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Outcomes of research biopsies in clinical trials of EGFR mutation-positive non-small cell lung cancer patients pretreated with EGFR-tyrosine kinase inhibitors
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Journal of the Formosan Medical Association (2017) xx, 1e6
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.jfma-online.com
Original Article
Outcomes of research biopsies in clinical trials of EGFR mutation-positive non-small cell lung cancer patients pretreated with EGFR-tyrosine kinase inhibitors Bin-Chi Liao a,f,i, Ya-Ying Bai a, Jih-Hsiang Lee a,c, Chia-Chi Lin a,g, Shu-Yung Lin b,e, Yee-Fan Lee d, Chao-Chi Ho b, Jin-Yuan Shih b, Yeun-Chung Chang d,*, Chong-Jen Yu b, James Chih-Hsin Yang a,h,i, Pan-Chyr Yang b a
Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan c Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan d Department of Medical Imaging, National Taiwan University Hospital, Taipei, Taiwan e Department of Internal Medicine, National Taiwan University Hospital Jinshan Branch, New Taipei City, Taiwan f National Taiwan University Cancer Center, College of Medicine, National Taiwan University, Taipei, Taiwan g Department of Urology, College of Medicine, National Taiwan University, Taipei, Taiwan h Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan i Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan b
Received 24 October 2016; received in revised form 15 February 2017; accepted 25 April 2017
KEYWORDS Complications; Computed tomography-guided percutaneous core needle biopsy; EGFR mutation; Non-small cell lung cancer;
Background/purpose: Research biopsies (RBs) are crucial for developing novel molecular targeted agents. However, the safety and diagnostic yields of RBs have not been investigated in EGFR mutation-positive non-small cell lung cancer (NSCLC) patients pretreated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Methods: We searched the medical records of NSCLC patients who participated in lung cancer clinical trials and underwent mandatory RBs between 2012 and 2014 at our institution. Only patients with EGFR mutation-positive NSCLC pretreated with at least 1 EGFR-TKI were enrolled. Results: Of 140 enrolled patients, 73 (52.1%) and 59 (42.1%) had exon 19 deletions and exon 21 L858R mutation, respectively. Before RBs, 108 (77.1%), 83 (59.3%), and 36 (25.7%) patients had
* Corresponding author. Department of Medical Imaging, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, 100, Taiwan. E-mail address: [email protected] (Y.-C. Chang). http://dx.doi.org/10.1016/j.jfma.2017.04.018 0929-6646/Copyright ª 2017, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Liao B-C, et al., Outcomes of research biopsies in clinical trials of EGFR mutation-positive non-small cell lung cancer patients pretreated with EGFR-tyrosine kinase inhibitors, Journal of the Formosan Medical Association (2017), http:// dx.doi.org/10.1016/j.jfma.2017.04.018
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B.-C. Liao et al. Research biopsies
been treated with gefitinib, erlotinib, and afatinib, respectively. Computed tomographyguided percutaneous core needle biopsy was the most frequently used modality among 181 RBs performed (50.8%), followed by ultrasonography-guided (32.0%) and endoscopic RBs (16.0%). The most common RB sites were the lung (69.6%), pleura (8.8%), and liver (6.1%). Pathologic examinations revealed malignant cells in most RB specimens (72.9%). Complications due to RBs included pneumothorax (11.6%), bleeding (6.1%), and infection (1.1%). Only 1 patient required chest tube placement for pneumothorax, and 2 patients underwent endotracheal intubation because of bleeding. Conclusions: RBs in this patient population were generally safe. Pneumothorax was the most frequent complication; bleeding, while infrequent, increased the risk of severe events. The diagnostic yields and complications of any particular modality should therefore be discussed with prospective clinical trial participants. Copyright ª 2017, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).
Introduction In the era of personalized/precise anti-cancer therapy, physicians identify patients whose tumors harbor driver mutations in order to select appropriate treatments. For example, in patients with non-small cell lung cancer (NSCLC), EGFR mutation status (especially exon 19 deletions and exon 21 L858R mutation) is a good predictor of tumor response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs).1e3 The current standard of care is to select patients with activating EGFR mutations to undergo first-line EGFR-TKI monotherapy, such as gefitinib, erlotinib, or afatinib.4e7 This prolongs progression-free survival compared to platinum-based doublet chemotherapy; overall survival is even prolonged in patients with exon 19 deletions who undergo first-line afatinib monotherapy compared to cisplatin plus pemetrexed or gemcitabine chemotherapy.8 However, acquired resistance inevitably develops after a period of responsiveness. Common mechanisms of acquired resistance to EGFR-TKI therapy include EGFR exon 20 T790M mutation and MET amplification9e12; physicians identify these factors by performing tumor biopsies upon disease progression. Novel therapeutic agents are designed to overcome these common resistance mechanisms; for example, third-generation EGFR-TKIs and MET inhibitors can overcome EGFR T790M mutation and MET amplification, respectively.13,14 However, it is mandatory to obtain research biopsies (RBs) to identify patient populations eligible to enroll in clinical trials of novel targeted therapies. RBs have been controversial because of ethical considerations, safety, patient attitudes, feasibility, and other factors.15e20 However, in recent trials such as the Biomarkerintegrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) study conducted in the United States (in which patients with heavily pretreated advanced NSCLC prospectively underwent lung tumor re-biopsy to guide subsequent treatment based on identified molecular biomarkers), the complication rates of lung RBs were very low. Pneumothorax occurred in 11.5% of 139 patients; a single grade 3 event also occurred.21 EGFR mutations were detected in only 15% of patients in that study, only 45% of whom
had been treated with erlotinib. These results suggested that RBs may not be as risky as previously assumed. Therefore, we sought to determine the safety and diagnostic yield of RBs in EGFR mutation-positive NSCLC patients pretreated with advanced EGFR-TKI at our medical center.
Materials and methods Patients We reviewed medical records of patients aged 20 years with advanced EGFR mutation-positive NSCLC pretreated with EGFR-TKIs who participated in therapeutic clinical trials and underwent RBs between January 2012 and December 2014. The patient list was obtained from the Thoracic Oncology Multidisciplinary Team at National Taiwan University Hospital.
