Evaluation of treatment efficacy of tyrosine kinase inhibitors in rare single EGFR Exon 21 L861Q mutation; single center experience.

Evaluation of treatment efficacy of tyrosine kinase inhibitors in rare single EGFR Exon 21 L861Q mutation; single center experience. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Evaluation of treatment efficacy of tyrosine kinase inhibitors in rare single EGFR Exon 21 L861Q mutation; single center experience. pınar Gürsoy This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1161782/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Aim: Epidermal growth factor receptor (EGFR) mutations are the second most common oncogenic driver event in non-small cell lung cancer (NSCLC).We aimed to compare the first generation erlotinib treatment with the second generation afatinib treatment in patients with Non-small Cell Lung Cancer (NSCLC) with Epidermal growth factor receptor (EGFR) Exon 21 L861Q mutation. Patients and Methods: Progression-free survival (PFS) and overall survival (OS) of 30 NSCLC patients treated with erlotinib or afatinib due to single EGFR L861Q positivity were compared retrospectively. Results: There were twenty-three patients in the erlotinib arm and seven patients in the afatinib arm. Median PFS was 12.8 months in the erlotinib group and 9.3 months in the afatinib group. Median overall survival in erlotinib and afatinib groups were 77.9 months and 30.3 months, respectively. No statistically significant difference was found in the comparison of these survival times. Conclusion: Survival times of erlotinib and afatinib treatment are similar in patients with a single EGFR L861Q mutation. In patients receiving tyrosine kinase inhibitors ( TKI) treatment, female gender has a positive effect on PFS and being none-smoker has a positive effect on OS. In patients with rare mutation Exon 21 L861Q positivity both first-generation and second-generation TKIs should be considered. Non-small cell lung cancer Exon 21 L861Q Erlotinib Afatinib Figures Figure 1 Figure 2 Main Points L861Q mutation is a rare EGFR mutatıon.While many studies have reported TKI response for complex mutations, the number of studies with single exon 21 L861Q mutation is very limited. There ıs no study ın the lıterature comparısonıng the fırst generatıon EGFR-TKI and the second generatıon EGFR-TKI with single exon 21 L861Q mutation. Survival times of erlotinib and afatinib treatment are similar in patients with a single EGFR L861Q mutation In patients receiving tyrosine kinase inhibitors (TKI) treatment, female gender has a positive effect on PFS and being none-smoker has a positive effect on OS. 1. Introduction Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related death worldwide 1 . Epidermal growth factor receptor (EGFR) mutation in NSCLC is the most common mutation after K-RAS. EGFR mutation is found in 10-15% of all NSCLC cases in Western European populations, while the rate of EGFR mutation is 30% in East Asian populations 2 . Exon 19 and exon 21 L858R are called “classic EGFR mutations” and account for 85% of EGFR mutations 3 . These classic EGFR mutations show high sensitivity to treatment with Tyrosine kinase inhibitors (TKI). Studies have shown that TKI therapy results in prolongations in progression-free survival (PFS) compared to cytotoxic chemotherapy in these patients 4 . Exon 18, exon 20 and exon 21 L861Q mutations are rarer mutations, and their response to TKI and their prognosis are unclear 5 – 6 . Erlotinib and gefitinib are reversible first-generation TKIs, and afatinib is irreversible second-generation TKIs 7 – 8 . In studies with classical EGFR mutations, both first-generation TKI and second-generation TKI responses were found to be similar. Post-hoc analyses of LUX-lung 2, LUX-lung 3 and LUX-lung 6 studies have shown that "rare mutations" such as Exon 18, exon 20 and exon 21 L861Q are more susceptible to second generation TKI 9 . The Exon 21 L861Q mutation accounts for 3% of EGFR mutations, and this mutation is usually found in "complex" with G719X and Exon 19 del. While many studies have reported TKI response for complex mutations, the number of studies with Single Exon 21 L861Q mutation is very limited 10 . The aim of our study is to determine the characteristics of the rare single exon 21 L861Q patient group and to show whether there is a difference between the survival times according to the TKI used. 2. Patients And Methods 2.1.Patients: Patients who were followed up at Hospital between 2010 and 2020 and received TKI for single EGFR exon 21 L861Q positive metastatic NSCLC were included in the study. Patients with other mutations and complex mutations for EGFR were excluded from the study. EGFR mutation positivity in patients with NSCLC was determined by pyrosequencing method. Age, gender, smoking status, performance score, stages, metastasis sites, treatments received before and after, side effects and date of death of the patients were recorded. The general characteristics of these patients and the effectiveness of their treatment with TKI were evaluated retrospectively. 2.2.Ethical Considerations This study was approved by Ethical Committy of (Decision number: (21-7T/4) All patients gave written informed consent. 2.3.Statistical analysis: IBM SPSS Statistics Version 22 package program was used for statistical analysis. Whether the data was normally distributed was determined by Kolmogorov-Smirnov and Shapiro-Wilk tests. Mann-Whitney U test was used to compare continuous variables between groups, Chi-square test and Fisher's exact test were used to compare categorical variables. Kaplan-Meier test was used for survival analysis. Results are presented as, median (min-max) and number (percentage). A p value of <0.05 was considered statistically significant in all statistical analyzes. 3. Results 3.1. Patient characteristics: Thirty patients who received TKI therapy for metastatic NSCLC single exon 21 L861Q mutation positivity were included in the study. The pathological type of all patients was adenocarcinoma. The median age was 70 (52.0-84.0), 14 patients (46.7%) were female and 16 patients (53.3%) were male. Demographic and clinical characteristics of the patients were presented in Table 1. Twenty-three (76.7%) of the patients received first-generation TKI, and 7 (23.3%) of patients received second-generation TKI. TKIs were used in the first-line treatment in 15 (50%) patients, in the second-line treatment in 11 (36.7%) patients, and in the tertiary treatment in 4 (13.3%) patients. The treatments received by the patients before and after TKI were shown in Table 2. 3.2. PFS and OS: PFS was found to be 13.2 months (95%CI 7.8-18.7) in all patient groups. The PFS was 12.8 months (95%CI7.2-18.4) in the erlotinib group, and 9.3 months (95%CI 6.0-12.6) in the afatinib group, with no difference between the two groups (p=0.751) (Figure 1). When the PFS was compared according to gender, the PFS of female patients was found to be longer than male patients (19.3 vs 7.3 p= 0.005). Similarly, there was a statistically significant difference between the PFS of female patients and male patients in the Erlotinib group (19.4 months (95%CI 8.9-29.8) vs. 7.1 months (95%CI 4, 7-9.5), respectively p=0.008). Also, the PFS of female patients was longer in the afatinib group, but no statistical difference was found (10.4 months vs. 7.8 months p=0.823). When the PFS was compared according to the smoking status of the patients, the PFS was found to be 13.8 months in the none-smokers group and 9 months in the ex-smokers group (p=0.749). In the erlotinib group, patients who had never smoked had a longer PFS than patients who had smoked, although it was not statistically significant (14.6 months vs. 8.2 months p=0.320). In the afatinib group, the PFSs for these patients were found to be 10.9 months and 7.2 months, respectively (p=0.264). No better response was observed in any subgroup when PFSs were compared according to tumor stages, number of metastatic sites, and