{"paper_id":"4760a99c-77dd-4179-a7f9-1aefb72e7b33","body_text":"The allele frequency of EGFR T790M in ctDNA predicted clinical outcomes of Osimertinib in non-small cell lung cancer patients from a real-world study | 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 The allele frequency of EGFR T790M in ctDNA predicted clinical outcomes of Osimertinib in non-small cell lung cancer patients from a real-world study Xiao Fu, Tingting Shi, Mengjie Liu, Xiaoqiang Zheng, Haoran Zheng, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1658925/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 Background: The clinical and molecular factors that associated with the response to Osimertinib in the patients who have acquired resistance to the first or second-generation of epidermal growth factor receptor-tyrosine kinase inhibitors ( EGFR -TKIs) is elusive. Objectives: The purpose of this study is to investigate the clinical relevance to the allele frequency (AF) of T790M in circulating tumor DNA (ctDNA) by targeted next generation sequencing (NGS), and to analyze the prognostic value of T790M AF in patients with advanced non-small cell lung cancer (NSCLC) receiving Osimertinib after resistance to the first-or second-generation of EGFR -TKIs. Materials and methods: We retrospectively screened 3011 advanced NSCLC patients in the First Affiliated Hospital of Xi’an Jiaotong University from November 2015 to March 2021. 586 of them experienced the first- or second-generation EGFR-TKIs resistance and had complete follow-up information, 146 of them took NGS gene test and 48 were detected EGFR T790M in ctDNA. The associations among T790M AF, clinical characteristics and objective response rate (ORR) of Osimertinib was performed by Students’ t-test or one-way ANOVA. The patients were divided into T790M-high and T790M-low groups according to a receiver operation curve (ROC) determined cut-off value. The correlation between T790M AF and ORR of Osimertinib was performed by Students’ t-test, and the association between clinical factors and ORR of Osimertinib was assessed by Pearson’s χ 2 test or Fisher’s exact test, when appropriate. The survival curves were calculated by the Kaplan-Meier method and analyzed by the log-rank test. Cox proportional hazards regression models were also used to evaluate the association between clinical characteristics, T790M AF and survival endpoints. Results: Age ( P =0.004), EGFR active mutations ( P <0.001), EGFR T790M AF ( P =0.014), prior EGFR -TKIs ( P =0.024) and liver metastasis before Osimertinib treatment ( P =0.031) were significantly associated with progression-free survival (PFS). Multivariate analysis revealed that age (hazard ratio: 0.32, 95%CI: 0.13-0.75, P =0.009) and the AF of EGFR T790M (hazard ratio: 0.39, 95%CI: 0.17-0.90, P =0.027) were independent prognostic factors for PFS in EGFR T790M positive advanced NSCLC patients receiving Osimertinib. EGFR active mutations ( P <0.001) was significantly associated with overall survival (OS). EGFR T790M AF tended to be related to OS ( P =0.066). Moreover, high EGFR T790M AF (HR: 0.31, 95%CI: 0.10-0.92, P =0.035) and EGFR active mutations (HR: 2.28, 95%CI: 1.07-4.90, P =0.015) were independently predictive factors of OS in multivariate analysis. Conclusion: EGFR T790M AF in ctDNA independently predicted PFS and OS in T790M-positive advanced NSCLC who received Osimertinib after resistance to the first- or second-generation of EGFR -TKIs. EGFR T790M Osimertinib ctDNA Next Generation Sequencing Figures Figure 1 Figure 2 Introduction EGFR T790M mutation is the most common mutation leading to resistance to the first- or second-generation EGFR -TKIs, accounting for 50%-60% cases [ 1 ] . Osimertinib, the third-generation EGFR -TKI, has been approved as second-line therapy for advanced EGFR T790M-mutated NSCLC patients [ 2 ] . Exploring the molecular biomarkers for patients who received Osimertinib treatment may further improve the clinical outcome in these patients. In real world practice, tissue biopsy is not always available after acquired resistance to the first- or second-generation EGFR -TKIs [ 3 ] , due to inadequate tissue, intratumoral heterogeneity, poor ECOG status, and unwillingness of repeating tissue biopsy. Liquid biopsy is a non-invasive method to detect the molecular dynamic changes that occur during treatment, and to capture tumor heterogeneity more efficiently than tissue biopsy [ 4 ] . ctDNA-based EGFR mutation test has been validated high specificity (92%-100%) and positive predictive value (94.0%-98.6%) [ 5 ] , compared to the results of tissue biopsy. For example, BENEFIT trial (NCT02282267) confirmed that the patients selected for gefitinib treatment by ctDNA-based EGFR mutation analysis had a satisfactory clinical outcome and showed a similar ORR, PFS and OS with IPASS and WJOG3405 [ 6 ] . More importantly, BENEFIT trial provided a convincing evidence for predicting the efficacy of gefitinib by ctDNA-based EGFR mutation. By comparing the concordance, sensitivity, and specificity of ctDNA using 39 paired plasma and tissue biopsy, Li et al demonstrated that the concordance for ctDNA and tissue biopsy was 84.62% among all patients, and even higher among late stage patients (88.24%) [ 7 ] . However, the role of EGFR T790M in predicting the efficacy of Osimertinib remain controversial. Li et al found that higher AF of both EGFR sensitive mutation and T790M were observed in the partial response (PR) group than the stable disease (SD) + progressive disease (PD) group [ 7 ] , while O'Kane observed an inferior PFS in these patients [ 8 ] . Additionally, Zheng et al. found that T790M relative mutation purity, instead of T790M relative mutation abundance was significantly associated with ORR and PFS, and it was an independent predictive factor for T790M-positive advanced NSCLC patients [ 9 ] . In this study, we enrolled 48 advanced NSCLC patients who took liquid biopsy by targeted-NGS after resistance to the first- or second-generation EGFR -TKIs and had complete follow-up information in the First Affiliated Hospital of Xi’an Jiaotong University from November 2015 to March 2021. We analyzed the correlation between EGFR T790M AF in ctDNA with clinical characteristics, best response of Osimertinib, PFS and OS. Patients And Methods Patients enrollment and sample collection We retrospectively screened 3011 advanced NSCLC patients in the First Affiliated Hospital of Xi’an Jiaotong University from November 2015 to March 2021. 994 of them experienced the first- or second-generation EGFR TKIs resistance and had complete follow-up information, 146 of them took NGS gene test and 48 were detected EGFR T790M in ctDNA. Forty-eight advanced NSCLC patients harboring active EGFR mutation developed EGFR T790M mutation by targeted-NGS after resistance to the first- or second-generation of EGFR -TKIs, including Gefitinib, Erlotinib, Icotinib, and Afatinib, from November 2015 to March 2021 in the First Affiliated Hospital of Xi’an Jiaotong University were enrolled. All protocols were approved by the Ethics Committee of Xi'an Jiaotong University. The clinical characteristics of the patients were collected from the hospital medical records, and registered patients were prospectively followed up until July 1st, 2021. DNA extraction and NGS analyses ctDNA was extracted from 2ml plasma and purified by NucleoSpin Plasma XS kit with modified protocols. Targeted NGS were performed using a capture-based panel that covers 425 cancer-related genes according to protocols as previously described [ 10 ] . Deep Sequencing is performed on Illumina HiSeq 4000 using PE75 V1 Kit. Cluster generation and sequencing is performed according to manufacturer's protocol. Statistical analysis The association between EGFR T790M AF in ctDNA and clinical factors of 48 patients was performed by Students’ t - test or one-way ANOVA. The best response of Osimertinib was determined by RECIST1.1 after Osimertinib administration. The relation between EGFR T790M AF in ctDNA and best response of Osimertinib was performed by Students’ t - test, and the relation between clinical factors and best response of Osimertinib was determined by Pearson's χ2 test or Fisher’s exact test, when appropriate. Osimertinib-related PFS was defined as the first time patients took Osimertinib until the date of disease progression with Osimertinib, death or last follow-up, whenever came first. The survival curves were calculated by the Kaplan-Meier method and the results were presented as medium PFS (mPFS) ± standard deviation. The difference of PFS between different group, divided by clinical factors and T790M AF was analyzed by the log-rank test. The association of clinical characters, T790M AF and survival endpoint was evaluated by cox proportional hazards regression models, and the data were reported as HR and 95% CI. All tests were two-sided, and P -values of less than 0.05 was considered statistically significant. All of the statistical analyses were conducted using SPSS22.0 (Chicago, IL, US). Results Clinical and molecular characteristics of the patients Patients’ characteristics were summarized in Table 1. Median age is 65 years old (ranging from 40 to 83 years old). Sixteen patients were male. Twelve patients were current or previous smokers. Thirty-three patients received Osimertinib as second-line treatment. Thirty-four patients were previously treated with Gefitinib, four were treated with Erlotinib, seven were treated with Icotinib, two were treated with Gefitinib followed by Afatinib, and one was treated with Afatinib. Sixteen patients received chemotherapy and the rest of the patients did not receive chemotherapy before Osimertinib. Lung (25 patients) and bone (25 patients) are the most common metastatic sites, followed by brain (19 patients), pleura (15 patients), liver (6 patients), and adrenal glands (3 patients). Besides EGFR T790M mutation, active EGFR mutations were seen: exon 19 deletions in 31 patients，L858R in 14 patients, G719X in 2 patients and exon 20 insertion (A763_Y764insFQEA) in 1 patient. TP53 was detected in 22 patients. ATRX and KEAP1 were both seen in 2 patients. Other driver mutations, including EGFR amplification, MYC amplification, KARS G12C, and BRAF V600E mutations were also detected (Table 1). Table 1 Clinical and molecular characteristics of the patients Characteristics Number of Patients (%) Characteristics Number of Patients (%) Age Median (range) 64 (40–83) Pleura Metastasis Yes 15 (31.25) <65 years old 26 (54.17) No 33 (68.75) ≥65 years old 22 (45.83) Lung Metastasis Yes 25 (52.08) Gender Male 16 (33.33) No 23 (47.92) Female 32 (66.67) Bone Metastasis Yes 25 (52.08) Current/ Previous Smokers Yes 12 (25.00) No 23 (47.92) No 36 (75.00) Brain Metastasis Yes 19 (39.58) Lines of Osimertinib 2nd 33 (68.75) No 29 (60.42) 3rd and above 15 (31.25) Liver Metastasis Yes 6 (12.50) EGFR -TKIs before Osimertinib Gefinitib 34 (70.83) No 42 (87.50) Erlotinib 4 (8.33) Adrenal glands Metastasis Yes 3 (6.25) Icotinib 7 (14.58) No 45 (93.75) Gefinitib-Afatinib 2 (4.17) EGFR mutation 19del 31 (64.58) Afatinib 1 (2.08) L858R 14 (29.17) Previous Chemotherapy Yes 16 (33.33) G719X 2 (4.17) No 32 (66.67) 20exon insertion 1 (2.08) TP53 mutation Yes 22 (45.83) No 26 (54.17) The correlation between EGFR T790M abundance in ctDNA and clinical factors Patients over 65 years old (4.93±1.32% vs. 2.29±0.54%, P =0.075) and current or previous smokers (6.84±2.19% vs. 2.46±0.52%, P =0.075) tended to have higher T790M AF. Considering the metastatic sites, the patients with pleura or brain metastasis before Osimertinib treatment had significantly higher T790M AF (4.90±0.96% vs. 1.48±0.61%, P =0.048; 6.15±0.52% vs. 1.85±0.41%, P =0.013) than those who without. Other clinical factors, including gender, lines of treatment before Osimertinib, EGFR -TKIs before Osimertinib, prior chemotherapy, active EGFR mutations and TP53 mutation did not show significant difference in T790M AF (Table 2). Table 2 The correlation between EGFR T790M AF and clinical/molecular factors Characteristics Number of Patients (%) T790M AF (%) t/F P Age <65 years old 26 (54.17) 2.29±0.54 -1.85 0.075 ≥65 years old 22 (45.83) 4.93±1.32 Gender Male 16 (33.33) 3.51±0.09 -0.04 0.967 Female 32 (66.67) 3.57±0.10 Current/Previous Smokers Yes 12 (25.00) 6.84±2.19 -1.95 0.075 No 36 (75.00) 2.46±0.52 Lines of Osimertinib 2nd 33 (68.75) 3.87±0.96 0.66 0.512 3rd and above 15 (31.25) 2.58±0.89 Previous EGFR -TKIs Gefinitib 34 (70.83) 3.94±0.94 0.42 0.792 Erlotinib 4 (8.33) 1.53±0.87 Icotinib 7 (14.58) 3.92±1.53 Gefinitib-Afatinib 2 (4.17) 0.59±0.07 Afatinib 1 (2.08) 1.80 Previous Chemotherapy Yes 16 (33.33) 2.25±0.64 1.30 0.200 No 32 (66.67) 4.20±1.00 Pleura Metastasis Yes 15 (31.25) 4.90±0.96 2.03 0.048 No 33 (68.75) 1.48±0.61 Lung Metastasis Yes 25 (52.08) 3.99±1.18 -0.63 0.531 No 23 (47.92) 3.08±0.77 Bone Metastasis Yes 25 (52.08) 3.55±1.27 0.01 0.990 No 23 (47.92) 3.55±0.74 Brain Metastasis Yes 19 (39.58) 6.15±0.52 -2.72 0.013 No 29 (60.42) 1.85±0.41 Liver Metastasis Yes 6 (12.50) 5.31±1.97 -9.33 0.356 No 42 (87.50) 3.30±0.76 Adrenal glands Metastasis Yes 3 (6.25) 1.79±1.21 0.64 0.528 No 45 (93.75) 3.67±0.75 EGFR mutation 19del 31 (64.58) 3.65±0.99 0.35 0.790 L858R 14 (29.17) 3.20±1.05 G719X 2 (4.17) 6.14±0.01 20exon insertion 1 (2.08) 0.20 TP53 mutation Yes 22 (45.83) 3.63±0.76 -0.10 0.982 No 26 (54.17) 3.48±1.16 The correlation between EGFR T790M AF and Osimertinib efficacy Among the 48 patients, 11 patients achieved PR and the rest of them had SD, 6-8 weeks after Osimertinib administration. The overall ORR was 43.75% and disease control rate (DCR) was 100%. The average AFs of EGFR T790M were 4.58±1.44% and 2.76±0.57% for PR and SD patients respectively ( P =0.208, Figure 1A). Different EGFR active mutations tend to exhibit difference in response to Osimertinib, the ORRs were 54.84%, 28.57%, 0% and 0% for 19del, L858R, G719X and exon20 insertion, respectively ( P =0.096). Other clinical and molecular factors, including age, gender, lines of Osimertinib, EGFR -TKIs before Osimertinib, prior chemotherapy, metastatic sites, and TP53 mutation status did not present significant difference in ORR (Table 3). Table 3 The association between clinical factors and ORR Characteristics PR SD ORR (%) χ 2 P Age <65 years old 12 13 48.00 0.38 0.537 ≥65 years old 9 14 39.13 Gender Male 6 10 37.50 0.38 0.867 Female 15 17 46.88 Current/Previous Smokers Yes 5 7 41.67 0.03 1.000 No 16 20 44.44 Lines of Osimertinib 2nd 16 17 48.48 0.96 0.327 3rd and above 5 10 33.33 Previous EGFR TKIs Gefinitib 13 21 38.24 0.61 0.436 Erlotinib 3 1 75.00 Icotinib 4 3 57.14 Gefinitib-Afatinib 0 2 0.00 Afatinib 1 0 100.00 Previous Chemotherapy Yes 5 11 31.25 1.52 0.217 No 16 16 50.00 Brain Metastasis Yes 7 12 36.84 0.61 0.435 No 14 15 48.28 Bone Metastasis Yes 12 13 48.00 0.38 0.536 No 9 14 39.13 Lung Metastasis Yes 10 15 40.00 0.30 0.585 No 11 12 47.83 Pleura Metastasis Yes 4 11 26.67 1.68 0.195 No 17 16 51.52 Liver