Data collection We collected clinical data, including age, sex, tobacco use history, histological NSCLC type, EGFR mutation type, and treatments prior to participation in clinical trials and RBs. RB details recorded included the biopsy site, modality, and complications; results of pathologic exams and molecular biomarker tests; numbers of RBs undergone, and the clinical trials joined based on RB results. The protocol of this study was approved by the Research Ethics Committee of National Taiwan University Hospital (NTUH-REC No.201412023RINC).
Statistical analyses Patient characteristics, RB features, and outcomes were summarized by using descriptive statistics. Continuously scaled measures were summarized with descriptive statistical measures. Contingency tables were used to describe categorical data. The 95% confidence intervals of the risks of biopsy failure and complications were estimated based on binomial distributions. Fisher’s exact test was used to examine the association between 2 categorical variables. A p-value <0.05 denoted statistical significance.
Please cite this article in press as: Liao B-C, et al., Outcomes of research biopsies in clinical trials of EGFR mutation-positive non-small cell lung cancer patients pretreated with EGFR-tyrosine kinase inhibitors, Journal of the Formosan Medical Association (2017), http:// dx.doi.org/10.1016/j.jfma.2017.04.018
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Research biopsies in EGFR mutation-positive NSCLC
Results Clinical trial characteristics We identified 140 patients from 11 clinical trials, 6 of which investigated the safety and efficacy of novel thirdgeneration EGFR-TKIs, while 2 tested novel MET inhibitors. There were 3 phase I trials, 3 phase I/II trials, 4 phase II trials and 1 phase III trial. Ten trials were sponsored and 1 was investigator-initiated.
Patient characteristics Demographic data are shown in Table 1. The median patient age was 62 years; 57.1% were female and 90.7% were never smokers. All patients had Eastern Cooperative Oncology Group performance statuses of 0e1 per clinical trial inclusion criteria. Most patients (97.9%) had adenocarcinoma, and 52.1% and 42.1% had exon 19 deletions and exon 21 L858R mutation, respectively. Most patients (87.1%) had received at least 1 EGFR-TKI therapy for more than 6 months; 24.3% had not received any cytotoxic chemotherapy agent before undergoing RB. Most patients (54.3%) discontinued EGFR-TKI therapy less than 30 days before RB. Only 8 (5.7%), 3 (2.1%), and 1 (0.7%) patient used antiplatelet agents, enoxaparin, and warfarin therapy, respectively, prior to RB.
Sixteen patients (11.4%) underwent multiple RBs for a clinical trial to obtain adequate tissue samples, and 7 (5.0%) underwent multiple RBs for different clinical trials. Computed tomography (CT)-guided percutaneous core needle biopsy (CT-PNB) was the most frequently used modality (50.8%), followed by ultrasonography (US)-guided (32.0%) and endoscopic RBs (16.0%). Endoscopic RBs included 26 involving flexible bronchoscopy plus endobronchial US (EBUS), 2 flexible bronchoscopies, and 1 involving esophageal endoscopy plus endoscopic US. The most common RB sites were the lung (69.6%), pleura (8.8%), and liver (6.1%). The modality and site of RB were determined at the physician’s discretion (Table 2).
Results of RBs Pathologic examination results are shown in Table 2. There were no specimens in 3 RBs because of biopsy procedurerelated complications. Among the 181 RBs, 142 were performed to test for the presence of EGFR T790M mutation; 108 (76.1%) specimens were adequate for mutation testing.
Complications of RBs Overall, complications due to RBs included pneumothorax (21 episodes out of 181 [11.6%], including 2 patients who each Table 2
RB modalities and sites
Research biopsy features.
Variable
A total of 181 RBs were performed, including 13 paired RBs before and after the study treatment in the same patients. Table 1
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Total RB modality
Patient characteristics.
Variable
N
(%)
Total Sex
140 60 80 62 127 140 137 3 73 52
(100) (42.9) (57.1) (36e89) (90.7) (100) (97.9) (2.1) (52.1) (42.1)
15 108 83 36 98 94 43 40 34
(5.8) (77.1) (59.3) (25.7) (70.0) (67.1) (30.7) (28.6) (24.3)
Age (years) Smoking Performance status Histology EGFR mutation
EGFR-TKI therapy before RB Cytotoxic chemotherapy before RB
Male Female Median (range) Never-smoker 0e1 Adenocarcinoma Non-adenocarcinoma Exon 19 deletions Exon 21 L858R mutation Other mutations Gefitinib Erlotinib Afatinib Platinuma Pemetrexed Docetaxel Gemcitabine No prior cytotoxic chemotherapy
Abbreviations: EGFR, epidermal growth factor receptor; RB, research biopsy; TKI, tyrosine kinase inhibitor. a Cisplatin or carboplatin.
RB site
Pathologic exam of RB specimens
RB complication
CT-PNB US-guided Endoscopy Others Lung Pleura Liver Soft tissue Rib Bronchus Mediastinal LN Neck LN Adrenal gland Axillary LN Iliac bone Skin Presence of malignant cells No malignant cells Chronic inflammation Atypical cells Fibrosis No specimen Pneumothorax Bleeding Infection
N
(%)
181 92 58 29 2 126 16 11 7 5 4 3 3 3 1 1 1 132
(100) (50.8) (32.0) (16.0) (1.2) (69.6) (8.8) (6.1) (3.9) (2.8) (2.2) (1.7) (1.7) (1.7) (0.6) (0.6) (0.6) (72.9)
20 10 8 6 3 21 11 2
(11.0) (5.5) (4.4) (3.3) (1.7) (11.6) (6.1) (1.1)
Abbreviations: CT-PNB, computed tomography-guided percutaneous core needle biopsy; LN, lymph node; RB, research biopsy; US, ultrasonography.
