in Table 1.
Efficacy and Survival Comparisons For the EGFR mutation-positive patients, treatment with EGFR TKIs (n ¼ 22) led to significantly improved OS compared with treatment without EGFR TKIs (n ¼ 7; 18.04 months [95% CI, 13.47-22.61 months] and 13.18 months [95% CI, 5.22-21.13 months], respectively; P ¼ .015; Figure 2A). EGFR wild-type patients did not experience an improvement in OS from TKI therapy (n ¼ 27) compared with those (n ¼ 124) who did not receive TKI therapy (14.03 months [95% CI, 11.11-16.95 months] vs. 13.63 months [95% CI, 11.91-15.36 months]; P ¼ .927; Figure 2B).
Figure 1 Flow Diagram of Patients Studied
Clinical Assessments The clinical follow-up protocol included physical examination, an imaging examination, and routine laboratory tests, performed every 4 weeks. The objective tumor responses included complete response, partial response, stable disease, and progressive disease using the Response Evaluation Criteria in Solid Tumors, version 1.1.19 PFS was determined from the date of initiation of EGFR TKI therapy until the date of the first documented progression or the last follow-up visit. OS was measured from the date of diagnosis until the date of death or the last follow-up visit, whichever occurred first.
Statistical Analysis
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For descriptive purposes, the demographic and clinical data were summarized as the median and range for the continuous variables; categorical variables were expressed and summarized using absolute numbers and percentages. The survival results were summarized as
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Abbreviations: EGFR ¼ Epidermal Growth Factor Receptor; mutþ ¼ Mutation Positive; mut- ¼ Mutation Negative; SCC ¼ Squamous Cell Carcinoma; TKI ¼ Tyrosine Kinase Inhibitor.
Jianlin Xu et al Table 1 Demographic Data (n [ 180) EGFR Mutation-Positive (n [ 29) Characteristic
EGFR TKI Therapy (n [ 22)
No EGFR TKI Therapy (n [ 7)
EGFR Mutation-Negative (n [ 151) EGFR TKI Therapy (n [ 27)
No EGFR TKI Therapy (n [ 124)
Age (year) Median
64
65
61
65
Range
36-71
46-77
45-81
36-85
16 (72.7)
5 (71.4)
24 (89.9)
115 (92.7)
6 (27.3)
2 (28.6)
3 (11.1)
9 (7.3)
Former smoker
2 (9.1)
1 (14.3)
4 (14.8)
14 (11.3)
Current smoker
10 (45.5)
4 (57.1)
17 (63.0)
91 (73.4)
Never smoker
10 (45.5)
2 (28.6)
6 (22.2)
19 (15.3)
Gender Male Female Smoking status
Stage IIIB
2 (9.1)
1 (14.3)
2 (7.4)
9 (7.3)
IV
20 (90.9)
6 (85.7)
25 (92.6)
115 (92.7)
1
21 (95.5)
7 (100.0)
25 (92.6)
112 (90.3)
>1
1 (4.5)
2 (7.4)
12 (9.7)
NA
NA
ECOG PS 0 (0.0)
Mutation status Exon 19 deletion
10 (45.5)
4 (57.1)
L858R in exon 21
10 (45.5)
2 (28.6)
2 (9.1)
1 (14.3)
Other Chemotherapy None
1 (4.5)
1 (14.3)
2 (7.4)
18 (14.5)
First line
8 (36.4)
2 (28.6)
8 (29.6)
41 (33.1)
13 (59.1)
4 (57.1)
17 (63.0)
65 (52.4)
Second line or more EGFR TKI
NA
NA
Erlotinib
11 (50.0)
13 (48.1)
Gefitinib
7 (31.8)
8 (29.6)
Icotinib
4 (18.2)
6 (22.2)
Data presented as n (%). Abbreviations: ECOG ¼ Eastern Cooperative Oncology Group; EGFR ¼ epidermal growth factor receptor; NA ¼ not applicable; PS ¼ performance status; TKI ¼ tyrosine kinase inhibitor.
A total of 49 patients were treated with EGFR TKIs. The PFS for EGFR mutation-positive patients and EGFR wild-type patients was 3.94 months (95% CI, 2.73-5.15 months) and 1.94 months (95% CI, 0.89-2.99 months), respectively (P ¼ .004; Figure 3). Of the 22 EGFR mutation positive-patients, 7 achieved a partial response and 11 achieved stable disease from EGFR TKI treatment. Of the 27 EGFR wild-type patients, none achieved a partial response, although 15 had stable disease from EGFR TKI treatment (Table 2).