performance status (Table 3). OS of all patients was 73 months (95% CI 41.0-104). OS was 77.9 months (95%CI 44.2-111.5) in the erlotinib group and 30.3 months (95% CI 30.1-30.5) in the afatinib arm, and there was no statistically significant difference between the two groups (p=0.265) (figure 2). When OS was evaluated according to gender, the OS of male patients was found to be longer than female patients (76.1 vs 37.2 p=0.649). When OS was compared by smoking status, OS was statistically significantly longer in the none-smokers group (97.5 months (95%CI 65.6-129.3) vs. 40 months (95%CI 26.7-53.2 respectively, p=0.026). Similar results were also observed in the Erlotinib group (97.5 months vs. 45.1 months, respectively, p=0.083). In this study, 5 patients (16.7%) had brain metastases. Patients with brain metastases had a PFS of 12.0 months, and patients without brain metastases had a PFS of 14.6 months (p=0.862). All of these patients received erlotinib treatment, and the PFS of this group was calculated as 12.0 months (95%CI 4-19.9). The OS of the patients with brain metastases was 40.9 months (95% CI 20.2-61.6), and the OS of the patients without brain metastases was found to be statistically significantly longer (40.9 months vs. 89.1, respectively, p=0.045). Bone metastases are the most common site of metastasis, and there was no difference between the groups with and without bone metastases in terms of both PFS and OS (p: 0.407 vs p=0.558). There was no statistically significant difference between the PFS of the patients who received TKI in first line and those who received TKI in other steps (17.8 months vs 8.2 months p=0.082). However, when the OS was compared between the groups, a statistically significant difference was observed (39.4 months vs. 97.5 months, respectively, p=0.019). 3.3. Adverse effects: The most common side effects associated with erlotinib were rash (82.6%) and diarrhea (56.5%). In the afatinib group, rash was the most common side effect with a rate of 28.5%. Paronychia, which is frequently observed in TKI treatment, was observed in 3 patients (13%), while all patients were in the erlotinib group. When all side effects were evaluated, grade 3-4 side effects were presented with anemia in only 1 patient (4.3%). Interstitial lung disease, especially with a poor prognosis, was seen only in 1 patient (4.3%) who received erlotinib, and treatment-related death was not observed in either group. The side effects observed in patients due to TKI treatment were shown in Table 4. When the relationship between rash and PFS and OS was evaluated, there was a statistically significant difference between the PFS of the patients with and without rash (10.6 months vs. 12.9months, p=0.030, respectively), but there was no difference between the OS (p=0.863). 4. Discussion In studies with classical mutations (EGFR exon 19 and exon 21 L858R), a progression-free survival benefit was observed in patients receiving TKI compared with chemotherapy. There are no prospective studies evaluating the efficacy of TKI in rare mutations in the literature. Results evaluating the efficacy of TKI in these patients are generally obtained from post-hoc analyzes of other studies or case series. Exon 21 L861Q mutations may be a single mutation or part of complex mutations. Our study is the first in the literature to compare the efficacy of erlotinib and afatinib in a single EGFR exon 21 L861Q mutation positive patient group. There are analyses showing that EGFR phosphorylation is preserved in cells expressing L861Q following treatment with first-generation TKI, such as erlotinib, while EGFR phosphorylation is lost after treatment with afatinib. These data suggest that second-generation TKIs may be more effective in targeting L861Q mutations. Moreover, preclinical studies have shown that L861Q mutations are more resistant to first generation TKIs than L858R mutations, and more sensitive to afatinib and osimertinib treatment 11 . The reason for this sensitivity has been shown to be the irreversible covalent binding of these two drugs to the cysteine-797 residue in the ATP pocket 12 – 13 . In the post-hoc analysis of LUX-lung 2, LUX-lung 3 and LUX-lung 6 studies, single L861Q positivity was detected in 16 (16.0%) of 100 patients with positive rare mutation 9 . With afatinib treatment, ORR was 56.3%, PFS was 8.2 months, and OS was 17.1 months in these patients. Yang et al. reported that 8.2 months of PFS and 17.1 months of OS were observed in patients receiving afatinib treatment in their series of 12 cases 14 . In the literature by Chiu et al. and Xu et al., in studies with 57 and 15 patients, erlotinib/gefitinib was used in single L861Q positive patients, and PFS was 8.1 months and OS was 22.0 months 15 . In our study, OS and PFS were found to be longer in both erlotinib and afatinib groups compared to literature results. The OPTIMAL study is a phase III study comparing erlotinib and chemotherapy in classical EGFR mutation-positive patients. In this study, PFS was 13.1 months and OS was 22.8 months in the erlotinib arm. In our study, while the PFS of the erlotinib arm was the same as in the literature, OS was longer than the literature. The longer OS may be due to the higher proportion of patients receiving chemotherapy in the next steps. In the OPTIMAL study, the Exon 21 L858R classical mutation was more common in female and non-smokers 16 . In our study, the incidence of L861Q mutation was more common in the non-smoker group, but no difference was found in terms of gender. Studies on the pharmacokinetics of TKIs have shown that metabolic clearance of TKIs is increased in smokers compared to never-smokers. As a result, patients who none-smokers provided 36% more benefits 17 . In our study, PFS and OS were found to be longer in both the erlotinib and afatinib arms in none-smokers, and only the OS benefit was found to be statistically significant. Whether the development of rash is an indicator of TKI effectiveness has been investigated in many studies. Although this predictive effect was found in most of the studies, this relationship could not be clearly demonstrated in a few studies 18 . In our study, unlike the literature, patients who did not develop rash had longer PFS and no difference was found in terms of OS. The main limitations of our study are the small number of patients and its retrospective nature. Since afatinib treatment receives late repayment in our country, there is a difference in the number of patients between the groups. The TKIs chosen for treatment are the physician's choice and may affect the results. However, our study has important findings as it is the first study to compare the efficacy of erlotinib and afatinib in a single EGFR exon 21 L861Q mutation positive patient group. In conclusion, both PFS and OS were found to be similar with erlotinib and afatinib treatments in rare EGFR exon 21 L861Q mutation positive patients. In this patient group, female gender should be considered in terms of PFS benefit and being none-smoker should be considered in terms of OS benefit. However, randomized studies with larger numbers of patients are needed for clearer results. Declarations Disclosure statement The authors declare no conflict of interest with regard to the present study. Ethical approval This study was approved by Ethical Committee( 21-7T/4) . All patients gave written informed consent. References 1. Siegel RL, Miller KD, Jemal A (2019) Cancer statistics. CA Cancer J Clin 69:7–34. 2. D’Angelo S, Pietanza M.C, Johnson M.L, J Riely G, Miller V, S Sima C, et al. Incidence of EGFR exon 19 deletions and L858R in tumor specimens from men and cigarette smokers with lung adenocarcinomas, J. Clin.Oncol. 29 (15) (2011) 2066–2070. 3. Dogan S , Shen R, Ang D.C, Johnson M.L, D'Angelo S, Paik P.K, et al. Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers. Clin Cancer Res. 2012 Nov 15;18(22):6169-77. 4. Gazdar A.F. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene. 2009 Aug;28 Suppl 1.24-31. 