Please cite this article in press as: Liao B-C, et al., Outcomes of research biopsies in clinical trials of EGFR mutation-positive non-small cell lung cancer patients pretreated with EGFR-tyrosine kinase inhibitors, Journal of the Formosan Medical Association (2017), http:// dx.doi.org/10.1016/j.jfma.2017.04.018
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4 experienced 2 episodes of pneumothorax), bleeding (6.1%), and infection (1.1%). Most episodes of pneumothorax developed in patients who underwent CT-PNB of the thoracic tumors; the incidence of pneumothorax during such procedures was 23.5%. CT-PNB of the thoracic tumors was performed with a 19-gauge coaxial guiding needle and a 20-gauge automatic biopsy needle (Temno, Bauer Medical, Clearwater, FL, USA). The median lesion depth, measured from the pleura puncture site to the edge of the target intrapulmonary lesion along the needle path, was 1.4 cm (range, 0e4.8 cm). The incidence of pneumothorax in patients who underwent chest US-guided thoracic tumor RBs was 4.1%. This procedure was carried out with an 18-gauge quick-cut needle (Hakko Co. Ltd, Nagano, Japan). Only 1 patient required chest tube placement for pneumothorax. Two patients underwent endotracheal intubation because of RBrelated bleeding. No deaths were directly attributed to RBs.
Diagnostic yield of thoracic tumor RBs The diagnostic yield (defined as the presence of malignant cells on pathological examination of the specimens) of CTPNB, chest US-guided, and endoscopic RBs of thoracic tumors (including lung, pleural, bronchus, rib, and mediastinal lymph nodes) were 78.5%, 71.4%, and 41.4%, respectively. The median size of thoracic tumors undergoing CT-PNB was 2.7 cm (range, 0.7e7.8 cm); there were 1 pleural, 2 rib, 16 left lower lobe, 16 left upper lobe, 19 right lower lobe, 3 right middle lobe, and 24 right upper lobe tumors. The sizes of the tumors undergoing chest USguided and endoscopic RBs are not presented because not all tumor size data were available.
Clinical trial enrollment and biomarker tests Among the 140 patients, 77 (55.0%) were enrolled in clinical trials following RBs, including 2 who were enrolled in 2 different trials. Among 106 patients with known EGFR T790M status, 68 (64.1%) harbored this mutation. Of 51 patients with EGFR deletions in exon 19, the EGFR T790M mutation was detected in 38 (74.5%) of those with known mutation status. Among 49 patients with EGFR exon 21 L858R mutation, EGFR T790M mutation was detected in 28 (57.1%) of those with records available (p Z .09). Furthermore, 10 of 19 patients (52.6%) with known MET amplification status harbored the amplification.
Discussion We identified 140 patients with advanced EGFR mutationpositive NSCLC pretreated with at least 1 EGFR-TKI who participated in therapeutic clinical trials that required mandatory RBs. Most trials tested novel therapeutic agents with clear targets, such as the EGFR T790M mutation or MET amplification; eligibility was determined via molecular testing. In prior studies focused on breast cancer and phase I clinical trials, only 46e59% of patients were willing to undergo RBs.20e23 We did not survey attitudes toward RBs; however, 87.1% of the patients in our study had received at least 1 prior EGFR-TKI regimen for more than 6 months. Prior successful experiences with EGFR-TKI therapies may
B.-C. Liao et al. have led to their more positive attitude toward RBs despite being in the early phases of novel drugs development. While debating the ethics of RBs is beyond the scope of this study,17e19 most trials surveyed were global, and all were reviewed by Institutional Review Boards and health-care authorities in Taiwan (Ministry of Health and Welfare, Executive Yuan, Taiwan).24 The clinical trial participants underwent RBs within the bounds of clinical trial settings; therefore, ethical issues may have been less of a concern. In this study, RB methods were chosen by the treating physicians. For thoracic tumors, physicians often choose US-guided thoracic tumor biopsies for peripheral lesions contacting the pleura and EBUS transbronchial biopsies for central peribronchial or mediastinal lymph nodes that are difficult to approach with CT-PNB or have high bleeding risks.25e29 A prior study that compared US-guided biopsy and CT-PNB for pleural or peripheral pulmonary lesions concluded that the procedures were comparable in terms of sample accuracy. However, US-guided biopsies had reduced procedure times, exhibited fewer post-procedure pneumothorax incidents, and were free of ionizing radiation.30 Malignant cells were detected in 72.9% of the RB specimens in this study. In a prior study of EGFR mutationpositive patients who developed resistance to EGFR-TKI therapy, 155 of 162 specimens (95.7%) were adequate for analysis. However, 40 specimens (24.7%) were obtained by either surgical resection of the tumors, autopsy, or body fluid analysis.12 In our study, the diagnostic yield of CT-PNBs for thoracic tumors (median size 2.7 cm) was 78.5%, and the incidence of pneumothorax was 23.5%. These results were in line with our prior report that false-negatives for malignancy occurred in 6.5% of patients who underwent CTPNB for undiagnosed thoracic tumors; pneumothorax occurred in 38.0% and severe complications developed in 1.4%.26 Minor pneumothorax developed in 47.3% of the patients who underwent CT-PNB for undiagnosed small pulmonary lesions (3 cm) with persistent ground-glass opacity.31 In another study that evaluated the adequacy and safety of CT-guided lung tumor repeat biopsy in patients who developed resistance to prior chemotherapy or EGFR-TKI therapy, 75 of 94 specimens (80%) were adequate for mutational analysis.32 In that study, only 12 patients were known to have baseline EGFR mutation-positive disease. Six of the patient (6%) developed pneumothorax after the procedure with 2 of them requiring chest tubal placement.32 The diagnostic yield of US-guided transthoracic core biopsies in this study was 71.4%; in our previous study, the yield for undiagnosed peripheral lung lesions using this procedure was 96%, and the diagnostic accuracy for malignant lesions <3 cm was 92%.27,29 Regarding endoscopic RBs, most patients underwent EBUS-assisted flexible bronchoscopic RBs for thoracic tumors, producing a diagnostic yield of 41.4%. The procedure was performed with biopsy forceps as previously described.25 In our previous study, the diagnostic yield for malignancy using EBUS transbronchial biopsies was 77.9% in patients with untreated peripheral lung cancer.25 In another study, patients with undiagnosed but suspected lung lesions following at least 1 diagnostic procedure underwent flexible bronchoscopy plus EBUS biopsies. A definitive diagnosis was made in most patients (87.6%)33; however, not all patients in that study had lung cancer nor had all been treated with anti-neoplastic