Discussion Patients with ADC with sensitizing EGFR mutations can survive > 30 months from the onset of TKI therapy. However, evidence of the efficacy of EGFR TKIs for SCC according to EGFR mutation status is lacking. A retrospective study that focused on the assessment of erlotinib in the treatment of patients with lung SCC demonstrated a survival benefit20; however, most of these patients did not undergo testing to determine their EGFR
mutation status. In the present study, we summarized the clinical data from patients with lung SCC who had undergone EGFR testing. The results demonstrated that EGFR TKIs might be an option for the treatment of SCC. EGFR mutation detection helped to select a subgroup of patients who exhibited the best response to TKIs. In the present study, EGFR mutation-positive patients experienced a significantly improved OS from TKI therapy, but EGFR wild-type patients did not. These results were consistent with those of previous clinical trials. The OPTIMAL research study21 demonstrated that erlotinib was associated with survival benefits for patients with EGFR mutations, irrespective of the histologic type. The Tarceva Italian Lung Optimization Trial (TAILOR) study22 demonstrated that OS for EGFR wild-type patients with a SCC histologic type did not differ between the erlotinib-treated group and the control group. Thus, EGFR TKIs might be an option for EGFR mutation-positive patients but not for EGFR wildtype patients. The survival benefits for EGFR mutation-positive
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EGFR TKIs for Advanced SCC Figure 2 Kaplan-Meier Plots of Overall Survival (OS) of (A) Epidermal Growth Factor Receptor (EGFR) MutationPositive Patients and (B) EGFR Wild-Type Patients Stratified by Receipt of EGFR Tyrosine Kinase Inhibitor (TKI) Therapy
Table 2 Best Response to EGFR TKIs in Patients With Lung Squamous Cell Carcinoma EGFR Mutation Best Response CR PR SD PD ORR (CR þ PR) DCR (CR þ PR þ SD)
Yes (n [ 22) 0 7 11 6 7 18
(0) (31.8) (50.0) (27.3) (31.8) (81.8)
No (n [ 27) 0 0 15 12 0 15
(0) (0) (55.6) (44.4) (0) (55.6)
Data presented as n (%). Abbreviations: CR ¼ complete response; DCR ¼ disease control rate; EGFR ¼ epidermal growth factor receptor; ORR ¼ overall response rate; PD ¼ progressive disease; PR ¼ partial response; SD ¼ stable disease; TKIs ¼ tyrosine kinase inhibitors.
patients and the poor survival of EGFR wild-type patients suggests the importance of using EGFR mutation detection to guide the treatment of patients with SCC of the lung. To confirm the predictive value of EGFR mutation status for the benefit of EGFR TKI treatment in SCC of lung, we also compared the PFS and tumor response to EGFR TKI therapy between patients with EGFR mutations and those with wild-type EGFR. The results showed that the median PFS (3.94 months) was significantly longer for patients with EGFR mutations than that (1.94 months)
Figure 3 Kaplan-Meier Plots of Progression-Free Survival (PFS) for Patients Receiving Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) Therapy
312
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Abbreviation: mutþ ¼ Mutation Positive.