Metastasis Yes 4 2 66.67 0.59 0.441 No 17 25 40.48 Adenoglands Metastasis Yes 2 1 66.67 0.05 0.822 No 19 26 42.22 EGFR mutation 19del 17 14 54.84 6.35 0.096 L858R 4 10 28.57 G719X 0 2 0.00 20exon insertion 0 1 0.00 TP53 mutation Yes 8 14 36.36 0.90 0.343 No 13 13 High EGFR T790M AF in ctDNA predicted longer Osimertinib-related PFS and OS The median follow-up time was 44 months (ranging from 2 months to 101 months). ROC curve was used to determine the cut-off of T790M AF in ctDNA (Figure 1B), and 1.27% was used to identify two prognostic groups. Patients with high T790M AF had longer PFS (mPFS 21.00±2.17 months vs. 10.00±1.54 months, HR=0.36, 95%CI: 0.16-0.81, P =0.014, Figure 1C) and OS (mOS 72.00±5.79 months vs. 48.00±7.97 months, HR=0.41, 95%CI: 0.14-1.20, P =0.066, Figure 2B) than those who had low T790M AF. Patients over 65 years old had longer PFS, compared to younger patients (mPFS 20.00±4.70 months vs. 10.00±1.86 months, HR=0.30, 95%CI: 0.13-0.68, P =0.004). Patients with different active EGFR mutations, including exon 19del, L858R, G719X and exon 20 insertion also showed different PFS and OS (mPFS 14.00±5.28 months, 11.00±1.40 months, 5.5 months vs. 2 months, P <0.001; mOS 66.00±7.33 months, NR, 45 months vs. 20 months, P <0.001). Previously administrated EGFR -TKIs also led to significantly different mPFS: 12.00±1.34 months for Gefitinib, 8.00±2.45 months for Erlotinib, 33.00 months for Icotinib, 3.5 months for Gefitinib followed by Afatinib, and not reached (NR) for Afatinib. Liver metastasis predicted poor PFS (mPFS: 7.00±3.64 months vs. 14.00±2.62 months, HR=5.04, 95%CI: 1.16-21.58, log-rank P =0.031), while other metastatic sites before Osimertinib treatment did not show significant difference in PFS. Gender, lines of Osimertinib treatment, prior chemotherapy and TP53 mutation were not significantly associated with Osimertinib-related PFS (Supplementary Figure 1 and 2). Comparably, age, gender, previously used EGFR -TKIs, smoking status, lines of Osimertinib, prior chemotherapy, TP53 mutation and metastatic sites before Osimertinib were not significantly associated with OS (Supplementary Figure 3 and 4). Next we took age, the T790M AF in ctDNA, active EGFR mutations, and previously used EGFR -TKIs into cox proportional hazards regression models. Multivariate analysis revealed that over 65 years old (HR: 0.32, 95%CI: 0.13-0.75, P =0.009) and high T790M AF (HR: 0.39, 95%CI: 0.17-0.90, P =0.027) were independent prognostic factors for PFS, while both high T790M AF (HR: 0.31, 95%CI: 0.10-0.92, P =0.035) and active EGFR mutation (HR: 2.28, 95%CI: 1.07-4.90, P =0.015) were independent prognostic factors for OS (Table 4) in EGFR T790M-positive advanced NSCLC patients receiving Osimertinib after the first-or second-generation of EGFR -TKIs (Table 4). Table 3 Uni- and multivariate analysis for PFS by Cox proportional hazards regression model Univariate analyses Multivariate analyses Characteristics HR (95% CI) P Characteristics HR (95% CI) P Age Age <65 years old 1.00 (Reference) <65 years old 1.00 (Reference) ≥65 years old 0.37 (0.13-0.72) 0.007 ≥65 years old 0.32 (0.13-0.75) 0.009 T790M AF T790M AF <1.27% 1.00 (Reference) <1.27% 1.00 (Reference) ≥1.27% 0.38 (0.17-0.85) 0.019 ≥1.27% 0.39 (0.17-0.90) 0.027 Liver Metastasis No 1.00 (Reference) Yes 2.95 (1.04-8.38) 0.420 Previous EGFR -TKIs Gefinitib 1.00 (Reference) Erlotinib 2.13 (0.46-9.90) 0.340 Icotinib 0.26 (0.06-1.12) 0.071 Gefinitib-Afatinib 5.05 (1.07-23.80) 0.041 Afatinib 0 0.981 EGFR mutation 19del 1.00 (Reference) L858R 1.88 (0.78-4.54) 0.160 G719X 1.81 (0.23-14.37) 0.573 20ins 60.95 (3.69-1006.25) 0.004 Table 4 Uni- and multivariate analysis for OS by Cox proportional regression model Univariate analyses Multivariate analyses Characteristics HR (95% CI) P Characteristics HR (95% CI) P T790M AF T790M AF <1.27% 1.00 (Reference) <1.27% 1.00 (Reference) ≥1.27% 0.38 (0.14-1.08) 0.070 ≥1.27% 0.31 (0.10-0.92) 0.035 EGFR mutation EGFR mutation 19del 1.00 (Reference) 19del 1.00 (Reference) Other EGFR mutations 2.29 (1.07-4.90) 0.033 Other EGFR mutations 2.28 (1.07-4.90) 0.015 Discussion Osimertinib showed robust ORR and prolonged PFS and OS as the first-line and second-or later-line treatment for T790M mutation positive advanced NSCLC patients. Cobas® EGFR mutation test from tumor tissue was the gold standard for T790M detection in AURA3 and FLAURA studies [ 4 , 5 ] . Unfortunately, re-biopsy is not always available after resistance to the first- or second-generation EGFR -TKIs due to many reasons, such as poor location or size of the tumor that is not eligible for a biopsy, poor ECOG, rejection of re-biopsy. An observational real-world study from Italy showed that only 10.7% patients received tissue biopsy after progression and 64.5% of the them took liquid biopsy [ 11 ] . Other disadvantages, such as intratumoral heterogeneity, insufficient tumor tissue for molecular assessment limit the use of re-biopsy. Liquid biopsy overcomes these limitations and showed a relatively high accordance with tissue biopsy. Amplification refractory mutation system (ARMS) is widely used for EGFR mutation detection due to its cost-effectiveness, but its sensitivity is relative low, especially in plasma samples. Although Cobas® EGFR mutation test is the companion diagnostic test for Osimertinib, NGS performed improved sensitivity in AURA3 trial population, the plasma EGFR T790M positive percent agreement was 51% by Cobas® plasma, 58% by ddPCR, and increased to 66% by NGS, with Cobas® tissue test results as a reference [ 12 ] . High concordance of allelic fractions was demonstrated between NGS and ddPCR for activating EGFR mutations and T790M mutations [ 13 ] , but it can only detect certain known mutation. The advantage of NGS lies in excellent sensitivity and specificity, performed better for T790M mutation, uncommon EGFR mutation and novel mutations: the concordance rate was 82% between cobas® and the NGS approach for the EGFR sensitizing mutations (in exons 18, 19, 21) in patients with acquired resistance to EGFR -TKIs, while this concordance increased to 94% for the T790M mutation by NGS [ 14 ] . Liquid biopsy shows potential for prediction of EGFR -TKI efficacy and elucidation of clonal tumor evolution during targeted therapy [ 15 ] , but the association between EGFR T790M AF in ctDNA and Osimertinib-related survival still needs to be explored. High AF of T790M in plasma ctDNA before Osimertinib by ddPCR was found to be associated with a trend towards a shorter PFS and a significantly shorter OS [ 16 ] . A recent study from Australia revealed that DCR was superior in patients with higher plasma T790M AF; however, no significant association was found between T790M relative AF and survival benefit [ 17 ] . In this study, we demonstrated that high T790M AF before Osimertinib predicted longer PFS and OS, and is an independent survival factor for both PFS and OS. Although low T790M abundance in ctDNA reflected low tumor burden, we suppose high T790M AF in ctDNA response better to Osimertinib, leading to survival benefit. TP53 has been verified as one of the most common co-occurring mutations, while the role of TP53 in predicting EGFR -TKIs efficacy remain elusive. Previous studies indicated that pathological TP53 mutation was negatively correlated with Osimertinib efficacy and clinical outcome [ 18 , 19 ] . However, other studies did not find any association between TP53 with clinical endpoints [ 20 ] . Dual EGFR and TP53 missense mutations, instead of EGFR / TP53 mutation predicted marginally lower response rates and shorter PFS when treated with EGFR -TKIs [ 21 ] . TP53 mutations in different exons have been proved to be associated with PFS treated with EGFR -TKIs: mutations in exon 8 reduced responsiveness to EGFR -TKIs and worsen prognosis in EGFR -mutated NSCLC patients, mainly those carrying exon 19 deletions [ 22 ] , mutations in exon 4 or 7 served as independent poor prognostic factors for PFS and OS [ 23 ] . In our cohort, although TP53 was the most common concurrent mutation gene, we did not found any difference in Osimertinib-related PFS or OS between TP53 -mutant or TP53 -wild type patients. We also analyzed the prognostic role of TP53 according to mutation in different exons or different mutation type, but no significant difference was found. This negative result might due to the limited sample number in our study. “ EGFR sensitive tumor” was defined as tumors that did not harbor resistance co-mutations and in which the EGFR mutation had a high AF. Patients with “EGFR sensitive tumors” supposed to have significant longer PFS [ 24 ] . Interestingly, we noticed that one patient in T790M-high group who harbored EGFR and MYC amplification had shorter PFS (7 months vs. 21 months) and OS (39 months vs.72 months), compared to the mPFS and mOS in the same group. Another patient in T790M-low group had BRAF V600E mutation also showed shorter PFS (8 months vs. 11 months) and OS (27 months vs. 48months). These indicated that other driven mutations might play a more important role than T790M AF in Osimertinib-related PFS and OS. Loss of T790M has been proven as one of mechanisms leading to the resistance of Osimertinib [ 25 ] . Among the four PD patients who took targeted NGS after resistance to Osimertinib, two patients showed T790M AF decrease, while the other two showed stable or an increased T790M AF. Noticeably, the patient who had unchanged T790M AF (0.7%) before and after disease progression was detected to develop MET amplification as Osimertinib resistance mechanism. The last patient, whose T790M AF increased from 1.14–28.95%, developed EGFR exon20 C797S and EGFR amplification after disease progression. Due to the high cost of NGS test, not every NSCLC patient could afford NGS test in Northwest China. So one of the drawback of our study is the limited number of patients. Another limitation of our study is that we failed to follow the dynamic change of gene mutation in ctDNA before and after the use of Osimertinib in all patients. As quantification of longitudinal plasma T790M mutation may allow noninvasive assessment of drug resistance and guide follow-up treatment in EGFR -TKI-treated patients with NSCLC, we will further monitor and investigate the change of T790M mutation AF during EGFR TKIs treatment. In conclusion, we demonstrated that T790M AF is an independent prognostic factor for Osimertinib-related PFS and OS. Conclusion EGFR T790M AF in ctDNA independently predicted PFS and OS in T790M-positive advanced NSCLC who received Osimertinib after resistance to the first- or second-generation of EGFR-TKIs. Abbreviations ARMS: Amplification refractory mutation system AF: Allele frequency ctDNA: circulating tumor DNA DCR: Disease control rate () EGFR -TKIs: Epidermal growth factor receptor-tyrosine kinase inhibitors HR: Hazard ratio mPFS: medium PFS NGS: next generation sequencing NSCLC: non-small cell lung cancer ORR: Objective response rate () OS: Overall survival PD: Progressive disease PFS: Progression-free survival PR: Partial response ROC: Receiver operation curve SD: Stable disease Declarations Ethics approval and consent to participate All protocols were approved by the Ethics Committee of Xi'an Jiaotong University. Consent for publication Not applicable Availability of data and material The datasets used and analyzed in this study are available from the corresponding author upon reasonable request. Competing interests The authors disclose no potential conflicts of interest. Funding National Natural Science Foundation of China (No. 82002437), Research Project in Health--- Young Scientist Research Project in Lung Cancer (No. 1-13), Science and Technology Innovation Team of Shaanxi (No. 2021TD-44), University Joint Project of Shaanxi (No. 2020GXLH-Y-020). Authors' contributions XF, TT, and YY were in charge of the conception and design of the study; XF, TTS, MJL, and XQZ were in charge of analyzing the data; XF, HRZ, CXF, RZ and XC were in charge of collecting clinical data, TT, XF, LLJ, and WJW wrote the draft of the article; and YJY Dr. XL and ZPR revised the draft; all authors approved the final version. Acknowledgement We thanked all the patients and their families who participated in our study. Our study was also supported by National Natural Science Foundation of China (No. 82002437), Science and Technology Innovation Team of Shaanxi (No. 2021TD-44), University Joint Project of Shaanxi (No. 2020GXLH-Y-020). 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Expert Rev Mol Diagn, 2019. 19 (12): p. 1099–1108. Li, Y., et al., High MAF of EGFR mutations and high ratio of T790M sensitizing mutations in ctDNA predict better third-generation TKI outcomes . Thorac Cancer, 2020. 11 (6): p. 1503–1511. O'Kane, G.M., et al., The presence and variant allele fraction of EGFR mutations in ctDNA and development of resistance . Lung Cancer, 2019. 131 : p. 86–89. Zheng, Q., et al., EGFR T790M relative mutation purity predicts osimertinib treatment efficacy in non-small cell lung cancer patients . Clin Transl Med, 2020. 9 (1): p. 17. Fang, W., et al., Comprehensive Genomic Profiling Identifies Novel Genetic Predictors of Response to Anti-PD-(L)1 Therapies in Non-Small Cell Lung Cancer . Clin Cancer Res, 2019. 25 (16): p. 5015–5026. Reale, M.L., et al., Be-TeaM: An Italian real-world observational study on second-line therapy for EGFR-mutated NSCLC patients . Lung Cancer, 2020. 140 : p. 71–79. Papadimitrakopoulou, V.A., et al., Epidermal growth factor receptor mutation analysis in tissue and plasma from the AURA3 trial: Osimertinib versus platinum-pemetrexed for T790M mutation-positive advanced non-small cell lung cancer . Cancer, 2020. 126 (2): p. 373–380. Ding, P.N., et al., Plasma next generation sequencing and droplet digital PCR-based detection of epidermal growth factor receptor (EGFR) mutations in patients with advanced lung cancer treated with subsequent-line osimertinib . Thorac Cancer, 2019. 10 (10): p. 1879–1884. Papadopoulou, E., et al., Clinical feasibility of NGS liquid biopsy analysis in NSCLC patients . PLoS One, 2019. 14 (12): p. e0226853. Iwama, E., et al., Longitudinal monitoring of somatic genetic alterations in circulating cell-free DNA during treatment with epidermal growth factor receptor-tyrosine kinase inhibitors . Cancer, 2020. 126 (1): p. 219–227. Buder, A., M.J. Hochmair, and M. Filipits, The Allele Frequency of EGFR Mutations Predicts Survival in Advanced EGFR T790M-Positive Non-small Cell Lung Cancer Patients Treated with Osimertinib . Target Oncol, 2021. 16 (1): p. 77–84. Ding, P.N., et al., Plasma pre-treatment T790M relative allelic frequency in patients with advanced EGFR-mutated non-small cell lung cancer predicts treatment response to subsequent-line osimertinib . Transl Lung Cancer Res, 2021. 10 (4): p. 1623–1634. Zhao, J., et al., Next-generation sequencing based mutation profiling reveals heterogeneity of clinical response and resistance to osimertinib . Lung Cancer, 2019. Steendam, C.M.J., et al., Plasma Predictive Features in Treating EGFR-Mutated Non-Small Cell Lung Cancer . Cancers (Basel), 2020. 