Please cite this article in press as: Liao B-C, et al., Outcomes of research biopsies in clinical trials of EGFR mutation-positive non-small cell lung cancer patients pretreated with EGFR-tyrosine kinase inhibitors, Journal of the Formosan Medical Association (2017), http:// dx.doi.org/10.1016/j.jfma.2017.04.018
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Research biopsies in EGFR mutation-positive NSCLC therapy. We infer that the diagnostic yield of RBs might decrease following effective systemic anti-neoplastic therapy, especially EGFR-TKI therapy for EGFR mutationpositive patients. However, only 29 RBs used endoscopy in our study, and the diagnostic yield result should be confirmed in further studies with larger patient numbers. During our study period, no patient received video-assisted thoracoscopic surgery (VATS) for RBs. VATS has become popular given the requirement of abundant tissue specimens for pathologic review and molecular testing in clinical trials; however, the risks and benefit of VATS RBs should be reviewed with the clinical trial participants.34 The prognostic role of acquired EGFR T790M mutation was controversial before the era of third-generation EGFRTKIs.35 In this study, the incidence of EGFR T790M mutation was higher in patients with exon 19 deletions compared to patients with exon 21 L858R mutation (74.5 vs. 57.1%, respectively), although the difference was statistically insignificant. However, this highly specific population is not representative of the distribution of the resistant EGFR T790M mutation in the general population. Novel thirdgeneration EGFR-TKIs, such as osimertinib, rociletinib, EGF816, ASP8273, and HM61713, are under development13,14,36,37; osimertinib received the United States Food and Drug Administration approval in 2015; as did the companion diagnostic test (cobas EGFR Mutation Test v2) to detect EGFR T790M mutations. EGFR-TKI resistant tumor biopsy is currently the standard method for selecting patients for osimertinib therapy13; non-invasive methods are under development to detect EGFR-sensitizing and -resistant T790M mutations, such as using circulating tumor DNA in a patient’s plasma. However, the accuracy of such methods compared to obtaining actual tissue samples remains questionable.38 While 55% of the patients were enrolled in the clinical trials following RBs, their eligibilities were not based solely on molecular testing. In some early phase clinical trials, patients could still participate in the clinical trials of novel third-generation EGFR-TKIs even if molecular tests were negative (e.g., for EGFR T790M mutation) once they provided adequate tissues for analysis.13 This retrospective study has some limitations. First, methods of EGFR T790M mutation or MET amplification detection were not consistent across clinical trials. The requirement of tissue specimens for molecular testing was also not universal. Second, our selected patients did not represent the general population with respect to performance status, tumor burden, and rate of disease progression. Many patients with a large tumor burden or rapid tumor progression were not eligible for RBs because of a higher risk of procedure-related complications or because they required immediate anti-neoplasm therapy. Third, many RB procedural details that may influence diagnostic yields and complication rates were not evaluated; these include tumor depth, emphysema status, CT characteristics of the tumor, and number of tissue cores obtained.39,40 Such potentially confounding factors should be evaluated in this particular patient population in future studies. In conclusion, RBs appear to be generally safe and informative in EGFR mutation-positive NSCLC patients pretreated with EGFR-TKIs. Pneumothorax was the most frequent complication in our study; bleeding occurred infrequently but increased the risk of severe drawbacks.
5 The diagnostic yield and complications of individual RB modalities should be discussed with clinical trial subjects.
Funding/support The authors attest that this study was not supported by external funding sources. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflicts of interest James Chih-Hsin Yang is a consultant and has received honoraria from AstraZeneca, Roche/Genentech, Boehringer Ingelheim, MSD, Merck Serono, Novartis, Pfizer, Clovis Oncology, Eli Lilly, Bayer, Celgene, Astellas, Innopharmax, Ono Pharmaceutical, and Chugai Pharmaceutical; Jin-Yuan Shih has received honoraria from AstraZeneca, Roche/ Genentech, Boehringer Ingelheim, MSD, Novartis, Pfizer, and Eli Lilly; Chao-Chi Ho received grants for research from AstraZeneca. The authors have no conflicts of interest to declare.
Acknowledgments The authors would like to thank all the participants in the clinical trials and their families, as well as the research nurses and the Thoracic Oncology Multidisciplinary Team at National Taiwan University Hospital. The authors acknowledge the Medical Information Management Office at National Taiwan University Hospital for providing the electronic medical records of study patients. The authors also thank Editage (editage.com) for English language editing.