5. Pao W. Chmielecki J. Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer 10, 760–774. 6. Mitsudomi T, Kosaka T, Yatabe Y. Biological and clinical implications of EGFR mutations in lung cancer. Int J Clin Oncol 2006 Jun;11(3):190-8. 7. Zhou C, Wu YL, Chen G, Feng J, Liu X-Q, Wang C,et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. The Lancet Oncology. 2011; 12:735–742. 8. Sequist L.V, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. Journal of clinical oncology. 2013; 31:3327–3334. 9.Yang JC, Sequist L.V, Geater S.L, Tsai C-M, Mok T, Schuler M, et al. Clinical activity of afatinib in patients with advanced nonsmall-cell lung cancer harbouring uncommon EGFR mutations: a combined posthoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6, Lancet Oncol. 16 (2015) 830–838. 10. Chiu CH, Yang C, Shih J, Huang M-S , Su W-C, Lai R-S, et al. Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Treatment Response in Advanced Lung Adenocarcinomas with G719X/L861Q/S768I Mutations. J Thorac Oncol 2015;10:793-9. 11. Banno E, Togashi Y, NakamuraY, Chiba M , Kobayashi Y, Hayashi H, et al. Sensitivities to various epidermal growth factor receptor-tyrosine kinase inhibitors of uncommon epidermal growth factor receptor mutations L861Q and S768I: What is the optimal epidermal growth factor receptor-tyrosine kinase inhibitor? Cancer Sci. 2016 Aug;107(8):1134-40. 12. Zhou W, Ercan D, Chen L, Yun C-H, Li D, Capelletti M, e t al. Novel mutant‐selective EGFR kinase inhibitors against EGFR T790M. Nature 2009; 462: 1070–4. 13. Walter AO, Sjin RT, Haringsma HJ, Ohashi K, Sun J, Lee K,et al .Discovery of a mutant‐selective covalent inhibitor of EGFR that overcomes T790M‐mediated resistance in NSCLC. Cancer Discov 2013; 3: 1404–15. 14. Cho J.H, Lim S.H, An H.J, Kim K.H, Park K.U, Kang E.U,et al. An open-label, multicenter, phase II single arm trial of osimertinib in non-small cell lung cancer patients with uncommon EGFR mutation (KCSG-LU15-09), J. Clin. Oncol. 36 (15_suppl) (2018) 9050. 15. Rosell R, Ichinose Y, Taron M, Sarries C, Queralt C, Mendez P, et al . Mutations in the tyrosine kinase domain of the EGFR gene associated with gefitinib response in non-small-cell lung cancer. Lung Cancer 2005;50:25-33. 16. Rosell R ,Carcereny E , Gervais R , Vergnenegre A, Massuti B, Felip E, et al . Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13:239–46. 17.Hamilton M.Wolf J.L, Rusk J, Beard S-E, Clark G-M, Witt K,et al. Effects of smoking on the pharmacokinetics of erlotinib.Clin Cancer Res. 2006; 12: 2166-2171. 18. Kainis I, Syrigos N, Kopitopoulou A, Gkiozos I, Filiou E, Nikolaou V,et al. Erlotinib-Associated Rash in Advanced Non-Small Cell Lung Cancer: Relation to Clinicopathological Characteristics, Treatment Response, and Survival. Oncol Res. 2018; 26(1): 59–69. Tables Table 1: Demographic data and clinical characteristics Patients characteristics n (%) Age (mean) (min-max) 70.0 (52.0-84.0) Sex n(%) Female Male 14 (46.7%) 16 (53.3%) Smoking status n(%) None-smoker Ex-smoker 16 (53.3%) 14 (46.7%) Smoking package*year (min-max) 50.0 (30.0-60.0) ECOG performance status (%) 0 1 2 3 3(10%) 18 (60 %) 9 (30%) 0 (0 %) Stage n(%) I II III IV - 4 (13.3%) - 26 (86.7%) Metastasis n(%) Solitary Multiple 12 (40.0%) 18 (60.0%) Brain metastases n(%) 5 (16.7%) Bone metastases n(%) 12 (40.0%) TKI type n(%) Erlotinib Afatinib 23 (76.7%) 7 (23.3%) TKI treatment n(%) First line Second line Third line 15 (50.0%) 11 (36.7%) 4 (13.3%) Table 2: The treatments received by the patients before and after tyrosine kinase inhibitors. Type of treatment received First line (n) Second line (n) Third line (n) Paclitaxel-platinum 1 2 0 Docetaxel-platinum 5 0 5 Pemetrexed -platinum 6 3 0 Gemcitabine-platinum 0 4 0 Vinorelbine -platinum 3 0 0 Others 0 0 0 Table 3: Comparison of PFS and OS according to demographic and clinical characteristics PFS OS Median months (95% CI) P value Median months (95% CI) P value Overall 13.2 (7.8-18.7) 73.0 (41.9-104.1) Gender Male 7.3 (5.3-9.3) 0.005 76.1 (42.2-110) 0.649 Female 19.3 (9.8-29.2) 37.2 (33.2-41.2) Smoking status None-smoker 13.8 (6.9-20.8) 0.749 97.5 (65.6-29.3) 0.026 Ex-smoker 9.0 (6.4-11.6) 40.0 (26.7-53.2) Stage I - 0.282 - 0.762 II 12.7 (12.0-13.3) 36.3 (27.8-44.9) III - - IV 12.7 (6.9-18.5) 77.9 (44.2-111.5) ECOG 0 6.0 (5.3-6.7) 0.594 - 0.160 1 11.6 (8.8-14.5) 86.3 (52.6-119.9) 2 19.9 (8.8-30.1) 40.9 (20.2-61.6) 3 - - Metastasis type Solitary 8.3 (5.7-10.9) 0.341 74.7 (40.2-109) 0.448 Multiple 14.9 (7.7-22.1) 37.6 (34.4-40.9) Table 4: Evaluation of side effects according to tyrosine kinase type Erlotinib Afatinib Grade 1/2 n (%) Grade 3/4 n (%) Grade 1/2 n (%) Grade 3/4 n (%) Diarrhea 13 (56.5%) 0 2 (28.5%) 0 Rash 18 (78.2%) 1 (4.3%) 2 (28.5%) 0 Mucositis 11 (47.8%) 0 2 (28.5%) 0 ALT/AST elevation 1 (4.3%) 0 0 0 Paronychia 3 (13.0%) 0 0 0 Anemia 11 (47.8%) 1 (4.3%) 2 (28.5%) 0 Interstitial lung disease 1 (4.3%) 0 0 0 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1161782","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":69457099,"identity":"ebb40a38-96f2-43f7-a8ec-c3f2eaf119aa","order_by":0,"name":"pınar Gürsoy","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAElEQVRIiWNgGAWjYDACZgST/fefCpAIcwPRWhgkeM6ARBgJaEEGErxtIIqAFnN23oOfK34dzpdv7zEwkJxXG83fDtTyo2IbTi2WzXzJkmf7DltuOHPGIMFw2/HcGYcZGxh7ztzGqcXgMI+BZGPPYQMDiRyDA4nbjuU2ALUwM7bh1WL8E6RFfkaOYcPBOcdy5xOhxUyy4cdhA4YbOcaMjQ01uRsIabFs5jGzbGxINzA4c6yMmeHYgdyNQC0H8fnFnP+M8c2GP9YG8u3N25gZaupy550/fPDBjwo8DgMRjODo4ACxD4NFD+BUD9PC8AdEsD8AEnX4FI+CUTAKRsEIBQCealxBZ/NQKwAAAABJRU5ErkJggg==","orcid":"","institution":"ege unıversity","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"pınar","middleName":"","lastName":"Gürsoy","suffix":""}],"badges":[],"createdAt":"2021-12-11 11:38:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1161782/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1161782/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":16410615,"identity":"02702a48-1b88-48cd-9e20-188f9d498244","added_by":"auto","created_at":"2021-12-13 19:57:02","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":43529,"visible":true,"origin":"","legend":"Evaluation of PFS according to tyrosine kinase inhibitor types.","description":"","filename":"figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1161782/v1/e38979a33b5adce394a8b9c8.jpg"},{"id":16410616,"identity":"603aa12d-c010-4743-b953-abaa92d54606","added_by":"auto","created_at":"2021-12-13 19:57:02","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":44389,"visible":true,"origin":"","legend":" Evaluation of OS according to tyrosine kinase inhibitor types.","description":"","filename":"figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1161782/v1/c7c34f1aee718d4156d9b920.jpg"},{"id":16410617,"identity":"d97d05e9-e771-403e-9ea3-52515697ca98","added_by":"auto","created_at":"2021-12-13 19:57:05","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":309487,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1161782/v1/8477c672-9fec-4a9c-9fd0-f64d8d62d4d4.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eEvaluation of treatment efficacy of tyrosine kinase inhibitors in rare single EGFR Exon 21 L861Q mutation; single center experience.\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","fulltext":[{"header":"Main Points","content":"\u003col\u003e\n \u003cli\u003e\u0026nbsp;L861Q mutation is a rare EGFR mutatıon.While many studies have reported TKI response for complex mutations, the number of studies with single exon 21 \u0026nbsp;L861Q mutation is very limited.\u003c/li\u003e\n \u003cli\u003eThere ıs no study ın the lıterature comparısonıng the fırst generatıon EGFR-TKI and the second generatıon EGFR-TKI \u0026nbsp;with single exon 21 L861Q mutation.\u003c/li\u003e\n \u003cli\u003eSurvival times of erlotinib and afatinib treatment are similar in patients with a single \u0026nbsp; \u0026nbsp; EGFR \u0026nbsp; L861Q \u0026nbsp; mutation\u003c/li\u003e\n \u003cli\u003eIn patients receiving tyrosine kinase inhibitors (TKI) treatment, female gender has a \u0026nbsp; \u0026nbsp; positive effect on PFS and being none-smoker has a positive effect on OS.