12 (11). Christopoulos, P., et al., Risk stratification of EGFR(+) lung cancer diagnosed with panel-based next-generation sequencing . Lung Cancer, 2020. 148 : p. 105–112. Labbe, C., et al., Prognostic and predictive effects of TP53 co-mutation in patients with EGFR-mutated non-small cell lung cancer (NSCLC) . Lung Cancer, 2017. 111 : p. 23–29. Canale, M., et al., Impact of TP53 Mutations on Outcome in EGFR-Mutated Patients Treated with First-Line Tyrosine Kinase Inhibitors . Clin Cancer Res, 2017. 23 (9): p. 2195–2202. Li, X.M., et al., Predictive and Prognostic Potential of TP53 in Patients With Advanced Non-Small-Cell Lung Cancer Treated With EGFR-TKI: Analysis of a Phase III Randomized Clinical Trial (CTONG 0901) . Clin Lung Cancer, 2021. 22 (2): p. 100–109.e3. Friedlaender, A., et al., The Impact of Variant Allele Frequency in EGFR Mutated NSCLC Patients on Targeted Therapy . Front Oncol, 2021. 11 : p. 644472. Yang, Z., et al., Dynamics of Plasma EGFR T790M Mutation in Advanced NSCLC: A Multicenter Study . Target Oncol, 2019. 14 (6): p. 719–728. Additional Declarations No competing interests reported. Supplementary Files SupplementaryFigure1.jpg Supplementary Figure 1. The association between clinical factors and Osimertinib-related PFS. Age (A), Gender (B), Smoking status (C), EGFR active mutation (D), TP53 co-mutation (E), Previous chemotherapy (F), Prior EGFR -TKIs (G) and Lines of treatment before Osimertinib (H) and Osimertinib-related PFS. SupplementaryFigure2.jpg Supplementary Figure 2. The association between different metastatic sites and Osimertinib-related PFS. Bone (A), Lung (B), Brain (C), Pleura (D), Liver (E) and Adrenal glands (F) metastasis and Osimertinib-related PFS. SupplementaryFigure3.jpg Supplementary Figure 3. The association between clinical factors and OS. Age (A), Gender (B), Smoking status (C), EGFR active mutation (D), TP53 co-mutation (E), Previous chemotherapy (F), Prior EGFR -TKIs (G) and Lines of treatment before Osimertinib (H) and OS. SupplementaryFigure4.jpg Supplementary Figure 4. The association between different metastatic sites and OS. Bone (A), Lung (B), Brain (C), Pleura (D), Liver (E) and Adrenal glands (F) metastasis and OS 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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A. \\u003cem\\u003eEGFR\\u003c/em\\u003e T790M AF for patients with PR and SD after Osimertinib treatment. B. ROC curve of \\u003cem\\u003eEGFR \\u003c/em\\u003eT790M for PFS. C. The association between Osimertinib-related PFS and \\u003cem\\u003eEGFR \\u003c/em\\u003eT790M AF.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure1.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-1658925/v1/d3c3c2a282360a74ff8f952e.jpg\"},{\"id\":22695853,\"identity\":\"83f6a294-8f5a-4871-a8d4-290918159f4b\",\"added_by\":\"auto\",\"created_at\":\"2022-06-15 18:42:02\",\"extension\":\"jpg\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":81133,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cspan class=\\\"ql-cursor\\\"\\u003e\\u003c/span\\u003eThe association between OS and \\u003cem\\u003eEGFR\\u003c/em\\u003e T790M AF. A. ROC curve of \\u003cem\\u003eEGFR \\u003c/em\\u003eT790M for OS. B. The association between OS and \\u003cem\\u003eEGFR \\u003c/em\\u003eT790M AF.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure2.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-1658925/v1/2124b4c2ba781af19e6d5358.jpg\"},{\"id\":22695855,\"identity\":\"05e370d1-c0f3-4d82-8770-1e7de8cd8808\",\"added_by\":\"auto\",\"created_at\":\"2022-06-15 18:42:05\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":343639,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-1658925/v1/952bb615-3899-4b93-b393-f759131ea1f4.pdf\"},{\"id\":22695809,\"identity\":\"18e071a0-09ef-4e2c-a126-ee6b7574b58d\",\"added_by\":\"auto\",\"created_at\":\"2022-06-15 18:37:02\",\"extension\":\"jpg\",\"order_by\":1,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":364108,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eSupplementary Figure 1. The association between clinical factors and Osimertinib-related PFS. Age (A), Gender (B), Smoking status (C), \\u003cem\\u003eEGFR \\u003c/em\\u003eactive mutation (D), \\u003cem\\u003eTP53\\u003c/em\\u003e co-mutation (E), Previous chemotherapy (F), Prior \\u003cem\\u003eEGFR\\u003c/em\\u003e -TKIs (G) and Lines of treatment before Osimertinib (H) and Osimertinib-related PFS.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"SupplementaryFigure1.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-1658925/v1/c61eb009567459126f5bf0de.jpg\"},{\"id\":22695854,\"identity\":\"134bf9e1-8c63-4e09-b7a5-fdaac19c14d6\",\"added_by\":\"auto\",\"created_at\":\"2022-06-15 18:42:02\",\"extension\":\"jpg\",\"order_by\":2,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":267003,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eSupplementary Figure 2. The association between different metastatic sites and Osimertinib-related PFS. Bone (A), Lung (B), Brain (C), Pleura (D), Liver (E) and Adrenal glands (F) metastasis and Osimertinib-related PFS.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"SupplementaryFigure2.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-1658925/v1/99f815d99d24280d6301edb1.jpg\"},{\"id\":22695812,\"identity\":\"765bd727-daf0-4469-9371-241e40c0fa14\",\"added_by\":\"auto\",\"created_at\":\"2022-06-15 18:37:02\",\"extension\":\"jpg\",\"order_by\":3,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":326969,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eSupplementary Figure 3. The association between clinical factors and OS. Age (A), Gender (B), Smoking status (C), \\u003cem\\u003eEGFR \\u003c/em\\u003eactive mutation (D), \\u003cem\\u003eTP53\\u003c/em\\u003e co-mutation (E), Previous chemotherapy (F), Prior \\u003cem\\u003eEGFR\\u003c/em\\u003e -TKIs (G) and Lines of treatment before Osimertinib (H) and OS.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"SupplementaryFigure3.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-1658925/v1/60244b492c36730c8bf1bb3a.jpg\"},{\"id\":22695810,\"identity\":\"910d7eb2-a10e-4c24-a979-0012781e9470\",\"added_by\":\"auto\",\"created_at\":\"2022-06-15 18:37:02\",\"extension\":\"jpg\",\"order_by\":4,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":236176,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eSupplementary Figure 4. The association between different metastatic sites and OS. Bone (A), Lung (B), Brain (C), Pleura (D), Liver (E) and Adrenal glands (F) metastasis and OS\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"SupplementaryFigure4.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-1658925/v1/5867ca3fd9ad68385c78a772.jpg\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"The allele frequency of EGFR T790M in ctDNA predicted clinical outcomes of Osimertinib in non-small cell lung cancer patients from a real-world study\",\"fulltext\":[{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003e\\u003cem\\u003eEGFR\\u003c/em\\u003e T790M mutation is the most common mutation leading to resistance to the first- or second-generation \\u003cem\\u003eEGFR\\u003c/em\\u003e-TKIs, accounting for 50%-60% cases\\u003csup\\u003e[\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e]\\u003c/sup\\u003e. Osimertinib, the third-generation \\u003cem\\u003eEGFR\\u003c/em\\u003e-TKI, has been approved as second-line therapy for advanced \\u003cem\\u003eEGFR\\u003c/em\\u003e T790M-mutated NSCLC patients\\u003csup\\u003e[\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e]\\u003c/sup\\u003e. Exploring the molecular biomarkers for patients who received Osimertinib treatment may further improve the clinical outcome in these patients.\\u003c/p\\u003e \\u003cp\\u003eIn real world practice, tissue biopsy is not always available after acquired resistance to the first- or second-generation \\u003cem\\u003eEGFR\\u003c/em\\u003e-TKIs\\u003csup\\u003e[\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e]\\u003c/sup\\u003e, due to inadequate tissue, intratumoral heterogeneity, poor ECOG status, and unwillingness of repeating tissue biopsy. Liquid biopsy is a non-invasive method to detect the molecular dynamic changes that occur during treatment, and to capture tumor heterogeneity more efficiently than tissue biopsy \\u003csup\\u003e[\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e]\\u003c/sup\\u003e. ctDNA-based \\u003cem\\u003eEGFR\\u003c/em\\u003e mutation test has been validated high specificity (92%-100%) and positive predictive value (94.0%-98.6%)\\u003csup\\u003e[\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e]\\u003c/sup\\u003e, compared to the results of tissue biopsy. For example, BENEFIT trial (NCT02282267) confirmed that the patients selected for gefitinib treatment by ctDNA-based \\u003cem\\u003eEGFR\\u003c/em\\u003e mutation analysis had a satisfactory clinical outcome and showed a similar ORR, PFS and OS with IPASS and WJOG3405\\u003csup\\u003e[\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e]\\u003c/sup\\u003e. More importantly, BENEFIT trial provided a convincing evidence for predicting the efficacy of gefitinib by ctDNA-based \\u003cem\\u003eEGFR\\u003c/em\\u003e mutation. By comparing the concordance, sensitivity, and specificity of ctDNA using 39 paired plasma and tissue biopsy, Li et al demonstrated that the concordance for ctDNA and tissue biopsy was 84.62% among all patients, and even higher among late stage patients (88.24%)\\u003csup\\u003e[\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e]\\u003c/sup\\u003e. However, the role of \\u003cem\\u003eEGFR\\u003c/em\\u003e T790M in predicting the efficacy of Osimertinib remain controversial. Li et al found that higher AF of both \\u003cem\\u003eEGFR\\u003c/em\\u003e sensitive mutation and T790M were observed in the partial response (PR) group than the stable disease (SD)\\u0026thinsp;+\\u0026thinsp;progressive disease (PD) group\\u003csup\\u003e[\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e]\\u003c/sup\\u003e, while O'Kane observed an inferior PFS in these patients\\u003csup\\u003e[\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e]\\u003c/sup\\u003e. Additionally, Zheng et al. found that T790M relative mutation purity, instead of T790M relative mutation abundance was significantly associated with ORR and PFS, and it was an independent predictive factor for T790M-positive advanced NSCLC patients\\u003csup\\u003e[\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e]\\u003c/sup\\u003e.\\u003c/p\\u003e \\u003cp\\u003eIn this study, we enrolled 48 advanced NSCLC patients who took liquid biopsy by targeted-NGS after resistance to the first- or second-generation \\u003cem\\u003eEGFR\\u003c/em\\u003e-TKIs and had complete follow-up information in the First Affiliated Hospital of Xi\\u0026rsquo;an Jiaotong University from November 2015 to March 2021. We analyzed the correlation between \\u003cem\\u003eEGFR\\u003c/em\\u003e T790M AF in ctDNA with clinical characteristics, best response of Osimertinib, PFS and OS.\\u003c/p\\u003e\"},{\"header\":\"Patients And Methods\",\"content\":\"\\u003cp\\u003ePatients enrollment and sample collection\\u003c/p\\u003e \\u003cp\\u003eWe retrospectively screened 3011 advanced NSCLC patients in the First Affiliated Hospital of Xi\\u0026rsquo;an Jiaotong University from November 2015 to March 2021. 994 of them experienced the first- or second-generation EGFR TKIs resistance and had complete follow-up information, 146 of them took NGS gene test and 48 were detected EGFR T790M in ctDNA. Forty-eight advanced NSCLC patients harboring active \\u003cem\\u003eEGFR\\u003c/em\\u003e mutation developed EGFR T790M mutation by targeted-NGS after resistance to the first- or second-generation of \\u003cem\\u003eEGFR\\u003c/em\\u003e-TKIs, including Gefitinib, Erlotinib, Icotinib, and Afatinib, from November 2015 to March 2021 in the First Affiliated Hospital of Xi\\u0026rsquo;an Jiaotong University were enrolled. All protocols were approved by the Ethics Committee of Xi'an Jiaotong University. The clinical characteristics of the patients were collected from the hospital medical records, and registered patients were prospectively followed up until July 1st, 2021.\\u003c/p\\u003e \\u003cp\\u003eDNA extraction and NGS analyses\\u003c/p\\u003e \\u003cp\\u003ectDNA was extracted from 2ml plasma and purified by NucleoSpin Plasma XS kit with modified protocols. Targeted NGS were performed using a capture-based panel that covers 425 cancer-related genes according to protocols as previously described\\u003csup\\u003e[\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e]\\u003c/sup\\u003e. Deep Sequencing is performed on Illumina HiSeq 4000 using PE75 V1 Kit. Cluster generation and sequencing is performed according to manufacturer's protocol.\\u003c/p\\u003e \\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eStatistical analysis\\u003c/h2\\u003e \\u003cp\\u003eThe association between \\u003cem\\u003eEGFR\\u003c/em\\u003e T790M AF in ctDNA and clinical factors of 48 patients was performed by Students\\u0026rsquo; t\\u003cem\\u003e-\\u003c/em\\u003etest or one-way ANOVA. The best response of Osimertinib was determined by RECIST1.1 after Osimertinib administration. The relation between \\u003cem\\u003eEGFR\\u003c/em\\u003e T790M AF in ctDNA and best response of Osimertinib was performed by Students\\u0026rsquo; t\\u003cem\\u003e-\\u003c/em\\u003etest, and the relation between clinical factors and best response of Osimertinib was determined by Pearson's χ2 test or Fisher\\u0026rsquo;s exact test, when appropriate. Osimertinib-related PFS was defined as the first time patients took Osimertinib until the date of disease progression with Osimertinib, death or last follow-up, whenever came first. The survival curves were calculated by the Kaplan-Meier method and the results were presented as medium PFS (mPFS)\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;standard deviation. The difference of PFS between different group, divided by clinical factors and T790M AF was analyzed by the log-rank test. The association of clinical characters, T790M AF and survival endpoint was evaluated by cox proportional hazards regression models, and the data were reported as HR and 95% CI. All tests were two-sided, and \\u003cem\\u003eP\\u003c/em\\u003e-values of less than 0.05 was considered statistically significant. All of the statistical analyses were conducted using SPSS22.0 (Chicago, IL, US).