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patients with peripheral lung cancer receiving EBUS-assisted bronchoscopy. Lung Cancer 2013;82:420e5. Chang Y-C, Yu C-J, Lee W-J, Kuo S-H, Hsiao C-H, Jan I-S, et al. Imprint cytology improves accuracy of computed tomographyguided percutaneous transthoracic needle biopsy. Eur Respir J 2008;31:54e61. Liao W-Y, Jerng J-S, Chen K-Y, Chang Y-L, Yang P-C, Kuo S-H. Value of imprint cytology for ultrasound-guided transthoracic core biopsy. Eur Respir J 2004;24:905e9. Huang C-T, Tsai Y-J, Liao W-Y, Wu P-C, Ho C-C, Yu C-J, et al. Endobronchial ultrasound-guided transbronchial biopsy of peripheral pulmonary lesions: how many specimens are necessary? Respiration 2012;84:128e34. Liao W-Y, Chen M-Z, Chang Y-L, Wu H-D, Yu C-J, Kuo P-H, et al. US-guided transthoracic cutting biopsy for peripheral thoracic lesions less than 3 cm in diameter. Radiology 2000;217: 685e91. Sconfienza LM, Mauri G, Grossi F, Truini M, Serafini G, Sardanelli F, et al. Pleural and peripheral lung lesions: comparison of US- and CT-guided biopsy. Radiology 2013;266: 930e5. Lu C-H, Hsiao C-H, Chang Y-C, Lee J-M, Shih J-Y, Wu L-A, et al. Percutaneous computed tomography-guided coaxial core biopsy for small pulmonary lesions with ground-glass attenuation. J Thorac Oncol 2012;7:143e50. Yoon HJ, Lee HY, Lee KS, Choi Y-L, Ahn M-J, Park K, et al. Repeat biopsy for mutational analysis of nonesmall cell lung cancers resistant to previous chemotherapy: adequacy and complications. Radiology 2012;265:939e48. Bugalho A, Ferreira D, Eberhardt R, Dias SS, Videira PA, Herth FJ, et al. Diagnostic value of endobronchial and endoscopic ultrasound-guided fine needle aspiration for accessible lung cancer lesions after non-diagnostic conventional techniques: a prospective study. BMC Cancer 2013;13:130. Lin M-W, Tseng Y-H, Lee Y-F, Hsieh M-S, Ko W-C, Chen J-Y. et al. Computed tomography-guided patent blue vital dye localization of pulmonary nodules in uniportal thoracoscopy. J Thorac Cardiovasc Surg. In press. doi: 10.1016/j.jtcvs.2016.04.052. Sun J-M, Ahn M-J, Choi Y-L, Ahn JS, Park K. Clinical implications of T790M mutation in patients with acquired resistance to EGFR tyrosine kinase inhibitors. Lung Cancer 2013;82:294e8. Jia Y, Juarez J, Li J, Manuia M, Niederst MJ, Tompkins C, et al. EGF816 exerts anticancer effects in nonesmall cell lung cancer by irreversibly and selectively targeting primary and acquired activating mutations in the EGF receptor. Cancer Res 2016;76: 1591e602. Yu HA, Oxnard GR, Spira AI, Horn L, Weiss J, Feng Y, et al. Phase I dose escalation study of ASP8273, a mutant-selective irreversible EGFR inhibitor, in subjects with EGFR mutation positive NSCLC [abstract]. J Clin Oncol 2015;33(15_suppl): 8083. Sundaresan TK, Sequist LV, Heymach JV, Riely GJ, Janne PA, Koch WH, et al. Detection of T790M, the acquired resistance EGFR mutation, by tumor biopsy versus noninvasive bloodbased analyses. Clin Cancer Res 2016;22:1103e10. Heyer CM, Reichelt S, Peters SA, Walther JW, Mu ¨ller KM, Nicolas V. Computed tomographyenavigated transthoracic core biopsy of pulmonary lesions: which factors affect diagnostic yield and complication rates? Acad Radiol 2008;15: 1017e26. Priola AM, Priola SM, Cataldi A, Errico L, Di Franco M, Campisi P, et al. Accuracy of CT-guided transthoracic needle biopsy of lung lesions: factors affecting diagnostic yield. Radiol Med 2007;112:1142e59.
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Journal of the Formosan Medical Association (2017) xx, 1e6
Available online at www.sciencedirect.com
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Original Article
Outcomes of research biopsies in clinical trials of EGFR mutation-positive non-small cell lung cancer patients pretreated with EGFR-tyrosine kinase inhibitors Bin-Chi Liao a,f,i, Ya-Ying Bai a, Jih-Hsiang Lee a,c, Chia-Chi Lin a,g, Shu-Yung Lin b,e, Yee-Fan Lee d, Chao-Chi Ho b, Jin-Yuan Shih b, Yeun-Chung Chang d,*, Chong-Jen Yu b, James Chih-Hsin Yang a,h,i, Pan-Chyr Yang b a
Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan c Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan d Department of Medical Imaging, National Taiwan University Hospital, Taipei, Taiwan e Department of Internal Medicine, National Taiwan University Hospital Jinshan Branch, New Taipei City, Taiwan f National Taiwan University Cancer Center, College of Medicine, National Taiwan University, Taipei, Taiwan g Department of Urology, College of Medicine, National Taiwan University, Taipei, Taiwan h Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan i Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan b
Received 24 October 2016; received in revised form 15 February 2017; accepted 25 April 2017
KEYWORDS Complications; Computed tomography-guided percutaneous core needle biopsy; EGFR mutation; Non-small cell lung cancer;
Background/purpose: Research biopsies (RBs) are crucial for developing novel molecular targeted agents. However, the safety and diagnostic yields of RBs have not been investigated in EGFR mutation-positive non-small cell lung cancer (NSCLC) patients pretreated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Methods: We searched the medical records of NSCLC patients who participated in lung cancer clinical trials and underwent mandatory RBs between 2012 and 2014 at our institution. Only patients with EGFR mutation-positive NSCLC pretreated with at least 1 EGFR-TKI were enrolled. Results: Of 140 enrolled patients, 73 (52.1%) and 59 (42.1%) had exon 19 deletions and exon 21 L858R mutation, respectively. Before RBs, 108 (77.1%), 83 (59.3%), and 36 (25.7%) patients had
* Corresponding author. Department of Medical Imaging, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, 100, Taiwan. E-mail address: [email protected] (Y.-C. Chang). http://dx.doi.org/10.1016/j.jfma.2017.04.018 0929-6646/Copyright ª 2017, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Liao B-C, et al., Outcomes of research biopsies in clinical trials of EGFR mutation-positive non-small cell lung cancer patients pretreated with EGFR-tyrosine kinase inhibitors, Journal of the Formosan Medical Association (2017), http:// dx.doi.org/10.1016/j.jfma.2017.04.018
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been treated with gefitinib, erlotinib, and afatinib, respectively. Computed tomographyguided percutaneous core needle biopsy was the most frequently used modality among 181 RBs performed (50.8%), followed by ultrasonography-guided (32.0%) and endoscopic RBs (16.0%). The most common RB sites were the lung (69.6%), pleura (8.8%), and liver (6.1%). Pathologic examinations revealed malignant cells in most RB specimens (72.9%). Complications due to RBs included pneumothorax (11.6%), bleeding (6.1%), and infection (1.1%). Only 1 patient required chest tube placement for pneumothorax, and 2 patients underwent endotracheal intubation because of bleeding. Conclusions: RBs in this patient population were generally safe. Pneumothorax was the most frequent complication; bleeding, while infrequent, increased the risk of severe events. The diagnostic yields and complications of any particular modality should therefore be discussed with prospective clinical trial participants. Copyright ª 2017, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).