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"1. Introduction","content":"\u003cp\u003eNon-small cell lung cancer (NSCLC) is the most common cause of cancer-related death worldwide\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Epidermal growth factor receptor (EGFR) mutation in NSCLC is the most common mutation after K-RAS. EGFR mutation is found in 10-15% of all NSCLC cases in Western European populations, while the rate of EGFR mutation is 30% in East Asian populations\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Exon 19 and exon 21 L858R are called \u0026ldquo;classic EGFR mutations\u0026rdquo; and account for 85% of EGFR mutations\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. These classic EGFR mutations show high sensitivity to treatment with Tyrosine kinase inhibitors (TKI). Studies have shown that TKI therapy results in prolongations in progression-free survival (PFS) compared to cytotoxic chemotherapy in these patients\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Exon 18, exon 20 and exon 21 L861Q mutations are rarer mutations, and their response to TKI and their prognosis are unclear\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eErlotinib and gefitinib are reversible first-generation TKIs, and afatinib is irreversible second-generation TKIs\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. In studies with classical EGFR mutations, both first-generation TKI and second-generation TKI responses were found to be similar. Post-hoc analyses of LUX-lung 2, LUX-lung 3 and LUX-lung 6 studies have shown that \"rare mutations\" such as Exon 18, exon 20 and exon 21 L861Q are more susceptible to second generation TKI\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe Exon 21 L861Q mutation accounts for 3% of EGFR mutations, and this mutation is usually found in \"complex\" with G719X and Exon 19 del. While many studies have reported TKI response for complex mutations, the number of studies with Single Exon 21 L861Q mutation is very limited\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe aim of our study is to determine the characteristics of the rare single exon 21 L861Q patient group and to show whether there is a difference between the survival times according to the TKI used.\u003c/p\u003e"},{"header":"2. Patients And Methods","content":"\u003cp\u003e\u003cstrong\u003e2.1.Patients:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients who were followed up at Hospital between 2010 and 2020 and received TKI for single EGFR exon 21 L861Q positive metastatic NSCLC were included in the study. Patients with other mutations and complex mutations for EGFR were excluded from the study.\u0026nbsp;EGFR mutation positivity in patients with NSCLC was determined by pyrosequencing method.\u0026nbsp;Age, gender, smoking status, performance score, stages, metastasis sites, treatments received before and after, side effects and date of death of the patients were recorded. The general characteristics of these patients and the effectiveness of their treatment with TKI were evaluated retrospectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e2.2.Ethical Considerations \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by Ethical Committy of (Decision number:\u0026nbsp;(21-7T/4)\u0026nbsp;All patients gave written informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.3.Statistical analysis:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIBM SPSS Statistics Version 22 package program was used for statistical analysis. Whether the data was normally distributed was determined by Kolmogorov-Smirnov and Shapiro-Wilk tests. Mann-Whitney U test was used to compare continuous variables between groups, Chi-square test and Fisher\u0026apos;s exact test were used to compare categorical variables. Kaplan-Meier test was used for survival analysis. Results are presented as, median (min-max) and number (percentage). A p value of \u0026lt;0.05 was considered statistically significant in all statistical analyzes.\u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003e\u003cstrong\u003e3.1. Patient characteristics:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThirty patients who received TKI therapy for metastatic NSCLC single exon 21 L861Q mutation positivity were included in the study. The pathological type of all patients was adenocarcinoma. The median age was 70 (52.0-84.0), 14 patients (46.7%) were female and 16 patients (53.3%) were male. Demographic and clinical characteristics of the patients were presented in Table 1. Twenty-three (76.7%) of the patients received first-generation TKI, and 7 (23.3%) of patients received second-generation TKI. TKIs were used in the first-line treatment in 15 (50%) patients, in the second-line treatment in 11 (36.7%) patients, and in the tertiary treatment in 4 (13.3%) patients. The treatments received by the patients before and after TKI were shown in Table 2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2. PFS and OS:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePFS was found to be 13.2 months (95%CI 7.8-18.7) in all patient groups. The PFS was 12.8 months (95%CI7.2-18.4) in the erlotinib group, and 9.3 months (95%CI 6.0-12.6) in the afatinib group, with no difference between the two groups (p=0.751) (Figure 1).\u003c/p\u003e\n\u003cp\u003eWhen the PFS was compared according to gender, the PFS of female patients was found to be longer than male patients (19.3 vs 7.3 p= 0.005). Similarly, there was a statistically significant difference between the PFS of female patients and male patients in the Erlotinib group (19.4 months (95%CI 8.9-29.8) vs. 7.1 months (95%CI 4, 7-9.5), respectively p=0.008). Also, the PFS of female patients was longer in the afatinib group, but no statistical difference was found (10.4 months vs. 7.8 months p=0.823).\u003c/p\u003e\n\u003cp\u003eWhen the PFS was compared according to the smoking status of the patients, the PFS was found to be 13.8 months in the none-smokers group and 9 months in the ex-smokers group (p=0.749). In the erlotinib group, patients who had never smoked had a longer PFS than patients who had smoked, although it was not statistically significant (14.6 months vs. 8.2 months p=0.320). In the afatinib group, the PFSs for these patients were found to be 10.9 months and 7.2 months, respectively (p=0.264).\u003c/p\u003e\n\u003cp\u003eNo better response was observed in any subgroup when PFSs were compared according to tumor stages, number of metastatic sites, and performance status (Table 3).\u003c/p\u003e\n\u003cp\u003eOS of all patients was 73 months (95% CI 41.0-104). OS was 77.9 months (95%CI 44.2-111.5) in the erlotinib group and 30.3 months (95% CI 30.1-30.5) in the afatinib arm, and there was no statistically significant difference between the two groups (p=0.265) (figure 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWhen OS was evaluated according to gender, the OS of male patients was found to be longer than female patients (76.1 vs 37.2 p=0.649).\u003c/p\u003e\n\u003cp\u003eWhen OS was compared by smoking status, OS was statistically significantly longer in the none-smokers group (97.5 months (95%CI 65.6-129.3) vs. 40 months (95%CI 26.7-53.2 respectively, p=0.026). Similar results were also observed in the Erlotinib group (97.5 months vs. 45.1 months, respectively, p=0.083).\u003c/p\u003e\n\u003cp\u003eIn this study, 5 patients (16.7%) had brain metastases. Patients with brain metastases had a PFS of 12.0 months, and patients without brain metastases had a PFS of 14.6 months (p=0.862). All of these patients received erlotinib treatment, and the PFS of this group was calculated as 12.0 months (95%CI 4-19.9). The OS of the patients with brain metastases was 40.9 months (95% CI 20.2-61.6), and the OS of the patients without brain metastases was found to be statistically significantly longer (40.9 months vs. 89.1, respectively, p=0.045).