\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cp\\u003e\\u003cem\\u003eClinical and molecular characteristics of the patients\\u003c/em\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003ePatients\\u0026rsquo; characteristics were summarized in Table 1. Median age is 65 years old (ranging from 40 to 83 years old). Sixteen patients were male. Twelve patients were current or previous smokers. Thirty-three patients received Osimertinib as second-line treatment. Thirty-four patients were previously treated with Gefitinib, four were treated with Erlotinib, seven were treated with Icotinib, two were treated with Gefitinib followed by Afatinib, and one was treated with Afatinib. Sixteen patients received chemotherapy and the rest of the patients did not receive chemotherapy before Osimertinib. Lung (25 patients) and bone (25 patients) are the most common metastatic sites, followed by brain (19 patients), pleura (15 patients), liver (6 patients), and adrenal glands (3 patients). Besides \\u003cem\\u003eEGFR\\u003c/em\\u003e T790M mutation, active \\u003cem\\u003eEGFR\\u003c/em\\u003e mutations were seen: exon 19 deletions in 31 patients，L858R in 14 patients, G719X in 2 patients and exon 20 insertion (A763_Y764insFQEA) in 1 patient. \\u003cem\\u003eTP53\\u003c/em\\u003e was detected in 22 patients. \\u003cem\\u003eATRX\\u003c/em\\u003e and \\u003cem\\u003eKEAP1\\u003c/em\\u003e were both seen in 2 patients. Other driver mutations, including \\u003cem\\u003eEGFR\\u003c/em\\u003e amplification, \\u003cem\\u003eMYC\\u003c/em\\u003e amplification, \\u003cem\\u003eKARS\\u0026nbsp;\\u003c/em\\u003eG12C, and \\u003cem\\u003eBRAF\\u003c/em\\u003e V600E mutations were also detected (Table 1).\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eTable 1 Clinical and molecular characteristics of the patients\\u003c/p\\u003e\\n\\u003cdiv\\u003e\\n \\u003ctable border=\\\"0\\\" cellpadding=\\\"0\\\" cellspacing=\\\"0\\\" width=\\\"0\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" width=\\\"39.57219251336898%\\\"\\u003e\\n \\u003cp\\u003eCharacteristics\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.93404634581105%\\\"\\u003e\\n \\u003cp\\u003eNumber of Patients (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" width=\\\"27.45098039215686%\\\"\\u003e\\n \\u003cp\\u003eCharacteristics\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.0427807486631%\\\"\\u003e\\n \\u003cp\\u003eNumber of Patients (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"17.97153024911032%\\\"\\u003e\\n \\u003cp\\u003eAge\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.530249110320284%\\\"\\u003e\\n \\u003cp\\u003eMedian (range)\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.90391459074733%\\\"\\u003e\\n \\u003cp\\u003e64 (40\\u0026ndash;83)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.87900355871886%\\\"\\u003e\\n \\u003cp\\u003ePleura Metastasis\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.701067615658364%\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.01423487544484%\\\"\\u003e\\n \\u003cp\\u003e15 (31.25)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"17.97153024911032%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.530249110320284%\\\"\\u003e\\n \\u003cp\\u003e\\u0026lt;65 years old\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.90391459074733%\\\"\\u003e\\n \\u003cp\\u003e26 (54.17)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.87900355871886%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.701067615658364%\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.01423487544484%\\\"\\u003e\\n \\u003cp\\u003e33 (68.75)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"17.97153024911032%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.530249110320284%\\\"\\u003e\\n \\u003cp\\u003e\\u0026ge;65 years old\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.90391459074733%\\\"\\u003e\\n \\u003cp\\u003e22 (45.83)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.87900355871886%\\\"\\u003e\\n \\u003cp\\u003eLung Metastasis\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.701067615658364%\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.01423487544484%\\\"\\u003e\\n \\u003cp\\u003e25 (52.08)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"17.97153024911032%\\\"\\u003e\\n \\u003cp\\u003eGender\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.530249110320284%\\\"\\u003e\\n \\u003cp\\u003eMale\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.90391459074733%\\\"\\u003e\\n \\u003cp\\u003e16 (33.33)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.87900355871886%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.701067615658364%\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.01423487544484%\\\"\\u003e\\n \\u003cp\\u003e23 (47.92)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"17.97153024911032%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.530249110320284%\\\"\\u003e\\n \\u003cp\\u003eFemale\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.90391459074733%\\\"\\u003e\\n \\u003cp\\u003e32 (66.67)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.87900355871886%\\\"\\u003e\\n \\u003cp\\u003eBone Metastasis\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.701067615658364%\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.01423487544484%\\\"\\u003e\\n \\u003cp\\u003e25 (52.08)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"17.97153024911032%\\\"\\u003e\\n \\u003cp\\u003eCurrent/\\u003c/p\\u003e\\n \\u003cp\\u003ePrevious Smokers\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.530249110320284%\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.90391459074733%\\\"\\u003e\\n \\u003cp\\u003e12 (25.00)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.87900355871886%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.701067615658364%\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.01423487544484%\\\"\\u003e\\n \\u003cp\\u003e23 (47.92)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"17.97153024911032%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.530249110320284%\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.90391459074733%\\\"\\u003e\\n \\u003cp\\u003e36 (75.00)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.87900355871886%\\\"\\u003e\\n \\u003cp\\u003eBrain Metastasis\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.701067615658364%\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.01423487544484%\\\"\\u003e\\n \\u003cp\\u003e19 (39.58)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"17.97153024911032%\\\"\\u003e\\n \\u003cp\\u003eLines of Osimertinib\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.530249110320284%\\\"\\u003e\\n \\u003cp\\u003e2nd\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.90391459074733%\\\"\\u003e\\n \\u003cp\\u003e33 (68.75)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.87900355871886%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.701067615658364%\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.01423487544484%\\\"\\u003e\\n \\u003cp\\u003e29 (60.42)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"17.97153024911032%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.530249110320284%\\\"\\u003e\\n \\u003cp\\u003e3rd and above\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.90391459074733%\\\"\\u003e\\n \\u003cp\\u003e15 (31.25)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.87900355871886%\\\"\\u003e\\n \\u003cp\\u003eLiver Metastasis\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.701067615658364%\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.01423487544484%\\\"\\u003e\\n \\u003cp\\u003e6 (12.50)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"17.97153024911032%\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003eEGFR\\u003c/em\\u003e-TKIs before Osimertinib\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.530249110320284%\\\"\\u003e\\n \\u003cp\\u003eGefinitib\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.90391459074733%\\\"\\u003e\\n \\u003cp\\u003e34 (70.83)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.87900355871886%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.701067615658364%\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.01423487544484%\\\"\\u003e\\n \\u003cp\\u003e42 (87.50)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"17.97153024911032%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.530249110320284%\\\"\\u003e\\n \\u003cp\\u003eErlotinib\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.90391459074733%\\\"\\u003e\\n \\u003cp\\u003e4 (8.33)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.87900355871886%\\\"\\u003e\\n \\u003cp\\u003eAdrenal glands Metastasis\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.701067615658364%\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.01423487544484%\\\"\\u003e\\n \\u003cp\\u003e3 (6.25)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"17.97153024911032%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.530249110320284%\\\"\\u003e\\n \\u003cp\\u003eIcotinib\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.90391459074733%\\\"\\u003e\\n \\u003cp\\u003e7 (14.58)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.87900355871886%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.701067615658364%\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.01423487544484%\\\"\\u003e\\n \\u003cp\\u003e45 (93.75)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"17.97153024911032%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.530249110320284%\\\"\\u003e\\n \\u003cp\\u003eGefinitib-Afatinib\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.90391459074733%\\\"\\u003e\\n \\u003cp\\u003e2 (4.17)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.87900355871886%\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003eEGFR\\u003c/em\\u003e mutation\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.701067615658364%\\\"\\u003e\\n \\u003cp\\u003e19del\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.01423487544484%\\\"\\u003e\\n \\u003cp\\u003e31 (64.58)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"17.97153024911032%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.530249110320284%\\\"\\u003e\\n \\u003cp\\u003eAfatinib\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.90391459074733%\\\"\\u003e\\n \\u003cp\\u003e1 (2.08)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.87900355871886%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.701067615658364%\\\"\\u003e\\n \\u003cp\\u003eL858R\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.01423487544484%\\\"\\u003e\\n \\u003cp\\u003e14 (29.17)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"17.97153024911032%\\\"\\u003e\\n \\u003cp\\u003ePrevious Chemotherapy\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.530249110320284%\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.90391459074733%\\\"\\u003e\\n \\u003cp\\u003e16 (33.33)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.87900355871886%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.701067615658364%\\\"\\u003e\\n \\u003cp\\u003eG719X\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.01423487544484%\\\"\\u003e\\n \\u003cp\\u003e2 (4.17)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"17.97153024911032%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.530249110320284%\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.90391459074733%\\\"\\u003e\\n \\u003cp\\u003e32 (66.67)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.87900355871886%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.701067615658364%\\\"\\u003e\\n \\u003cp\\u003e20exon insertion\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.01423487544484%\\\"\\u003e\\n \\u003cp\\u003e1 (2.08)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"17.97153024911032%\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003eTP53\\u003c/em\\u003e mutation\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.530249110320284%\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.90391459074733%\\\"\\u003e\\n \\u003cp\\u003e22 (45.83)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.87900355871886%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.701067615658364%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.01423487544484%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"17.97153024911032%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"21.530249110320284%\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.90391459074733%\\\"\\u003e\\n \\u003cp\\u003e26 (54.17)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.87900355871886%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"13.701067615658364%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.01423487544484%\\\"\\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\\u003c/div\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eThe correlation between EGFR T790M abundance in ctDNA and clinical factors\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003ePatients over 65 years old (4.93\\u0026plusmn;1.32% vs. 2.29\\u0026plusmn;0.54%, \\u003cem\\u003eP\\u003c/em\\u003e=0.075) and current or previous smokers (6.84\\u0026plusmn;2.19% vs. 2.46\\u0026plusmn;0.52%, \\u003cem\\u003eP\\u003c/em\\u003e=0.075) tended to have higher T790M AF. Considering the metastatic sites, the patients with pleura or brain metastasis before Osimertinib treatment had significantly higher T790M AF (4.90\\u0026plusmn;0.96% vs. 1.48\\u0026plusmn;0.61%, \\u003cem\\u003eP\\u003c/em\\u003e=0.048; 6.15\\u0026plusmn;0.52% vs. 1.85\\u0026plusmn;0.41%, \\u003cem\\u003eP\\u003c/em\\u003e=0.013) than those who without. Other clinical factors, including gender, lines of treatment before Osimertinib, \\u003cem\\u003eEGFR\\u003c/em\\u003e-TKIs before Osimertinib, prior chemotherapy, active \\u003cem\\u003eEGFR\\u003c/em\\u003e mutations and \\u003cem\\u003eTP53\\u003c/em\\u003e mutation did not show significant difference in T790M AF (Table 2).