Introduction In the era of personalized/precise anti-cancer therapy, physicians identify patients whose tumors harbor driver mutations in order to select appropriate treatments. For example, in patients with non-small cell lung cancer (NSCLC), EGFR mutation status (especially exon 19 deletions and exon 21 L858R mutation) is a good predictor of tumor response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs).1e3 The current standard of care is to select patients with activating EGFR mutations to undergo first-line EGFR-TKI monotherapy, such as gefitinib, erlotinib, or afatinib.4e7 This prolongs progression-free survival compared to platinum-based doublet chemotherapy; overall survival is even prolonged in patients with exon 19 deletions who undergo first-line afatinib monotherapy compared to cisplatin plus pemetrexed or gemcitabine chemotherapy.8 However, acquired resistance inevitably develops after a period of responsiveness. Common mechanisms of acquired resistance to EGFR-TKI therapy include EGFR exon 20 T790M mutation and MET amplification9e12; physicians identify these factors by performing tumor biopsies upon disease progression. Novel therapeutic agents are designed to overcome these common resistance mechanisms; for example, third-generation EGFR-TKIs and MET inhibitors can overcome EGFR T790M mutation and MET amplification, respectively.13,14 However, it is mandatory to obtain research biopsies (RBs) to identify patient populations eligible to enroll in clinical trials of novel targeted therapies. RBs have been controversial because of ethical considerations, safety, patient attitudes, feasibility, and other factors.15e20 However, in recent trials such as the Biomarkerintegrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) study conducted in the United States (in which patients with heavily pretreated advanced NSCLC prospectively underwent lung tumor re-biopsy to guide subsequent treatment based on identified molecular biomarkers), the complication rates of lung RBs were very low. Pneumothorax occurred in 11.5% of 139 patients; a single grade 3 event also occurred.21 EGFR mutations were detected in only 15% of patients in that study, only 45% of whom
had been treated with erlotinib. These results suggested that RBs may not be as risky as previously assumed. Therefore, we sought to determine the safety and diagnostic yield of RBs in EGFR mutation-positive NSCLC patients pretreated with advanced EGFR-TKI at our medical center.
Materials and methods Patients We reviewed medical records of patients aged 20 years with advanced EGFR mutation-positive NSCLC pretreated with EGFR-TKIs who participated in therapeutic clinical trials and underwent RBs between January 2012 and December 2014. The patient list was obtained from the Thoracic Oncology Multidisciplinary Team at National Taiwan University Hospital.
Data collection We collected clinical data, including age, sex, tobacco use history, histological NSCLC type, EGFR mutation type, and treatments prior to participation in clinical trials and RBs. RB details recorded included the biopsy site, modality, and complications; results of pathologic exams and molecular biomarker tests; numbers of RBs undergone, and the clinical trials joined based on RB results. The protocol of this study was approved by the Research Ethics Committee of National Taiwan University Hospital (NTUH-REC No.201412023RINC).
Statistical analyses Patient characteristics, RB features, and outcomes were summarized by using descriptive statistics. Continuously scaled measures were summarized with descriptive statistical measures. Contingency tables were used to describe categorical data. The 95% confidence intervals of the risks of biopsy failure and complications were estimated based on binomial distributions. Fisher’s exact test was used to examine the association between 2 categorical variables. A p-value <0.05 denoted statistical significance.
Please cite this article in press as: Liao B-C, et al., Outcomes of research biopsies in clinical trials of EGFR mutation-positive non-small cell lung cancer patients pretreated with EGFR-tyrosine kinase inhibitors, Journal of the Formosan Medical Association (2017), http:// dx.doi.org/10.1016/j.jfma.2017.04.018
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Research biopsies in EGFR mutation-positive NSCLC
Results Clinical trial characteristics We identified 140 patients from 11 clinical trials, 6 of which investigated the safety and efficacy of novel thirdgeneration EGFR-TKIs, while 2 tested novel MET inhibitors. There were 3 phase I trials, 3 phase I/II trials, 4 phase II trials and 1 phase III trial. Ten trials were sponsored and 1 was investigator-initiated.
Patient characteristics Demographic data are shown in Table 1. The median patient age was 62 years; 57.1% were female and 90.7% were never smokers. All patients had Eastern Cooperative Oncology Group performance statuses of 0e1 per clinical trial inclusion criteria. Most patients (97.9%) had adenocarcinoma, and 52.1% and 42.1% had exon 19 deletions and exon 21 L858R mutation, respectively. Most patients (87.1%) had received at least 1 EGFR-TKI therapy for more than 6 months; 24.3% had not received any cytotoxic chemotherapy agent before undergoing RB. Most patients (54.3%) discontinued EGFR-TKI therapy less than 30 days before RB. Only 8 (5.7%), 3 (2.1%), and 1 (0.7%) patient used antiplatelet agents, enoxaparin, and warfarin therapy, respectively, prior to RB.
Sixteen patients (11.4%) underwent multiple RBs for a clinical trial to obtain adequate tissue samples, and 7 (5.0%) underwent multiple RBs for different clinical trials. Computed tomography (CT)-guided percutaneous core needle biopsy (CT-PNB) was the most frequently used modality (50.8%), followed by ultrasonography (US)-guided (32.0%) and endoscopic RBs (16.0%). Endoscopic RBs included 26 involving flexible bronchoscopy plus endobronchial US (EBUS), 2 flexible bronchoscopies, and 1 involving esophageal endoscopy plus endoscopic US. The most common RB sites were the lung (69.6%), pleura (8.8%), and liver (6.1%). The modality and site of RB were determined at the physician’s discretion (Table 2).
Results of RBs Pathologic examination results are shown in Table 2. There were no specimens in 3 RBs because of biopsy procedurerelated complications. Among the 181 RBs, 142 were performed to test for the presence of EGFR T790M mutation; 108 (76.1%) specimens were adequate for mutation testing.
Complications of RBs Overall, complications due to RBs included pneumothorax (21 episodes out of 181 [11.6%], including 2 patients who each Table 2
RB modalities and sites
Research biopsy features.
Variable
A total of 181 RBs were performed, including 13 paired RBs before and after the study treatment in the same patients. Table 1
3
Total RB modality
Patient characteristics.
Variable
N
(%)
Total Sex
140 60 80 62 127 140 137 3 73 52
(100) (42.9) (57.1) (36e89) (90.7) (100) (97.9) (2.1) (52.1) (42.1)
15 108 83 36 98 94 43 40 34
(5.8) (77.1) (59.3) (25.7) (70.0) (67.1) (30.7) (28.6) (24.3)
Age (years) Smoking Performance status Histology EGFR mutation
EGFR-TKI therapy before RB Cytotoxic chemotherapy before RB
Male Female Median (range) Never-smoker 0e1 Adenocarcinoma Non-adenocarcinoma Exon 19 deletions Exon 21 L858R mutation Other mutations Gefitinib Erlotinib Afatinib Platinuma Pemetrexed Docetaxel Gemcitabine No prior cytotoxic chemotherapy
Abbreviations: EGFR, epidermal growth factor receptor; RB, research biopsy; TKI, tyrosine kinase inhibitor. a Cisplatin or carboplatin.