\u003c/p\u003e\n\u003cp\u003eBone metastases are the most common site of metastasis, and there was no difference between the groups with and without bone metastases in terms of both PFS and OS (p: 0.407 vs p=0.558).\u003c/p\u003e\n\u003cp\u003eThere was no statistically significant difference between the PFS of the patients who received TKI in first line and those who received TKI in other steps (17.8 months vs 8.2 months p=0.082). However, when the OS was compared between the groups, a statistically significant difference was observed (39.4 months vs. 97.5 months, respectively, p=0.019).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.3. Adverse effects:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe most common side effects associated with erlotinib were rash (82.6%) and diarrhea (56.5%). In the afatinib group, rash was the most common side effect with a rate of 28.5%. Paronychia, which is frequently observed in TKI treatment, was observed in 3 patients (13%), while all patients were in the erlotinib group. When all side effects were evaluated, grade 3-4 side effects were presented with anemia in only 1 patient (4.3%). Interstitial lung disease, especially with a poor prognosis, was seen only in 1 patient (4.3%) who received erlotinib, and treatment-related death was not observed in either group. The side effects observed in patients due to TKI treatment were shown in Table 4.\u003c/p\u003e\n\u003cp\u003eWhen the relationship between rash and PFS and OS was evaluated, there was a statistically significant difference between the PFS of the patients with and without rash (10.6 months vs. 12.9months, p=0.030, respectively), but there was no difference between the OS (p=0.863).\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eIn studies with classical mutations (EGFR exon 19 and exon 21 L858R), a progression-free survival benefit was observed in patients receiving TKI compared with chemotherapy. There are no prospective studies evaluating the efficacy of TKI in rare mutations in the literature. Results evaluating the efficacy of TKI in these patients are generally obtained from post-hoc analyzes of other studies or case series. Exon 21 L861Q mutations may be a single mutation or part of complex mutations. Our study is the first in the literature to compare the efficacy of erlotinib and afatinib in a single EGFR exon 21 L861Q mutation positive patient group.\u003c/p\u003e \u003cp\u003eThere are analyses showing that EGFR phosphorylation is preserved in cells expressing L861Q following treatment with first-generation TKI, such as erlotinib, while EGFR phosphorylation is lost after treatment with afatinib. These data suggest that second-generation TKIs may be more effective in targeting L861Q mutations. Moreover, preclinical studies have shown that L861Q mutations are more resistant to first generation TKIs than L858R mutations, and more sensitive to afatinib and osimertinib treatment\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. The reason for this sensitivity has been shown to be the irreversible covalent binding of these two drugs to the cysteine-797 residue in the ATP pocket\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn the post-hoc analysis of LUX-lung 2, LUX-lung 3 and LUX-lung 6 studies, single L861Q positivity was detected in 16 (16.0%) of 100 patients with positive rare mutation\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. With afatinib treatment, ORR was 56.3%, PFS was 8.2 months, and OS was 17.1 months in these patients. Yang et al. reported that 8.2 months of PFS and 17.1 months of OS were observed in patients receiving afatinib treatment in their series of 12 cases\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn the literature by Chiu et al. and Xu et al., in studies with 57 and 15 patients, erlotinib/gefitinib was used in single L861Q positive patients, and PFS was 8.1 months and OS was 22.0 months\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. In our study, OS and PFS were found to be longer in both erlotinib and afatinib groups compared to literature results.\u003c/p\u003e \u003cp\u003eThe OPTIMAL study is a phase III study comparing erlotinib and chemotherapy in classical EGFR mutation-positive patients. In this study, PFS was 13.1 months and OS was 22.8 months in the erlotinib arm. In our study, while the PFS of the erlotinib arm was the same as in the literature, OS was longer than the literature. The longer OS may be due to the higher proportion of patients receiving chemotherapy in the next steps.\u003c/p\u003e \u003cp\u003eIn the OPTIMAL study, the Exon 21 L858R classical mutation was more common in female and non-smokers\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. In our study, the incidence of L861Q mutation was more common in the non-smoker group, but no difference was found in terms of gender.\u003c/p\u003e \u003cp\u003eStudies on the pharmacokinetics of TKIs have shown that metabolic clearance of TKIs is increased in smokers compared to never-smokers. As a result, patients who none-smokers provided 36% more benefits\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. In our study, PFS and OS were found to be longer in both the erlotinib and afatinib arms in none-smokers, and only the OS benefit was found to be statistically significant.\u003c/p\u003e \u003cp\u003eWhether the development of rash is an indicator of TKI effectiveness has been investigated in many studies. Although this predictive effect was found in most of the studies, this relationship could not be clearly demonstrated in a few studies\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. In our study, unlike the literature, patients who did not develop rash had longer PFS and no difference was found in terms of OS.\u003c/p\u003e \u003cp\u003eThe main limitations of our study are the small number of patients and its retrospective nature. Since afatinib treatment receives late repayment in our country, there is a difference in the number of patients between the groups. The TKIs chosen for treatment are the physician's choice and may affect the results. However, our study has important findings as it is the first study to compare the efficacy of erlotinib and afatinib in a single EGFR exon 21 L861Q mutation positive patient group.\u003c/p\u003e \u003cp\u003eIn conclusion, both PFS and OS were found to be similar with erlotinib and afatinib treatments in rare EGFR exon 21 L861Q mutation positive patients. In this patient group, female gender should be considered in terms of PFS benefit and being none-smoker should be considered in terms of OS benefit. However, randomized studies with larger numbers of patients are needed for clearer results.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDisclosure statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest with regard to the present study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by Ethical Committee( 21-7T/4) . All patients gave written informed consent.\u003c/p\u003e"},{"header":"References","content":"\u003cp\u003e1. Siegel RL, Miller KD, Jemal A (2019) Cancer statistics. 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Journal of clinical oncology. 2013; 31:3327\u0026ndash;3334.\u003c/p\u003e\n\u003cp\u003e9.Yang JC, Sequist L.V, Geater S.L,\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Tsai+CM\u0026cauthor_id=26051236\"\u003e\u0026nbsp;Tsai\u003c/a\u003e C-M,\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Mok+TS\u0026cauthor_id=26051236\"\u003e\u0026nbsp;Mok\u003c/a\u003e T,\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Schuler+M\u0026cauthor_id=26051236\"\u003e\u0026nbsp;Schuler\u003c/a\u003e M,\u0026nbsp;et al. Clinical activity of afatinib in patients with advanced nonsmall-cell lung cancer harbouring uncommon EGFR mutations: a combined posthoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6, Lancet Oncol. 16 (2015) 830\u0026ndash;838.