\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eTable 2 The correlation between \\u003cem\\u003eEGFR\\u003c/em\\u003e T790M AF and clinical/molecular factors\\u003c/p\\u003e\\n\\u003cdiv\\u003e\\n \\u003ctable border=\\\"0\\\" cellpadding=\\\"0\\\" cellspacing=\\\"0\\\" width=\\\"0\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eCharacteristics\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003eNumber of Patients (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003eT790M AF (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003et/F\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003eP\\u003c/em\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eAge\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003e\\u0026lt;65 years old\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e26 (54.17)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e2.29\\u0026plusmn;0.54\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e-1.85\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e0.075\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003e\\u0026ge;65 years old\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e22 (45.83)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e4.93\\u0026plusmn;1.32\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eGender\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eMale\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e16 (33.33)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e3.51\\u0026plusmn;0.09\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e-0.04\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e0.967\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eFemale\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e32 (66.67)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e3.57\\u0026plusmn;0.10\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eCurrent/Previous Smokers\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e12 (25.00)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e6.84\\u0026plusmn;2.19\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e-1.95\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e0.075\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e36 (75.00)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e2.46\\u0026plusmn;0.52\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eLines of Osimertinib\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003e2nd\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e33 (68.75)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e3.87\\u0026plusmn;0.96\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e0.66\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e0.512\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003e3rd and above\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e15 (31.25)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e2.58\\u0026plusmn;0.89\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003ePrevious \\u003cem\\u003eEGFR\\u003c/em\\u003e -TKIs\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eGefinitib\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e34 (70.83)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e3.94\\u0026plusmn;0.94\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e0.42\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e0.792\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eErlotinib\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e4 (8.33)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e1.53\\u0026plusmn;0.87\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eIcotinib\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e7 (14.58)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e3.92\\u0026plusmn;1.53\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eGefinitib-Afatinib\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e2 (4.17)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e0.59\\u0026plusmn;0.07\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eAfatinib\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e1 (2.08)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e1.80\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003ePrevious Chemotherapy\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e16 (33.33)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e2.25\\u0026plusmn;0.64\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e1.30\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e0.200\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e32 (66.67)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e4.20\\u0026plusmn;1.00\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003ePleura Metastasis\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e15 (31.25)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e4.90\\u0026plusmn;0.96\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e2.03\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e0.048\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e33 (68.75)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e1.48\\u0026plusmn;0.61\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eLung Metastasis\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e25 (52.08)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e3.99\\u0026plusmn;1.18\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e-0.63\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e0.531\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e23 (47.92)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e3.08\\u0026plusmn;0.77\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eBone Metastasis\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e25 (52.08)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e3.55\\u0026plusmn;1.27\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e0.01\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e0.990\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e23 (47.92)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e3.55\\u0026plusmn;0.74\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eBrain Metastasis\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e19 (39.58)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e6.15\\u0026plusmn;0.52\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e-2.72\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e0.013\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e29 (60.42)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e1.85\\u0026plusmn;0.41\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eLiver Metastasis\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e6 (12.50)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e5.31\\u0026plusmn;1.97\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e-9.33\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e0.356\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e42 (87.50)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e3.30\\u0026plusmn;0.76\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eAdrenal glands Metastasis\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e3 (6.25)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e1.79\\u0026plusmn;1.21\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e0.64\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e0.528\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e45 (93.75)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e3.67\\u0026plusmn;0.75\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003eEGFR\\u003c/em\\u003e mutation\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003e19del\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e31 (64.58)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e3.65\\u0026plusmn;0.99\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e0.35\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e0.790\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eL858R\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e14 (29.17)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e3.20\\u0026plusmn;1.05\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eG719X\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e2 (4.17)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e6.14\\u0026plusmn;0.01\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003e20exon insertion\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e1 (2.08)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e0.20\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003eTP53\\u003c/em\\u003e mutation\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e22 (45.83)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e3.63\\u0026plusmn;0.76\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e-0.10\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\u003e\\n \\u003cp\\u003e0.982\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"34.55497382198953%\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"28.097731239092496%\\\"\\u003e\\n \\u003cp\\u003e26 (54.17)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.720767888307154%\\\"\\u003e\\n \\u003cp\\u003e3.48\\u0026plusmn;1.16\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.37696335078534%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.24956369982548%\\\"\\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\\u003c/div\\u003e\\n\\u003cp\\u003eThe correlation between \\u003cem\\u003eEGFR\\u003c/em\\u003e T790M AF and Osimertinib efficacy\\u003c/p\\u003e\\n\\u003cp\\u003eAmong the 48 patients, 11 patients achieved PR and the rest of them had SD, 6-8 weeks after Osimertinib administration. The overall ORR was 43.75% and disease control rate (DCR) was 100%. The average AFs of \\u003cem\\u003eEGFR\\u003c/em\\u003e T790M were 4.58\\u0026plusmn;1.44% and 2.76\\u0026plusmn;0.57% for PR and SD patients respectively (\\u003cem\\u003eP\\u003c/em\\u003e=0.208, Figure 1A). Different \\u003cem\\u003eEGFR\\u003c/em\\u003e active mutations tend to exhibit difference in response to Osimertinib, the ORRs were 54.84%, 28.57%, 0% and 0% for 19del, L858R, G719X and exon20 insertion, respectively (\\u003cem\\u003eP\\u003c/em\\u003e=0.096). Other clinical and molecular factors, including age, gender, lines of Osimertinib, \\u003cem\\u003eEGFR\\u003c/em\\u003e -TKIs before Osimertinib, prior chemotherapy, metastatic sites, and \\u003cem\\u003eTP53\\u003c/em\\u003e mutation status did not present significant difference in ORR (Table 3).\\u003c/p\\u003e\\n\\u003cp\\u003eTable 3 The association between clinical factors and ORR\\u003c/p\\u003e\\n\\u003ctable border=\\\"0\\\" cellpadding=\\\"0\\\" cellspacing=\\\"0\\\" width=\\\"0\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" width=\\\"40.43261231281198%\\\"\\u003e\\n \\u003cp\\u003eCharacteristics\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.153078202995008%\\\"\\u003e\\n \\u003cp\\u003ePR\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.151414309484194%\\\"\\u003e\\n \\u003cp\\u003eSD\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.306156405990016%\\\"\\u003e\\n \\u003cp\\u003eORR (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"14.642262895174708%\\\"\\u003e\\n \\u003cp\\u003e\\u0026chi;\\u003csup\\u003e2\\u003c/sup\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"11.314475873544094%\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003eP\\u003c/em\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"21.13144758735441%\\\"\\u003e\\n \\u003cp\\u003eAge\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.30116472545757%\\\"\\u003e\\n \\u003cp\\u003e\\u0026lt;65 years old\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.153078202995008%\\\"\\u003e\\n \\u003cp\\u003e12\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.151414309484194%\\\"\\u003e\\n \\u003cp\\u003e13\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.306156405990016%\\\"\\u003e\\n \\u003cp\\u003e48.00\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"14.642262895174708%\\\"\\u003e\\n \\u003cp\\u003e0.38\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"11.314475873544094%\\\"\\u003e\\n \\u003cp\\u003e0.537\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"21.13144758735441%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.30116472545757%\\\"\\u003e\\n \\u003cp\\u003e\\u0026ge;65 years old\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.153078202995008%\\\"\\u003e\\n \\u003cp\\u003e9\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.151414309484194%\\\"\\u003e\\n \\u003cp\\u003e14\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.306156405990016%\\\"\\u003e\\n \\u003cp\\u003e39.13\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"14.642262895174708%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"11.314475873544094%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"21.13144758735441%\\\"\\u003e\\n \\u003cp\\u003eGender\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.30116472545757%\\\"\\u003e\\n \\u003cp\\u003eMale\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.153078202995008%\\\"\\u003e\\n \\u003cp\\u003e6\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.151414309484194%\\\"\\u003e\\n \\u003cp\\u003e10\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.306156405990016%\\\"\\u003e\\n \\u003cp\\u003e37.50\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"14.642262895174708%\\\"\\u003e\\n \\u003cp\\u003e0.38\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"11.314475873544094%\\\"\\u003e\\n \\u003cp\\u003e0.867\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"21.13144758735441%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.30116472545757%\\\"\\u003e\\n \\u003cp\\u003eFemale\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.153078202995008%\\\"\\u003e\\n \\u003cp\\u003e15\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.151414309484194%\\\"\\u003e\\n \\u003cp\\u003e17\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.306156405990016%\\\"\\u003e\\n \\u003cp\\u003e46.88\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"14.642262895174708%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"11.314475873544094%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"21.13144758735441%\\\"\\u003e\\n \\u003cp\\u003eCurrent/Previous Smokers\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.30116472545757%\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.153078202995008%\\\"\\u003e\\n \\u003cp\\u003e5\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.151414309484194%\\\"\\u003e\\n \\u003cp\\u003e7\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.306156405990016%\\\"\\u003e\\n \\u003cp\\u003e41.67\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"14.642262895174708%\\\"\\u003e\\n \\u003cp\\u003e0.03\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"11.314475873544094%\\\"\\u003e\\n \\u003cp\\u003e1.000\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"21.13144758735441%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.30116472545757%\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.153078202995008%\\\"\\u003e\\n \\u003cp\\u003e16\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.151414309484194%\\\"\\u003e\\n \\u003cp\\u003e20\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.306156405990016%\\\"\\u003e\\n \\u003cp\\u003e44.44\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"14.642262895174708%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"11.314475873544094%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"21.13144758735441%\\\"\\u003e\\n \\u003cp\\u003eLines of Osimertinib\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.30116472545757%\\\"\\u003e\\n \\u003cp\\u003e2nd\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.153078202995008%\\\"\\u003e\\n \\u003cp\\u003e16\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.151414309484194%\\\"\\u003e\\n \\u003cp\\u003e17\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.306156405990016%\\\"\\u003e\\n \\u003cp\\u003e48.48\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"14.642262895174708%\\\"\\u003e\\n \\u003cp\\u003e0.96\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"11.314475873544094%\\\"\\u003e\\n \\u003cp\\u003e0.327\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"21.13144758735441%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.30116472545757%\\\"\\u003e\\n \\u003cp\\u003e3rd and above\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.153078202995008%\\\"\\u003e\\n \\u003cp\\u003e5\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.151414309484194%\\\"\\u003e\\n \\u003cp\\u003e10\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.306156405990016%\\\"\\u003e\\n \\u003cp\\u003e33.33\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"14.642262895174708%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"11.314475873544094%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"21.13144758735441%\\\"\\u003e\\n \\u003cp\\u003ePrevious EGFR TKIs\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.30116472545757%\\\"\\u003e\\n \\u003cp\\u003eGefinitib\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.153078202995008%\\\"\\u003e\\n \\u003cp\\u003e13\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.151414309484194%\\\"\\u003e\\n \\u003cp\\u003e21\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.306156405990016%\\\"\\u003e\\n \\u003cp\\u003e38.24\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"14.642262895174708%\\\"\\u003e\\n \\u003cp\\u003e0.61\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"11.314475873544094%\\\"\\u003e\\n \\u003cp\\u003e0.436\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"21.13144758735441%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.30116472545757%\\\"\\u003e\\n \\u003cp\\u003eErlotinib\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.153078202995008%\\\"\\u003e\\n \\u003cp\\u003e3\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.151414309484194%\\\"\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.306156405990016%\\\"\\u003e\\n \\u003cp\\u003e75.00\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"14.642262895174708%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"11.314475873544094%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"21.13144758735441%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.30116472545757%\\\"\\u003e\\n \\u003cp\\u003eIcotinib\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.153078202995008%\\\"\\u003e\\n \\u003cp\\u003e4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.151414309484194%\\\"\\u003e\\n \\u003cp\\u003e3\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.306156405990016%\\\"\\u003e\\n \\u003cp\\u003e57.14\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"14.642262895174708%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"11.314475873544094%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"21.13144758735441%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.30116472545757%\\\"\\u003e\\n \\u003cp\\u003eGefinitib-Afatinib\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.153078202995008%\\\"\\u003e\\n \\u003cp\\u003e0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.151414309484194%\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.306156405990016%\\\"\\u003e\\n \\u003cp\\u003e0.00\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"14.642262895174708%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"11.314475873544094%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"21.13144758735441%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.30116472545757%\\\"\\u003e\\n \\u003cp\\u003eAfatinib\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.153078202995008%\\\"\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.151414309484194%\\\"\\u003e\\n \\u003cp\\u003e0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.306156405990016%\\\"\\u003e\\n \\u003cp\\u003e100.00\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"14.642262895174708%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"11.314475873544094%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"21.13144758735441%\\\"\\u003e\\n \\u003cp\\u003ePrevious Chemotherapy\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.30116472545757%\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.153078202995008%\\\"\\u003e\\n \\u003cp\\u003e5\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.151414309484194%\\\"\\u003e\\n \\u003cp\\u003e11\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.306156405990016%\\\"\\u003e\\n \\u003cp\\u003e31.25\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"14.642262895174708%\\\"\\u003e\\n \\u003cp\\u003e1.52\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"11.314475873544094%\\\"\\u003e\\n \\u003cp\\u003e0.217\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"21.13144758735441%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.30116472545757%\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.153078202995008%\\\"\\u003e\\n \\u003cp\\u003e16\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.151414309484194%\\\"\\u003e\\n \\u003cp\\u003e16\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.306156405990016%\\\"\\u003e\\n \\u003cp\\u003e50.00\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"14.642262895174708%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"11.314475873544094%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"21.13144758735441%\\\"\\u003e\\n \\u003cp\\u003eBrain Metastasis\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.30116472545757%\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.153078202995008%\\\"\\u003e\\n \\u003cp\\u003e7\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.151414309484194%\\\"\\u003e\\n \\u003cp\\u003e12\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.306156405990016%\\\"\\u003e\\n \\u003cp\\u003e36.84\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"14.642262895174708%\\\"\\u003e\\n \\u003cp\\u003e0.61\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"11.314475873544094%\\\"\\u003e\\n \\u003cp\\u003e0.435\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"21.13144758735441%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.30116472545757%\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.153078202995008%\\\"\\u003e\\n \\u003cp\\u003e14\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.151414309484194%\\\"\\u003e\\n 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\\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"21.13144758735441%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.30116472545757%\\\"\\u003e\\n \\u003cp\\u003eG719X\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.153078202995008%\\\"\\u003e\\n \\u003cp\\u003e0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.151414309484194%\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.306156405990016%\\\"\\u003e\\n \\u003cp\\u003e0.00\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"14.642262895174708%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"11.314475873544094%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"21.13144758735441%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.30116472545757%\\\"\\u003e\\n \\u003cp\\u003e20exon insertion\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.153078202995008%\\\"\\u003e\\n \\u003cp\\u003e0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.151414309484194%\\\"\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.306156405990016%\\\"\\u003e\\n \\u003cp\\u003e0.00\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"14.642262895174708%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"11.314475873544094%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"21.13144758735441%\\\"\\u003e\\n \\u003cp\\u003eTP53 mutation\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.30116472545757%\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.153078202995008%\\\"\\u003e\\n \\u003cp\\u003e8\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.151414309484194%\\\"\\u003e\\n \\u003cp\\u003e14\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.306156405990016%\\\"\\u003e\\n \\u003cp\\u003e36.36\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"14.642262895174708%\\\"\\u003e\\n \\u003cp\\u003e0.90\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"11.314475873544094%\\\"\\u003e\\n \\u003cp\\u003e0.343\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"21.13144758735441%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.30116472545757%\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.153078202995008%\\\"\\u003e\\n \\u003cp\\u003e13\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.151414309484194%\\\"\\u003e\\n \\u003cp\\u003e13\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"16.306156405990016%\\\"\\u003e\\n \\u003col\\u003e\\n \\u003cli\\u003e\\u0026nbsp;\\u003c/li\\u003e\\n \\u003c/ol\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"14.642262895174708%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"11.314475873544094%\\\"\\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\\u003cem\\u003eHigh EGFR T790M AF in ctDNA predicted longer Osimertinib-related PFS and OS\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe median follow-up time was 44 months (ranging from 2 months to 101 months). ROC curve was used to determine the cut-off of T790M AF in ctDNA (Figure 1B), and 1.27% was used to identify two prognostic groups. Patients with high T790M AF had longer PFS (mPFS 21.00\\u0026plusmn;2.17 months vs. 10.00\\u0026plusmn;1.54 months, HR=0.36, 95%CI: 0.16-0.81, \\u003cem\\u003eP\\u003c/em\\u003e=0.014, Figure 1C) and OS (mOS 72.00\\u0026plusmn;5.79 months vs. 48.00\\u0026plusmn;7.97 months, HR=0.41, 95%CI: 0.14-1.20, \\u003cem\\u003eP\\u003c/em\\u003e=0.066, Figure 2B) than those who had low T790M AF.\\u003c/p\\u003e\\n\\u003cp\\u003ePatients over 65 years old had longer PFS, compared to younger patients (mPFS 20.00\\u0026plusmn;4.70 months vs. 10.00\\u0026plusmn;1.86 months, HR=0.30, 95%CI: 0.13-0.68, \\u003cem\\u003eP\\u003c/em\\u003e=0.004). Patients with different active \\u003cem\\u003eEGFR\\u003c/em\\u003e mutations, including exon 19del, L858R, G719X and exon 20 insertion also showed different PFS and OS (mPFS 14.00\\u0026plusmn;5.28 months, 11.00\\u0026plusmn;1.40 months, 5.5 months vs. 2 months, \\u003cem\\u003eP\\u003c/em\\u003e\\u0026lt;0.001; mOS 66.00\\u0026plusmn;7.33 months, NR, 45 months vs. 20 months, \\u003cem\\u003eP\\u003c/em\\u003e\\u0026lt;0.001). Previously administrated \\u003cem\\u003eEGFR\\u003c/em\\u003e-TKIs also led to significantly different mPFS: 12.00\\u0026plusmn;1.34 months for Gefitinib, 8.00\\u0026plusmn;2.45 months for Erlotinib, 33.00 months for Icotinib, 3.5 months for Gefitinib followed by Afatinib, and not reached (NR) for Afatinib. Liver metastasis predicted poor PFS (mPFS: 7.00\\u0026plusmn;3.64 months vs. 14.00\\u0026plusmn;2.62 months, HR=5.04, 95%CI: 1.16-21.58, log-rank\\u003cem\\u003e\\u0026nbsp;P\\u003c/em\\u003e=0.031), while other metastatic sites before Osimertinib treatment did not show significant difference in PFS. Gender, lines of Osimertinib treatment, prior chemotherapy and \\u003cem\\u003eTP53\\u003c/em\\u003e mutation were not significantly associated with Osimertinib-related PFS (Supplementary Figure 1 and 2). Comparably, age, gender, previously used \\u003cem\\u003eEGFR\\u003c/em\\u003e-TKIs, smoking status, lines of Osimertinib, prior chemotherapy, \\u003cem\\u003eTP53\\u003c/em\\u003e mutation and metastatic sites before Osimertinib were not significantly associated with OS (Supplementary Figure 3 and 4).\\u003c/p\\u003e\\n\\u003cp\\u003eNext we took age, the T790M AF in ctDNA, active \\u003cem\\u003eEGFR\\u003c/em\\u003e mutations, and previously used \\u003cem\\u003eEGFR\\u003c/em\\u003e-TKIs into cox proportional hazards regression models. Multivariate analysis revealed that over 65 years old (HR: 0.32, 95%CI:\\u0026nbsp;0.13-0.75, \\u003cem\\u003eP\\u003c/em\\u003e=0.009) and high T790M AF (HR: 0.39, 95%CI:\\u0026nbsp;0.17-0.90, \\u003cem\\u003eP\\u003c/em\\u003e=0.027) were independent prognostic factors for PFS, while both high T790M AF (HR: 0.31, 95%CI: 0.10-0.92, \\u003cem\\u003eP\\u003c/em\\u003e=0.035) and active \\u003cem\\u003eEGFR\\u003c/em\\u003e mutation (HR: 2.28, 95%CI:\\u0026nbsp;1.07-4.90, \\u003cem\\u003eP\\u003c/em\\u003e=0.015) were independent prognostic factors for OS (Table 4) in \\u003cem\\u003eEGFR\\u003c/em\\u003e T790M-positive advanced NSCLC patients receiving Osimertinib after the first-or second-generation of \\u003cem\\u003eEGFR\\u003c/em\\u003e-TKIs (Table 4).\\u003c/p\\u003e\\n\\u003cp\\u003eTable 3 Uni- and multivariate analysis for PFS by Cox proportional hazards regression model\\u003c/p\\u003e\\n\\u003cdiv\\u003e\\n \\u003ctable border=\\\"0\\\" cellpadding=\\\"0\\\" cellspacing=\\\"0\\\" width=\\\"0\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"20.20033388981636%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" width=\\\"31.385642737896493%\\\"\\u003e\\n \\u003cp\\u003eUnivariate analyses\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"20.534223706176963%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" width=\\\"27.879799666110184%\\\"\\u003e\\n \\u003cp\\u003eMultivariate analyses\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"20.20033388981636%\\\"\\u003e\\n \\u003cp\\u003eCharacteristics\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"23.37228714524207%\\\"\\u003e\\n \\u003cp\\u003eHR (95% CI)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003eP\\u003c/em\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"20.534223706176963%\\\"\\u003e\\n \\u003cp\\u003eCharacteristics\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.86644407345576%\\\"\\u003e\\n \\u003cp\\u003eHR (95% CI)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003eP\\u003c/em\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"20.20033388981636%\\\"\\u003e\\n \\u003cp\\u003eAge\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"23.37228714524207%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"20.534223706176963%\\\"\\u003e\\n \\u003cp\\u003eAge\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.86644407345576%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"20.20033388981636%\\\"\\u003e\\n \\u003cp\\u003e\\u0026lt;65 years old\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" width=\\\"31.385642737896493%\\\"\\u003e\\n \\u003cp\\u003e1.00 (Reference)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"20.534223706176963%\\\"\\u003e\\n \\u003cp\\u003e\\u0026lt;65 years old\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" width=\\\"27.879799666110184%\\\"\\u003e\\n \\u003cp\\u003e1.00 (Reference)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"20.20033388981636%\\\"\\u003e\\n \\u003cp\\u003e\\u0026ge;65 years old\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"23.37228714524207%\\\"\\u003e\\n \\u003cp\\u003e0.37 (0.13-0.72)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e0.007\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"20.534223706176963%\\\"\\u003e\\n \\u003cp\\u003e\\u0026ge;65 years