RB site
Pathologic exam of RB specimens
RB complication
CT-PNB US-guided Endoscopy Others Lung Pleura Liver Soft tissue Rib Bronchus Mediastinal LN Neck LN Adrenal gland Axillary LN Iliac bone Skin Presence of malignant cells No malignant cells Chronic inflammation Atypical cells Fibrosis No specimen Pneumothorax Bleeding Infection
N
(%)
181 92 58 29 2 126 16 11 7 5 4 3 3 3 1 1 1 132
(100) (50.8) (32.0) (16.0) (1.2) (69.6) (8.8) (6.1) (3.9) (2.8) (2.2) (1.7) (1.7) (1.7) (0.6) (0.6) (0.6) (72.9)
20 10 8 6 3 21 11 2
(11.0) (5.5) (4.4) (3.3) (1.7) (11.6) (6.1) (1.1)
Abbreviations: CT-PNB, computed tomography-guided percutaneous core needle biopsy; LN, lymph node; RB, research biopsy; US, ultrasonography.
Please cite this article in press as: Liao B-C, et al., Outcomes of research biopsies in clinical trials of EGFR mutation-positive non-small cell lung cancer patients pretreated with EGFR-tyrosine kinase inhibitors, Journal of the Formosan Medical Association (2017), http:// dx.doi.org/10.1016/j.jfma.2017.04.018
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4 experienced 2 episodes of pneumothorax), bleeding (6.1%), and infection (1.1%). Most episodes of pneumothorax developed in patients who underwent CT-PNB of the thoracic tumors; the incidence of pneumothorax during such procedures was 23.5%. CT-PNB of the thoracic tumors was performed with a 19-gauge coaxial guiding needle and a 20-gauge automatic biopsy needle (Temno, Bauer Medical, Clearwater, FL, USA). The median lesion depth, measured from the pleura puncture site to the edge of the target intrapulmonary lesion along the needle path, was 1.4 cm (range, 0e4.8 cm). The incidence of pneumothorax in patients who underwent chest US-guided thoracic tumor RBs was 4.1%. This procedure was carried out with an 18-gauge quick-cut needle (Hakko Co. Ltd, Nagano, Japan). Only 1 patient required chest tube placement for pneumothorax. Two patients underwent endotracheal intubation because of RBrelated bleeding. No deaths were directly attributed to RBs.
Diagnostic yield of thoracic tumor RBs The diagnostic yield (defined as the presence of malignant cells on pathological examination of the specimens) of CTPNB, chest US-guided, and endoscopic RBs of thoracic tumors (including lung, pleural, bronchus, rib, and mediastinal lymph nodes) were 78.5%, 71.4%, and 41.4%, respectively. The median size of thoracic tumors undergoing CT-PNB was 2.7 cm (range, 0.7e7.8 cm); there were 1 pleural, 2 rib, 16 left lower lobe, 16 left upper lobe, 19 right lower lobe, 3 right middle lobe, and 24 right upper lobe tumors. The sizes of the tumors undergoing chest USguided and endoscopic RBs are not presented because not all tumor size data were available.
Clinical trial enrollment and biomarker tests Among the 140 patients, 77 (55.0%) were enrolled in clinical trials following RBs, including 2 who were enrolled in 2 different trials. Among 106 patients with known EGFR T790M status, 68 (64.1%) harbored this mutation. Of 51 patients with EGFR deletions in exon 19, the EGFR T790M mutation was detected in 38 (74.5%) of those with known mutation status. Among 49 patients with EGFR exon 21 L858R mutation, EGFR T790M mutation was detected in 28 (57.1%) of those with records available (p Z .09). Furthermore, 10 of 19 patients (52.6%) with known MET amplification status harbored the amplification.
Discussion We identified 140 patients with advanced EGFR mutationpositive NSCLC pretreated with at least 1 EGFR-TKI who participated in therapeutic clinical trials that required mandatory RBs. Most trials tested novel therapeutic agents with clear targets, such as the EGFR T790M mutation or MET amplification; eligibility was determined via molecular testing. In prior studies focused on breast cancer and phase I clinical trials, only 46e59% of patients were willing to undergo RBs.20e23 We did not survey attitudes toward RBs; however, 87.1% of the patients in our study had received at least 1 prior EGFR-TKI regimen for more than 6 months. Prior successful experiences with EGFR-TKI therapies may
B.-C. Liao et al. have led to their more positive attitude toward RBs despite being in the early phases of novel drugs development. While debating the ethics of RBs is beyond the scope of this study,17e19 most trials surveyed were global, and all were reviewed by Institutional Review Boards and health-care authorities in Taiwan (Ministry of Health and Welfare, Executive Yuan, Taiwan).24 The clinical trial participants underwent RBs within the bounds of clinical trial settings; therefore, ethical issues may have been less of a concern. In this study, RB methods were chosen by the treating physicians. For thoracic tumors, physicians often choose US-guided thoracic tumor biopsies for peripheral lesions contacting the pleura and EBUS transbronchial biopsies for central peribronchial or mediastinal lymph nodes that are difficult to approach with CT-PNB or have high bleeding risks.25e29 A prior study that compared US-guided biopsy and CT-PNB for pleural or peripheral pulmonary lesions concluded that the procedures were comparable in terms of sample accuracy. However, US-guided biopsies had reduced procedure times, exhibited fewer post-procedure pneumothorax incidents, and were free of ionizing radiation.30 Malignant cells were detected in 72.9% of the RB specimens in this study. In a prior study of EGFR mutationpositive patients who developed resistance to EGFR-TKI therapy, 155 of 162 specimens (95.7%) were adequate for analysis. However, 40 specimens (24.7%) were obtained by either surgical resection of the tumors, autopsy, or body fluid analysis.12 In our study, the diagnostic yield of CT-PNBs for thoracic tumors (median size 2.7 cm) was 78.5%, and the incidence of pneumothorax was 23.5%. These results were in line with our prior report that false-negatives for malignancy occurred in 6.5% of patients who underwent CTPNB for undiagnosed thoracic tumors; pneumothorax occurred in 38.0% and severe complications developed in 1.4%.26 Minor pneumothorax developed in 47.3% of the patients who underwent CT-PNB for undiagnosed small pulmonary lesions (3 cm) with persistent ground-glass opacity.31 In another study that evaluated the adequacy and safety of CT-guided lung tumor repeat biopsy in patients who developed resistance to prior chemotherapy or EGFR-TKI therapy, 75 of 94 specimens (80%) were adequate for mutational