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for patients with wild-type EGFR. Similarly, Fang et al,16 in a retrospective study, demonstrated that the PFS of EGFR-mutated patients and EGFR wild-type patients was 3.9 and 1.9 months, respectively. Hata et al17 reported that the median PFS of the EGFR-mutated and EGFR wild-type SCC patients was 1.4 and 1.8 months, respectively. However, the overall response rate (25.0% vs. 9.1%) and OS (14.6 vs. 11.0 months) have shown that EGFRTKIs seem to be more effective against EGFR-mutated SCC. A pooled analysis of 15 published reports analyzed the data from 27 patients with EGFR-mutated lung SCC who had received gefitinib therapy and reported that 8 of these 27 patients demonstrated a response to gefitinib.23 In that study, 7 of the 27 EGFR mutationpositive patients demonstrated a response to EGFR TKIs. However, none of the 27 EGFR wild-type patients with lung SCC achieved a response to EGFR TKIs. Precision EGFR detection can also help to select patients with EGFR-mutated SCC for EGFR TKI therapy to achieve the best efficacy. The EGFR mutation status should be considered in the prediction of clinical benefits from EGFR TKIs.24 Considering the importance of the classification of lung SCC using molecular diagnostics, experts have recommended that selected SCC tumors (from patients with minimal or remote smoking history) should be strongly considered for testing.25 Previously, the INFORM and ISEL studies demonstrated that EGFR TKIs failed to show efficacy in patients with lung SCC compared with placebo.10,11 This could be explained in part by the low frequency of EGFR mutations in lung SCC. In the present study, 223 patients underwent EGFR testing, and 33 patients were found to harbor EGFR mutations. According to previous studies, the EGFR mutation rate in SCC varies in different ethnicities, ranging from 1% to 15%.7,26,27 Most of these studies detected the EGFR gene mutation using direct DNA sequencing. In the present study, we used the ARMS method, which has a sensitivity much greater than that of DNA sequencing.28 The frequency of EGFR mutations in the present study was similar to that of our prospective multicenter study (IGNITE study), which showed that in an Asian population with lung SCC, the EGFR mutation frequency was 10%.29 We should also note the inferior efficacy of EGFR TKIs in patients with lung SCC compared with patients with ADC. In the present study, the PFS and OS for EGFR mutation-positive patients with SCC of the lung was 3.94 and 18.04 months, respectively, far
Jianlin Xu et al shorter than the PFS and OS for patients with ADC, who were treated with EGFR TKIs in a previous clinical trial.23 The reason for the inferior efficacy of EGFR TKIs in patients with lung SCC is not clear. It was reported that the alterations in the PI3K/RTK/RAS signaling pathway that are associated with smoking might be one of the most important reasons for the inferior efficacy.30,31 Recently, Soria et al32 reported that the second-generation EGFR TKI afatinib was associated with improved PFS and OS compared with the first-generation EGFR TKI erlotinib in EGFR-unselected patients with SCC. The reason for the superior efficacy of afatinib compared with erlotinib in patients with lung SCC warrants additional investigation. Moreover, as first- or second-line therapy for EGFR mutation-positive patients with lung SCC, whether chemotherapy or EGFR TKIs will provide better survival benefits should also be determined. In the present study, most patients received TKIs as second- or third-line therapy, which could explain, in part, the relatively short PFS (3.94 months). In the future, a clinical trial might be necessary to make a direct comparison between the effectiveness of TKIs and chemotherapy in this population. The results of the present study should be interpreted with the consideration of several limitations. First, the major limitation of the present study was its retrospective nature. Second, the small sample size in each cohort might have affected the statistical analysis. Furthermore, the present study might have included patients with tumors of mixed histologic features. Roggli et al33 addressed histologic heterogeneity in a comprehensive study of 27 patients with SCC, of whom, 4 (15%) had an ADC component. Some experts have suggested that most EGFR-mutated non-ADC patients had mixed ADC histologic features, and the sensitivity of EGFR TKIs in these patients might depend on the proportion of EGFR-mutated ADC components in the whole tumor.9,17 The diagnostic criteria in the World Health Organization classification of lung carcinomas34 require examination of the entire tumor. However, in “real-world” situations, the classification of most lung carcinomas is performed using small diagnostic biopsy or cytology type samples. Owing to the difficulty and complexity of pathologic diagnoses, especially those from small biopsy samples, it is impractical to determine whether all cases of lung SCC have an ADC component.
Conclusion The survival benefits for EGFR mutation-positive patients with SCC suggest that TKI therapy might be an option for the treatment of this population. Considering the different efficacy of EGFR TKIs in EGFR mutation-positive patients and EGFR wild-type patients, precision EGFR mutation detection should be used to help guide the treatment of patients with SCC.
Clinical Practice Points EGFR mutation-positive patients with SCC experienced survival
benefits from EGFR TKI therapy. EGFR wild-type patients with SCC failed to experience survival
benefits from EGFR TKI therapy. EGFR TKIs might also be an option for the treatment of SCC. EGFR gene mutation status has a predictive role in the treatment
of SCC.
Acknowledgments This work was supported by Key Projects of the Biomedicine Department, Science and Technology Commission of Shanghai Municipality (Project No. 11411951200). The funders played no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. We acknowledge support from the Department of Pathology, Shanghai Chest Hospital. We also thank Bo Jin, Tianqing Chu, Huiming Wang, Hua Zhong, Chunlei Shi, Aiqing Gu, Liwen Xiong, and Yizhuo Zhao for their provision of study materials or patients for the present study.
Disclosure The authors have stated that they have no conflicts of interest.
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