old\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.86644407345576%\\\"\\u003e\\n \\u003cp\\u003e0.32 (0.13-0.75)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e0.009\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"20.20033388981636%\\\"\\u003e\\n \\u003cp\\u003eT790M AF\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"23.37228714524207%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" width=\\\"40.40066777963272%\\\"\\u003e\\n \\u003cp\\u003eT790M AF\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"20.20033388981636%\\\"\\u003e\\n \\u003cp\\u003e\\u0026lt;1.27%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" width=\\\"31.385642737896493%\\\"\\u003e\\n \\u003cp\\u003e1.00 (Reference)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"20.534223706176963%\\\"\\u003e\\n \\u003cp\\u003e\\u0026lt;1.27%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" width=\\\"27.879799666110184%\\\"\\u003e\\n \\u003cp\\u003e1.00 (Reference)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"20.20033388981636%\\\"\\u003e\\n \\u003cp\\u003e\\u0026ge;1.27%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"23.37228714524207%\\\"\\u003e\\n \\u003cp\\u003e0.38 (0.17-0.85)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e0.019\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"20.534223706176963%\\\"\\u003e\\n \\u003cp\\u003e\\u0026ge;1.27%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.86644407345576%\\\"\\u003e\\n \\u003cp\\u003e0.39 (0.17-0.90)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e0.027\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" width=\\\"43.57262103505843%\\\"\\u003e\\n \\u003cp\\u003eLiver Metastasis\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"20.534223706176963%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.86644407345576%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"20.20033388981636%\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" width=\\\"31.385642737896493%\\\"\\u003e\\n \\u003cp\\u003e1.00 (Reference)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"20.534223706176963%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.86644407345576%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"20.20033388981636%\\\"\\u003e\\n \\u003cp\\u003eYes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"23.37228714524207%\\\"\\u003e\\n \\u003cp\\u003e2.95 (1.04-8.38)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e0.420\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"20.534223706176963%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.86644407345576%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"2\\\" width=\\\"43.57262103505843%\\\"\\u003e\\n \\u003cp\\u003ePrevious \\u003cem\\u003eEGFR\\u003c/em\\u003e -TKIs\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"20.534223706176963%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.86644407345576%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"20.20033388981636%\\\"\\u003e\\n \\u003cp\\u003eGefinitib\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" width=\\\"31.385642737896493%\\\"\\u003e\\n \\u003cp\\u003e1.00 (Reference)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"20.534223706176963%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.86644407345576%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"20.20033388981636%\\\"\\u003e\\n \\u003cp\\u003eErlotinib\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"23.37228714524207%\\\"\\u003e\\n \\u003cp\\u003e2.13 (0.46-9.90)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e0.340\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"20.534223706176963%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.86644407345576%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"20.20033388981636%\\\"\\u003e\\n \\u003cp\\u003eIcotinib\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"23.37228714524207%\\\"\\u003e\\n \\u003cp\\u003e0.26 (0.06-1.12)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e0.071\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"20.534223706176963%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.86644407345576%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"20.20033388981636%\\\"\\u003e\\n \\u003cp\\u003eGefinitib-Afatinib\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"23.37228714524207%\\\"\\u003e\\n \\u003cp\\u003e5.05 (1.07-23.80)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e0.041\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"20.534223706176963%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.86644407345576%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"20.20033388981636%\\\"\\u003e\\n \\u003cp\\u003eAfatinib\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"23.37228714524207%\\\"\\u003e\\n \\u003cp\\u003e0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e0.981\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"20.534223706176963%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.86644407345576%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"20.20033388981636%\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003eEGFR\\u003c/em\\u003e mutation\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"23.37228714524207%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"20.534223706176963%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.86644407345576%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"20.20033388981636%\\\"\\u003e\\n \\u003cp\\u003e19del\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" width=\\\"31.385642737896493%\\\"\\u003e\\n \\u003cp\\u003e1.00 (Reference)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"20.534223706176963%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.86644407345576%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"20.20033388981636%\\\"\\u003e\\n \\u003cp\\u003eL858R\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"23.37228714524207%\\\"\\u003e\\n \\u003cp\\u003e1.88 (0.78-4.54)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e0.160\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"20.534223706176963%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.86644407345576%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"20.20033388981636%\\\"\\u003e\\n \\u003cp\\u003eG719X\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"23.37228714524207%\\\"\\u003e\\n \\u003cp\\u003e1.81 (0.23-14.37)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e0.573\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"20.534223706176963%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.86644407345576%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"20.20033388981636%\\\"\\u003e\\n \\u003cp\\u003e20ins\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"23.37228714524207%\\\"\\u003e\\n \\u003cp\\u003e60.95 (3.69-1006.25)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\u003e\\n \\u003cp\\u003e0.004\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"20.534223706176963%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.86644407345576%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.013355592654424%\\\"\\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\\u003c/div\\u003e\\n\\u003cp\\u003eTable 4 Uni- and multivariate analysis for OS by Cox proportional regression model\\u003c/p\\u003e\\n\\u003cdiv align=\\\"center\\\"\\u003e\\n \\u003ctable border=\\\"0\\\" cellpadding=\\\"0\\\" cellspacing=\\\"0\\\" width=\\\"0\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"19.576719576719576%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" width=\\\"30.687830687830687%\\\"\\u003e\\n \\u003cp\\u003eUnivariate analyses\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.753086419753085%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" width=\\\"29.98236331569665%\\\"\\u003e\\n \\u003cp\\u003eMultivariate analyses\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"19.6113074204947%\\\"\\u003e\\n \\u003cp\\u003eCharacteristics\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"22.261484098939928%\\\"\\u003e\\n \\u003cp\\u003eHR (95% CI)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.303886925795053%\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003eP\\u003c/em\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.78798586572438%\\\"\\u003e\\n \\u003cp\\u003eCharacteristics\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"20.671378091872793%\\\"\\u003e\\n \\u003cp\\u003eHR (95% CI)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.363957597173146%\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003eP\\u003c/em\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"19.6113074204947%\\\"\\u003e\\n \\u003cp\\u003eT790M AF\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"22.261484098939928%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.303886925795053%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" width=\\\"40.459363957597176%\\\"\\u003e\\n \\u003cp\\u003eT790M AF\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.363957597173146%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"19.576719576719576%\\\"\\u003e\\n \\u003cp\\u003e\\u0026lt;1.27%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" width=\\\"30.687830687830687%\\\"\\u003e\\n \\u003cp\\u003e1.00 (Reference)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.753086419753085%\\\"\\u003e\\n \\u003cp\\u003e\\u0026lt;1.27%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" width=\\\"29.98236331569665%\\\"\\u003e\\n \\u003cp\\u003e1.00 (Reference)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"19.6113074204947%\\\"\\u003e\\n \\u003cp\\u003e\\u0026ge;1.27%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"22.261484098939928%\\\"\\u003e\\n \\u003cp\\u003e0.38 (0.14-1.08)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.303886925795053%\\\"\\u003e\\n \\u003cp\\u003e0.070\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.78798586572438%\\\"\\u003e\\n \\u003cp\\u003e\\u0026ge;1.27%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"20.671378091872793%\\\"\\u003e\\n \\u003cp\\u003e0.31 (0.10-0.92)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.363957597173146%\\\"\\u003e\\n \\u003cp\\u003e0.035\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"19.6113074204947%\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003eEGFR\\u003c/em\\u003e mutation\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"22.261484098939928%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.303886925795053%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" width=\\\"40.459363957597176%\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003eEGFR\\u003c/em\\u003e mutation\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.363957597173146%\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"19.576719576719576%\\\"\\u003e\\n \\u003cp\\u003e19del\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" width=\\\"30.687830687830687%\\\"\\u003e\\n \\u003cp\\u003e1.00 (Reference)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.753086419753085%\\\"\\u003e\\n \\u003cp\\u003e19del\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" width=\\\"29.98236331569665%\\\"\\u003e\\n \\u003cp\\u003e1.00 (Reference)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"19.6113074204947%\\\"\\u003e\\n \\u003cp\\u003eOther \\u003cem\\u003eEGFR\\u003c/em\\u003e mutations\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"22.261484098939928%\\\"\\u003e\\n \\u003cp\\u003e2.29 (1.07-4.90)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"8.303886925795053%\\\"\\u003e\\n \\u003cp\\u003e0.033\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"19.78798586572438%\\\"\\u003e\\n \\u003cp\\u003eOther \\u003cem\\u003eEGFR\\u003c/em\\u003e mutations\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"20.671378091872793%\\\"\\u003e\\n \\u003cp\\u003e2.28 (1.07-4.90)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"9.363957597173146%\\\"\\u003e\\n \\u003cp\\u003e0.015\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n \\u003c/table\\u003e\\n\\u003c/div\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eOsimertinib showed robust ORR and prolonged PFS and OS as the first-line and second-or later-line treatment for T790M mutation positive advanced NSCLC patients. Cobas\\u0026reg; \\u003cem\\u003eEGFR\\u003c/em\\u003e mutation test from tumor tissue was the gold standard for T790M detection in AURA3 and FLAURA studies \\u003csup\\u003e[\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e]\\u003c/sup\\u003e. Unfortunately, re-biopsy is not always available after resistance to the first- or second-generation \\u003cem\\u003eEGFR\\u003c/em\\u003e-TKIs due to many reasons, such as poor location or size of the tumor that is not eligible for a biopsy, poor ECOG, rejection of re-biopsy. An observational real-world study from Italy showed that only 10.7% patients received tissue biopsy after progression and 64.5% of the them took liquid biopsy\\u003csup\\u003e[\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e]\\u003c/sup\\u003e. Other disadvantages, such as intratumoral heterogeneity, insufficient tumor tissue for molecular assessment limit the use of re-biopsy. Liquid biopsy overcomes these limitations and showed a relatively high accordance with tissue biopsy.\\u003c/p\\u003e \\u003cp\\u003eAmplification refractory mutation system (ARMS) is widely used for EGFR mutation detection due to its cost-effectiveness, but its sensitivity is relative low, especially in plasma samples. Although Cobas\\u0026reg; \\u003cem\\u003eEGFR\\u003c/em\\u003e mutation test is the companion diagnostic test for Osimertinib, NGS performed improved sensitivity in AURA3 trial population, the plasma \\u003cem\\u003eEGFR\\u003c/em\\u003e T790M positive percent agreement was 51% by Cobas\\u0026reg; plasma, 58% by ddPCR, and increased to 66% by NGS, with Cobas\\u0026reg; tissue test results as a reference\\u003csup\\u003e[\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e]\\u003c/sup\\u003e. High concordance of allelic fractions was demonstrated between NGS and ddPCR for activating EGFR mutations and T790M mutations \\u003csup\\u003e[\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e]\\u003c/sup\\u003e, but it can only detect certain known mutation. The advantage of NGS lies in excellent sensitivity and specificity, performed better for T790M mutation, uncommon \\u003cem\\u003eEGFR\\u003c/em\\u003e mutation and novel mutations: the concordance rate was 82% between cobas\\u0026reg; and the NGS approach for the \\u003cem\\u003eEGFR\\u003c/em\\u003e sensitizing mutations (in exons 18, 19, 21) in patients with acquired resistance to \\u003cem\\u003eEGFR\\u003c/em\\u003e-TKIs, while this concordance increased to 94% for the T790M mutation by NGS \\u003csup\\u003e[\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e]\\u003c/sup\\u003e.