\u003c/p\u003e\n\u003cp\u003e10. Chiu CH, Yang C, Shih J,\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Huang+MS\u0026cauthor_id=25668120\"\u003e\u0026nbsp;Huang\u003c/a\u003e M-S\u003csup\u003e\u0026nbsp;\u0026nbsp;\u003c/sup\u003e,\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Su+WC\u0026cauthor_id=25668120\"\u003e\u0026nbsp;Su\u003c/a\u003eW-C,\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Lai+RS\u0026cauthor_id=25668120\"\u003e\u0026nbsp;Lai\u003c/a\u003e R-S,\u0026nbsp;et al. Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Treatment Response in Advanced Lung Adenocarcinomas with G719X/L861Q/S768I Mutations. J Thorac Oncol 2015;10:793-9.\u003c/p\u003e\n\u003cp\u003e11.\u0026nbsp;Banno E, Togashi Y, NakamuraY,\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Chiba+M\u0026cauthor_id=27240419\"\u003e\u0026nbsp;Chiba\u003c/a\u003e M\u003csup\u003e\u0026nbsp;\u003c/sup\u003e,\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Kobayashi+Y\u0026cauthor_id=27240419\"\u003e\u0026nbsp;Kobayashi\u003c/a\u003e Y,\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Hayashi+H\u0026cauthor_id=27240419\"\u003e\u0026nbsp;Hayashi\u003c/a\u003e H,\u0026nbsp;et al. Sensitivities to various epidermal growth factor receptor-tyrosine kinase inhibitors of uncommon epidermal growth factor receptor\u0026nbsp;mutations L861Q and S768I: What is the optimal epidermal growth factor receptor-tyrosine kinase inhibitor?\u0026nbsp;Cancer Sci.\u0026nbsp;2016 Aug;107(8):1134-40.\u003c/p\u003e\n\u003cp\u003e12. Zhou W, Ercan D, Chen L,\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Yun+CH\u0026cauthor_id=20033049\"\u003e\u0026nbsp;Yun\u003c/a\u003e C-H,\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Li+D\u0026cauthor_id=20033049\"\u003e\u0026nbsp;Li\u003c/a\u003e D,\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Capelletti+M\u0026cauthor_id=20033049\"\u003e\u0026nbsp;Capelletti\u003c/a\u003e M,\u0026nbsp;e\u003cem\u003et al.\u003c/em\u003e Novel mutant‐selective EGFR kinase inhibitors against EGFR T790M.\u0026nbsp;Nature\u0026nbsp;2009;\u0026nbsp;462: 1070\u0026ndash;4.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;13. Walter AO, Sjin RT, Haringsma HJ,\u0026nbsp;\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Ohashi+K\u0026cauthor_id=24065731\"\u003e\u0026nbsp;Ohashi\u003c/a\u003e K,\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Sun+J\u0026cauthor_id=24065731\"\u003e\u0026nbsp;Sun\u003c/a\u003e J,\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Lee+K\u0026cauthor_id=24065731\"\u003e\u0026nbsp;Lee\u003c/a\u003e K,et al\u0026nbsp;.Discovery of a mutant‐selective covalent inhibitor of EGFR that overcomes T790M‐mediated resistance in NSCLC.\u0026nbsp;Cancer Discov\u0026nbsp;2013;\u0026nbsp;3: 1404\u0026ndash;15.\u003c/p\u003e\n\u003cp\u003e14.\u0026nbsp;Cho J.H, Lim S.H, An H.J,\u0026nbsp;\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Kim+KH\u0026cauthor_id=31825714\"\u003e\u0026nbsp;Kim\u003c/a\u003e K.H,\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Park+KU\u0026cauthor_id=31825714\"\u003e\u0026nbsp;Park\u003c/a\u003e K.U,\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Kang+EJ\u0026cauthor_id=31825714\"\u003eKang\u003c/a\u003e E.U,et al. An open-label, multicenter, phase II single arm trial of osimertinib in non-small cell lung cancer patients with uncommon EGFR mutation (KCSG-LU15-09), J. Clin. Oncol. 36 (15_suppl) (2018) 9050.\u003c/p\u003e\n\u003cp\u003e15.\u0026nbsp;Rosell R, Ichinose Y, Taron M,\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Sarries+C\u0026cauthor_id=16011858\"\u003e\u0026nbsp;Sarries\u003c/a\u003e C,\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Queralt+C\u0026cauthor_id=16011858\"\u003e\u0026nbsp;Queralt\u003c/a\u003e C,\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Mendez+P\u0026cauthor_id=16011858\"\u003e\u0026nbsp;Mendez\u003c/a\u003e P,\u0026nbsp;et al . Mutations in the tyrosine kinase domain of the EGFR gene associated with gefitinib response in non-small-cell lung cancer. Lung Cancer 2005;50:25-33.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e16.\u0026nbsp;Rosell R ,Carcereny E , Gervais R ,\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Vergnenegre+A\u0026cauthor_id=22285168\"\u003eVergnenegre\u003c/a\u003e A,\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Massuti+B\u0026cauthor_id=22285168\"\u003eMassuti\u003c/a\u003e B,\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Felip+E\u0026cauthor_id=22285168\"\u003e\u0026nbsp;Felip\u003c/a\u003e E,\u0026nbsp;et al\u0026nbsp;.\u0026nbsp;Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.\u0026nbsp;Lancet Oncol\u0026nbsp;2012;13:239\u0026ndash;46.\u003c/p\u003e\n\u003cp\u003e17.Hamilton M.Wolf J.L, Rusk J,\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Beard+SE\u0026cauthor_id=16609030\"\u003e\u0026nbsp;Beard\u003c/a\u003e S-E,\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Clark+GM\u0026cauthor_id=16609030\"\u003e\u0026nbsp;Clark\u003c/a\u003e G-M,\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Witt+K\u0026cauthor_id=16609030\"\u003e\u0026nbsp;Witt\u003c/a\u003e K,et al. Effects of smoking on the pharmacokinetics of \u0026nbsp; \u0026nbsp; erlotinib.Clin Cancer Res.\u0026nbsp;2006; 12:\u0026nbsp;2166-2171.\u003c/p\u003e\n\u003cp\u003e18.\u0026nbsp;Kainis I, \u0026nbsp;Syrigos N, \u0026nbsp; Kopitopoulou A,\u0026nbsp;\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Gkiozos+I\u0026cauthor_id=28390118\"\u003e\u0026nbsp;Gkiozos\u003c/a\u003e I,\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Filiou+E\u0026cauthor_id=28390118\"\u003e\u0026nbsp;Filiou\u003c/a\u003e E,\u0026nbsp;\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/?term=Nikolaou+V\u0026cauthor_id=28390118\"\u003eNikolaou\u003c/a\u003e V,et al. Erlotinib-Associated Rash in Advanced Non-Small Cell Lung Cancer: Relation to Clinicopathological Characteristics, Treatment Response, and Survival.\u0026nbsp;\u003ca href=\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844560/\"\u003eOncol Res.\u003c/a\u003e 2018; 26(1): 59\u0026ndash;69.\u003c/p\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1: Demographic data and clinical characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003ePatients characteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eAge (mean) (min-max)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003e70.0 (52.0-84.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eSex n(%)\u003c/p\u003e\n \u003cp\u003eFemale\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e14 (46.7%)\u003c/p\u003e\n \u003cp\u003e16 (53.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eSmoking status n(%)\u003c/p\u003e\n \u003cp\u003eNone-smoker\u003c/p\u003e\n \u003cp\u003eEx-smoker\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e16 (53.3%)\u003c/p\u003e\n \u003cp\u003e14 (46.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eSmoking package*year (min-max)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003e50.0 (30.0-60.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eECOG performance status (%)\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3(10%)\u003c/p\u003e\n \u003cp\u003e18 (60 %)\u003c/p\u003e\n \u003cp\u003e9 (30%)\u003c/p\u003e\n \u003cp\u003e0 (0 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eStage n(%)\u003c/p\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e4 (13.3%)\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e26 (86.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eMetastasis n(%)\u003c/p\u003e\n \u003cp\u003eSolitary\u003c/p\u003e\n \u003cp\u003eMultiple\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e12 (40.0%)\u003c/p\u003e\n \u003cp\u003e18 (60.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eBrain metastases n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003e5 (16.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eBone metastases n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003e12 (40.