analysis.32 In that study, only 12 patients were known to have baseline EGFR mutation-positive disease. Six of the patient (6%) developed pneumothorax after the procedure with 2 of them requiring chest tubal placement.32 The diagnostic yield of US-guided transthoracic core biopsies in this study was 71.4%; in our previous study, the yield for undiagnosed peripheral lung lesions using this procedure was 96%, and the diagnostic accuracy for malignant lesions <3 cm was 92%.27,29 Regarding endoscopic RBs, most patients underwent EBUS-assisted flexible bronchoscopic RBs for thoracic tumors, producing a diagnostic yield of 41.4%. The procedure was performed with biopsy forceps as previously described.25 In our previous study, the diagnostic yield for malignancy using EBUS transbronchial biopsies was 77.9% in patients with untreated peripheral lung cancer.25 In another study, patients with undiagnosed but suspected lung lesions following at least 1 diagnostic procedure underwent flexible bronchoscopy plus EBUS biopsies. A definitive diagnosis was made in most patients (87.6%)33; however, not all patients in that study had lung cancer nor had all been treated with anti-neoplastic
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Research biopsies in EGFR mutation-positive NSCLC therapy. We infer that the diagnostic yield of RBs might decrease following effective systemic anti-neoplastic therapy, especially EGFR-TKI therapy for EGFR mutationpositive patients. However, only 29 RBs used endoscopy in our study, and the diagnostic yield result should be confirmed in further studies with larger patient numbers. During our study period, no patient received video-assisted thoracoscopic surgery (VATS) for RBs. VATS has become popular given the requirement of abundant tissue specimens for pathologic review and molecular testing in clinical trials; however, the risks and benefit of VATS RBs should be reviewed with the clinical trial participants.34 The prognostic role of acquired EGFR T790M mutation was controversial before the era of third-generation EGFRTKIs.35 In this study, the incidence of EGFR T790M mutation was higher in patients with exon 19 deletions compared to patients with exon 21 L858R mutation (74.5 vs. 57.1%, respectively), although the difference was statistically insignificant. However, this highly specific population is not representative of the distribution of the resistant EGFR T790M mutation in the general population. Novel thirdgeneration EGFR-TKIs, such as osimertinib, rociletinib, EGF816, ASP8273, and HM61713, are under development13,14,36,37; osimertinib received the United States Food and Drug Administration approval in 2015; as did the companion diagnostic test (cobas EGFR Mutation Test v2) to detect EGFR T790M mutations. EGFR-TKI resistant tumor biopsy is currently the standard method for selecting patients for osimertinib therapy13; non-invasive methods are under development to detect EGFR-sensitizing and -resistant T790M mutations, such as using circulating tumor DNA in a patient’s plasma. However, the accuracy of such methods compared to obtaining actual tissue samples remains questionable.38 While 55% of the patients were enrolled in the clinical trials following RBs, their eligibilities were not based solely on molecular testing. In some early phase clinical trials, patients could still participate in the clinical trials of novel third-generation EGFR-TKIs even if molecular tests were negative (e.g., for EGFR T790M mutation) once they provided adequate tissues for analysis.13 This retrospective study has some limitations. First, methods of EGFR T790M mutation or MET amplification detection were not consistent across clinical trials. The requirement of tissue specimens for molecular testing was also not universal. Second, our selected patients did not represent the general population with respect to performance status, tumor burden, and rate of disease progression. Many patients with a large tumor burden or rapid tumor progression were not eligible for RBs because of a higher risk of procedure-related complications or because they required immediate anti-neoplasm therapy. Third, many RB procedural details that may influence diagnostic yields and complication rates were not evaluated; these include tumor depth, emphysema status, CT characteristics of the tumor, and number of tissue cores obtained.39,40 Such potentially confounding factors should be evaluated in this particular patient population in future studies. In conclusion, RBs appear to be generally safe and informative in EGFR mutation-positive NSCLC patients pretreated with EGFR-TKIs. Pneumothorax was the most frequent complication in our study; bleeding occurred infrequently but increased the risk of severe drawbacks.
5 The diagnostic yield and complications of individual RB modalities should be discussed with clinical trial subjects.
Funding/support The authors attest that this study was not supported by external funding sources. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflicts of interest James Chih-Hsin Yang is a consultant and has received honoraria from AstraZeneca, Roche/Genentech, Boehringer Ingelheim, MSD, Merck Serono, Novartis, Pfizer, Clovis Oncology, Eli Lilly, Bayer, Celgene, Astellas, Innopharmax, Ono Pharmaceutical, and Chugai Pharmaceutical; Jin-Yuan Shih has received honoraria from AstraZeneca, Roche/ Genentech, Boehringer Ingelheim, MSD, Novartis, Pfizer, and Eli Lilly; Chao-Chi Ho received grants for research from AstraZeneca. The authors have no conflicts of interest to declare.
Acknowledgments The authors would like to thank all the participants in the clinical trials and their families, as well as the research nurses and the Thoracic Oncology Multidisciplinary Team at National Taiwan University Hospital. The authors acknowledge the Medical Information Management Office at National Taiwan University Hospital for providing the electronic medical records of study patients. The authors also thank Editage (editage.com) for English language editing.
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Please cite this article in press as: Liao B-C, et al., Outcomes of research biopsies in clinical trials of EGFR mutation-positive non-small cell lung cancer patients pretreated with EGFR-tyrosine kinase inhibitors, Journal of the Formosan Medical Association (2017), http:// dx.doi.org/10.1016/j.jfma.2017.04.018