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eTKI type n(%)\u003c/p\u003e\n \u003cp\u003eErlotinib\u003c/p\u003e\n \u003cp\u003eAfatinib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e23 (76.7%)\u003c/p\u003e\n \u003cp\u003e7 (23.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003eTKI treatment n(%)\u003c/p\u003e\n \u003cp\u003eFirst line\u003c/p\u003e\n \u003cp\u003eSecond line\u003c/p\u003e\n \u003cp\u003eThird line\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"50%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e15 (50.0%)\u003c/p\u003e\n \u003cp\u003e11 (36.7%)\u003c/p\u003e\n \u003cp\u003e4 (13.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eTable 2: The treatments received by the patients before and after tyrosine kinase inhibitors.\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"31.29139072847682%\"\u003e\n \u003cp\u003eType of treatment received\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.85430463576159%\"\u003e\n \u003cp\u003eFirst line (n)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.509933774834437%\"\u003e\n \u003cp\u003eSecond line (n)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.344370860927153%\"\u003e\n \u003cp\u003eThird line (n)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"31.29139072847682%\"\u003e\n \u003cp\u003ePaclitaxel-platinum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.85430463576159%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.509933774834437%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.344370860927153%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"31.29139072847682%\"\u003e\n \u003cp\u003eDocetaxel-platinum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.85430463576159%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.509933774834437%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.344370860927153%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"31.29139072847682%\"\u003e\n \u003cp\u003ePemetrexed -platinum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.85430463576159%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.509933774834437%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.344370860927153%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"31.29139072847682%\"\u003e\n \u003cp\u003eGemcitabine-platinum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.85430463576159%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.509933774834437%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.344370860927153%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"31.29139072847682%\"\u003e\n \u003cp\u003eVinorelbine -platinum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.85430463576159%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.509933774834437%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.344370860927153%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"31.29139072847682%\"\u003e\n \u003cp\u003eOthers\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.85430463576159%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.509933774834437%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.344370860927153%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eTable 3: Comparison of PFS and OS according to demographic and clinical characteristics\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"112%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"28.282828282828284%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"35.35353535353536%\"\u003e\n \u003cp\u003ePFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"36.36363636363637%\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"28.571428571428573%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003eMedian months (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.26530612244898%\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003eMedian months (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.306122448979592%\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"28.571428571428573%\"\u003e\n \u003cp\u003eOverall\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e13.2 (7.8-18.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.26530612244898%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e73.0 (41.9-104.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.306122448979592%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"28.571428571428573%\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.26530612244898%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.306122448979592%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"28.571428571428573%\"\u003e\n \u003cp\u003eMale\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e7.3 (5.3-9.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.26530612244898%\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e76.1 (42.2-110)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.306122448979592%\"\u003e\n \u003cp\u003e0.649\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"28.571428571428573%\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e19.3 (9.8-29.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.26530612244898%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e37.2 (33.2-41.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.306122448979592%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"28.571428571428573%\"\u003e\n \u003cp\u003eSmoking status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.26530612244898%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.306122448979592%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"28.571428571428573%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; None-smoker\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e13.8 (6.9-20.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.26530612244898%\"\u003e\n \u003cp\u003e0.749\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e97.5 (65.6-29.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.306122448979592%\"\u003e\n \u003cp\u003e0.026\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"28.571428571428573%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Ex-smoker\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e9.0 (6.4-11.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.26530612244898%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e40.0 (26.7-53.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.306122448979592%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"28.571428571428573%\"\u003e\n \u003cp\u003eStage\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.26530612244898%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.306122448979592%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"28.571428571428573%\"\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.26530612244898%\"\u003e\n \u003cp\u003e0.282\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.306122448979592%\"\u003e\n \u003cp\u003e0.762\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"28.571428571428573%\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e12.7 (12.0-13.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.26530612244898%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e36.3 (27.8-44.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.306122448979592%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"28.571428571428573%\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.26530612244898%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.306122448979592%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"28.571428571428573%\"\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e12.7 (6.9-18.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.26530612244898%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e77.9 (44.2-111.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.306122448979592%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"28.571428571428573%\"\u003e\n \u003cp\u003eECOG\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.26530612244898%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.306122448979592%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"28.571428571428573%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e6.0 (5.3-6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.26530612244898%\"\u003e\n \u003cp\u003e0.594\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.306122448979592%\"\u003e\n \u003cp\u003e0.160\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"28.571428571428573%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e11.6 (8.8-14.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.26530612244898%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e86.3 (52.6-119.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.306122448979592%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"28.571428571428573%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e19.9 (8.8-30.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.26530612244898%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e40.9 (20.2-61.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.306122448979592%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"28.571428571428573%\"\u003e\n \u003cp\u003e3\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.26530612244898%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.306122448979592%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"28.571428571428573%\"\u003e\n \u003cp\u003eMetastasis type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.26530612244898%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.306122448979592%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"28.571428571428573%\"\u003e\n \u003cp\u003eSolitary\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e8.3 (5.7-10.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.26530612244898%\"\u003e\n \u003cp\u003e0.341\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e74.7 (40.2-109)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.306122448979592%\"\u003e\n \u003cp\u003e0.448\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"28.571428571428573%\"\u003e\n \u003cp\u003eMultiple\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e14.9 (7.7-22.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.26530612244898%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.428571428571427%\"\u003e\n \u003cp\u003e37.6 (34.4-40.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.306122448979592%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eTable 4: Evaluation of side effects according to tyrosine kinase type\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"20%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"40%\"\u003e\n \u003cp\u003eErlotinib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"40%\"\u003e\n \u003cp\u003eAfatinib\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"20%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20%\"\u003e\n \u003cp\u003eGrade 1/2 n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20%\"\u003e\n \u003cp\u003eGrade 3/4 n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20%\"\u003e\n \u003cp\u003eGrade 1/2 n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20%\"\u003e\n \u003cp\u003eGrade 3/4 n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"20%\"\u003e\n \u003cp\u003eDiarrhea\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e13 (56.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"20%\"\u003e\n \u003cp\u003e2 (28.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"20%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"20%\"\u003e\n \u003cp\u003eRash\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e18 (78.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e1 (4.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"20%\"\u003e\n \u003cp\u003e2 (28.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"20%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"20%\"\u003e\n \u003cp\u003eMucositis\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e11 (47.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"20%\"\u003e\n \u003cp\u003e2 (28.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"20%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"20%\"\u003e\n \u003cp\u003eALT/AST elevation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1 (4.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"20%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"20%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"20%\"\u003e\n \u003cp\u003eParonychia\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e3 (13.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"20%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"20%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"20%\"\u003e\n \u003cp\u003eAnemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"20%\"\u003e\n \u003cp\u003e11 (47.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e1 (4.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"20%\"\u003e\n \u003cp\u003e2 (28.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"20%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"20%\"\u003e\n \u003cp\u003eInterstitial lung disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"20%\"\u003e\n \u003cp\u003e1 (4.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"20%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"20%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Non-small cell lung cancer, Exon 21, L861Q, Erlotinib, Afatinib","lastPublishedDoi":"10.21203/rs.3.rs-1161782/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1161782/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eAim:\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eEpidermal growth factor receptor (EGFR) mutations are the second most common oncogenic driver event in non-small cell lung cancer (NSCLC).We aimed to compare the first generation erlotinib treatment with the second generation afatinib treatment in patients with Non-small Cell Lung Cancer (NSCLC) with Epidermal growth factor receptor (EGFR) Exon 21 L861Q mutation.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003ePatients and Methods:\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eProgression-free survival (PFS) and overall survival (OS) of 30 NSCLC patients treated with erlotinib or afatinib due to single EGFR L861Q positivity were compared retrospectively.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eThere were twenty-three patients in the\u0026nbsp;erlotinib arm and seven patients in the afatinib arm. Median PFS was 12.8 months in the erlotinib group and 9.3 months in the afatinib group. Median overall survival in erlotinib and afatinib groups were 77.9 months and 30.3 months, respectively. No statistically significant difference was found in the comparison of these survival times.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eSurvival times of erlotinib and afatinib treatment are similar in patients with a single EGFR L861Q mutation. In patients receiving tyrosine kinase inhibitors\u003cstrong\u003e (\u003c/strong\u003eTKI) treatment, female gender has a positive effect on PFS and being none-smoker has a positive effect on OS. In patients with rare mutation Exon 21 L861Q positivity both first-generation and second-generation TKIs should be considered.\u003c/p\u003e","manuscriptTitle":"Evaluation of treatment efficacy of tyrosine kinase inhibitors in rare single EGFR Exon 21 L861Q mutation; single center experience.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-12-13 19:57:00","doi":"10.21203/rs.3.rs-1161782/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6e20a7c9-184e-4531-a899-ea461f0790d7","owner":[],"postedDate":"December 13th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2021-12-13T19:57:00+00:00","versionOfRecord":[],"versionCreatedAt":"2021-12-13 19:57:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1161782","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1161782","identity":"rs-1161782","version":["v1"]},"buildId":"cBFmMYwuxLRRLfASyISRj","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}