\\u003c/p\\u003e \\u003cp\\u003eLiquid biopsy shows potential for prediction of \\u003cem\\u003eEGFR\\u003c/em\\u003e-TKI efficacy and elucidation of clonal tumor evolution during targeted therapy \\u003csup\\u003e[\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e]\\u003c/sup\\u003e, but the association between \\u003cem\\u003eEGFR\\u003c/em\\u003e T790M AF in ctDNA and Osimertinib-related survival still needs to be explored. High AF of T790M in plasma ctDNA before Osimertinib by ddPCR was found to be associated with a trend towards a shorter PFS and a significantly shorter OS \\u003csup\\u003e[\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e]\\u003c/sup\\u003e. A recent study from Australia revealed that DCR was superior in patients with higher plasma T790M AF; however, no significant association was found between T790M relative AF and survival benefit \\u003csup\\u003e[\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e]\\u003c/sup\\u003e. In this study, we demonstrated that high T790M AF before Osimertinib predicted longer PFS and OS, and is an independent survival factor for both PFS and OS. Although low T790M abundance in ctDNA reflected low tumor burden, we suppose high T790M AF in ctDNA response better to Osimertinib, leading to survival benefit.\\u003c/p\\u003e \\u003cp\\u003e \\u003cem\\u003eTP53\\u003c/em\\u003e has been verified as one of the most common co-occurring mutations, while the role of \\u003cem\\u003eTP53\\u003c/em\\u003e in predicting \\u003cem\\u003eEGFR\\u003c/em\\u003e-TKIs efficacy remain elusive. Previous studies indicated that pathological \\u003cem\\u003eTP53\\u003c/em\\u003e mutation was negatively correlated with Osimertinib efficacy and clinical outcome \\u003csup\\u003e[\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e]\\u003c/sup\\u003e. However, other studies did not find any association between \\u003cem\\u003eTP53\\u003c/em\\u003e with clinical endpoints \\u003csup\\u003e[\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e]\\u003c/sup\\u003e. Dual \\u003cem\\u003eEGFR\\u003c/em\\u003e and \\u003cem\\u003eTP53\\u003c/em\\u003e missense mutations, instead of \\u003cem\\u003eEGFR\\u003c/em\\u003e/\\u003cem\\u003eTP53\\u003c/em\\u003e mutation predicted marginally lower response rates and shorter PFS when treated with \\u003cem\\u003eEGFR\\u003c/em\\u003e-TKIs \\u003csup\\u003e[\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e]\\u003c/sup\\u003e. \\u003cem\\u003eTP53\\u003c/em\\u003e mutations in different exons have been proved to be associated with PFS treated with \\u003cem\\u003eEGFR\\u003c/em\\u003e-TKIs: mutations in exon 8 reduced responsiveness to \\u003cem\\u003eEGFR\\u003c/em\\u003e-TKIs and worsen prognosis in \\u003cem\\u003eEGFR\\u003c/em\\u003e-mutated NSCLC patients, mainly those carrying exon 19 deletions \\u003csup\\u003e[\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e]\\u003c/sup\\u003e, mutations in exon 4 or 7 served as independent poor prognostic factors for PFS and OS \\u003csup\\u003e[\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e]\\u003c/sup\\u003e. In our cohort, although \\u003cem\\u003eTP53\\u003c/em\\u003e was the most common concurrent mutation gene, we did not found any difference in Osimertinib-related PFS or OS between \\u003cem\\u003eTP53\\u003c/em\\u003e-mutant or \\u003cem\\u003eTP53\\u003c/em\\u003e-wild type patients. We also analyzed the prognostic role of \\u003cem\\u003eTP53\\u003c/em\\u003e according to mutation in different exons or different mutation type, but no significant difference was found. This negative result might due to the limited sample number in our study.\\u003c/p\\u003e \\u003cp\\u003e\\u0026ldquo;\\u003cem\\u003eEGFR\\u003c/em\\u003e sensitive tumor\\u0026rdquo; was defined as tumors that did not harbor resistance co-mutations and in which the \\u003cem\\u003eEGFR\\u003c/em\\u003e mutation had a high AF. Patients with \\u0026ldquo;EGFR sensitive tumors\\u0026rdquo; supposed to have significant longer PFS\\u003csup\\u003e[\\u003cspan citationid=\\\"CR24\\\" class=\\\"CitationRef\\\"\\u003e24\\u003c/span\\u003e]\\u003c/sup\\u003e. Interestingly, we noticed that one patient in T790M-high group who harbored \\u003cem\\u003eEGFR\\u003c/em\\u003e and \\u003cem\\u003eMYC\\u003c/em\\u003e amplification had shorter PFS (7 months vs. 21 months) and OS (39 months vs.72 months), compared to the mPFS and mOS in the same group. Another patient in T790M-low group had BRAF V600E mutation also showed shorter PFS (8 months vs. 11 months) and OS (27 months vs. 48months). These indicated that other driven mutations might play a more important role than T790M AF in Osimertinib-related PFS and OS.\\u003c/p\\u003e \\u003cp\\u003eLoss of T790M has been proven as one of mechanisms leading to the resistance of Osimertinib \\u003csup\\u003e[\\u003cspan citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e]\\u003c/sup\\u003e. Among the four PD patients who took targeted NGS after resistance to Osimertinib, two patients showed T790M AF decrease, while the other two showed stable or an increased T790M AF. Noticeably, the patient who had unchanged T790M AF (0.7%) before and after disease progression was detected to develop MET amplification as Osimertinib resistance mechanism. The last patient, whose T790M AF increased from 1.14\\u0026ndash;28.95%, developed \\u003cem\\u003eEGFR\\u003c/em\\u003e exon20 C797S and \\u003cem\\u003eEGFR\\u003c/em\\u003e amplification after disease progression.\\u003c/p\\u003e \\u003cp\\u003eDue to the high cost of NGS test, not every NSCLC patient could afford NGS test in Northwest China. So one of the drawback of our study is the limited number of patients. Another limitation of our study is that we failed to follow the dynamic change of gene mutation in ctDNA before and after the use of Osimertinib in all patients. As quantification of longitudinal plasma T790M mutation may allow noninvasive assessment of drug resistance and guide follow-up treatment in \\u003cem\\u003eEGFR\\u003c/em\\u003e-TKI-treated patients with NSCLC, we will further monitor and investigate the change of T790M mutation AF during \\u003cem\\u003eEGFR\\u003c/em\\u003e TKIs treatment.\\u003c/p\\u003e \\u003cp\\u003eIn conclusion, we demonstrated that T790M AF is an independent prognostic factor for Osimertinib-related PFS and OS.\\u003c/p\\u003e\"},{\"header\":\"Conclusion\",\"content\":\"\\u003cp\\u003eEGFR T790M AF in ctDNA independently predicted PFS and OS in T790M-positive advanced NSCLC who received Osimertinib after resistance to the first- or second-generation of EGFR-TKIs.\\u003c/p\\u003e\"},{\"header\":\"Abbreviations\",\"content\":\"\\u003cp\\u003eARMS: Amplification refractory mutation system\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eAF: Allele frequency\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003ectDNA: circulating tumor DNA\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eDCR: Disease control rate ()\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eEGFR\\u003c/em\\u003e-TKIs: Epidermal growth factor receptor-tyrosine kinase inhibitors\\u0026nbsp;\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eHR: Hazard ratio\\u003c/p\\u003e\\n\\u003cp\\u003emPFS: medium PFS\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eNGS: next generation sequencing\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eNSCLC:\\u0026nbsp;non-small cell lung cancer\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eORR: Objective response rate ()\\u003c/p\\u003e\\n\\u003cp\\u003eOS: Overall survival\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003ePD: Progressive disease\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003ePFS: Progression-free survival\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003ePR: Partial response\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eROC: Receiver operation curve\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eSD: Stable disease \\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003eEthics approval and consent to participate\\u003c/p\\u003e\\n\\u003cp\\u003eAll protocols were approved by the Ethics Committee of Xi\\u0026apos;an Jiaotong University.\\u003c/p\\u003e\\n\\u003cp\\u003eConsent for publication\\u003c/p\\u003e\\n\\u003cp\\u003eNot applicable\\u003c/p\\u003e\\n\\u003cp\\u003eAvailability of data and material\\u003c/p\\u003e\\n\\u003cp\\u003eThe datasets used and analyzed in this study are available from the corresponding author upon reasonable request.\\u003c/p\\u003e\\n\\u003cp\\u003eCompeting interests\\u003c/p\\u003e\\n\\u003cp\\u003eThe authors disclose no potential conflicts of interest.\\u003c/p\\u003e\\n\\u003cp\\u003eFunding\\u003c/p\\u003e\\n\\u003cp\\u003eNational Natural Science Foundation of China (No.\\u0026nbsp;82002437), Research Project in Health--- Young Scientist Research Project in Lung Cancer (No. 1-13), Science and Technology Innovation Team of Shaanxi (No. 2021TD-44), University Joint Project of Shaanxi (No. 2020GXLH-Y-020).\\u003c/p\\u003e\\n\\u003cp\\u003eAuthors\\u0026apos; contributions\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eXF, TT, and YY were in charge of the conception and design of the study; XF, TTS, MJL, and XQZ were in charge of analyzing the data; XF, HRZ, CXF, RZ and XC were in charge of collecting clinical data, TT, XF, LLJ, and WJW wrote the draft of the article; and YJY Dr. XL and ZPR revised the draft; all authors approved the final version.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eAcknowledgement\\u003c/p\\u003e\\n\\u003cp\\u003eWe thanked all the patients and their families who participated in our study. Our study was also supported by National Natural Science Foundation of China (No. 82002437), Science and Technology Innovation Team of Shaanxi (No. 2021TD-44), University Joint Project of Shaanxi (No. 2020GXLH-Y-020).\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eWu, S.G., et al., \\u003cem\\u003eThe mechanism of acquired resistance to irreversible EGFR tyrosine kinase inhibitor-afatinib in lung adenocarcinoma patients\\u003c/em\\u003e. Oncotarget, 2016. \\u003cb\\u003e7\\u003c/b\\u003e(11): p.\\u0026nbsp;12404\\u0026ndash;13.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eCao, Y., et al., \\u003cem\\u003eEffectiveness and safety of osimertinib in patients with metastatic EGFR T790M-positive NSCLC: An observational real-world study\\u003c/em\\u003e. 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Lung Cancer, 2017. \\u003cb\\u003e111\\u003c/b\\u003e: p.\\u0026nbsp;23\\u0026ndash;29.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eCanale, M., et al., \\u003cem\\u003eImpact of TP53 Mutations on Outcome in EGFR-Mutated Patients Treated with First-Line Tyrosine Kinase Inhibitors\\u003c/em\\u003e. Clin Cancer Res, 2017. \\u003cb\\u003e23\\u003c/b\\u003e(9): p.\\u0026nbsp;2195\\u0026ndash;2202.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eLi, X.M., et al., \\u003cem\\u003ePredictive and Prognostic Potential of TP53 in Patients With Advanced Non-Small-Cell Lung Cancer Treated With EGFR-TKI: Analysis of a Phase III Randomized Clinical Trial (CTONG 0901)\\u003c/em\\u003e. Clin Lung Cancer, 2021. \\u003cb\\u003e22\\u003c/b\\u003e(2): p.\\u0026nbsp;100\\u0026ndash;109.e3.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eFriedlaender, A., et al., \\u003cem\\u003eThe Impact of Variant Allele Frequency in EGFR Mutated NSCLC Patients on Targeted Therapy\\u003c/em\\u003e. Front Oncol, 2021. \\u003cb\\u003e11\\u003c/b\\u003e: p.\\u0026nbsp;644472.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eYang, Z., et al., \\u003cem\\u003eDynamics of Plasma EGFR T790M Mutation in Advanced NSCLC: A Multicenter Study\\u003c/em\\u003e. Target Oncol, 2019. \\u003cb\\u003e14\\u003c/b\\u003e(6): p.\\u0026nbsp;719\\u0026ndash;728.\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"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\":\"info@researchsquare.com\",\"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\":\"EGFR T790M, Osimertinib, ctDNA, Next Generation Sequencing\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-1658925/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-1658925/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003eBackground: The clinical and molecular factors that associated with the response to Osimertinib in the patients who have acquired resistance to the first or second-generation of epidermal growth factor receptor-tyrosine kinase inhibitors (\\u003cem\\u003eEGFR\\u003c/em\\u003e-TKIs) is elusive.\\u003c/p\\u003e\\u003cp\\u003eObjectives: The purpose of this study is to investigate the clinical relevance to the allele frequency (AF) of T790M in circulating tumor DNA (ctDNA) by targeted next generation sequencing (NGS), and to analyze the prognostic value of T790M AF in patients with advanced non-small cell lung cancer (NSCLC) receiving Osimertinib after resistance to the first-or second-generation of \\u003cem\\u003eEGFR\\u003c/em\\u003e-TKIs.\\u003c/p\\u003e\\u003cp\\u003eMaterials and methods: We retrospectively screened 3011 advanced NSCLC patients in the First Affiliated Hospital of Xi’an Jiaotong University from November 2015 to March 2021. 586 of them experienced the first- or second-generation EGFR-TKIs resistance and had complete follow-up information, 146 of them took NGS gene test and 48 were detected EGFR T790M in ctDNA. The associations among T790M AF, clinical characteristics and objective response rate (ORR) of Osimertinib was performed by Students’ t-test or one-way ANOVA. The patients were divided into T790M-high and T790M-low groups according to a receiver operation curve (ROC) determined cut-off value. The correlation between T790M AF and ORR of Osimertinib was performed by Students’ t-test, and the association between clinical factors and ORR of Osimertinib was assessed by Pearson’s χ\\u003csup\\u003e2\\u003c/sup\\u003e test or Fisher’s exact test, when appropriate. The survival curves were calculated by the Kaplan-Meier method and analyzed by the log-rank test. Cox proportional hazards regression models were also used to evaluate the association between clinical characteristics, T790M AF and survival endpoints.\\u003c/p\\u003e\\u003cp\\u003eResults: Age (\\u003cem\\u003eP\\u003c/em\\u003e=0.004), \\u003cem\\u003eEGFR\\u003c/em\\u003e active mutations (\\u003cem\\u003eP\\u003c/em\\u003e\\u0026lt;0.001), \\u003cem\\u003eEGFR\\u003c/em\\u003e T790M AF (\\u003cem\\u003eP\\u003c/em\\u003e=0.014), prior \\u003cem\\u003eEGFR\\u003c/em\\u003e-TKIs (\\u003cem\\u003eP\\u003c/em\\u003e=0.024) and liver metastasis before Osimertinib treatment (\\u003cem\\u003eP\\u003c/em\\u003e=0.031) were significantly associated with progression-free survival (PFS). Multivariate analysis revealed that age (hazard ratio: 0.32, 95%CI: 0.13-0.75, \\u003cem\\u003eP\\u003c/em\\u003e=0.009) and the AF of \\u003cem\\u003eEGFR\\u003c/em\\u003e T790M (hazard ratio: 0.39, 95%CI: 0.17-0.90, \\u003cem\\u003eP\\u003c/em\\u003e=0.027) were independent prognostic factors for PFS in \\u003cem\\u003eEGFR\\u003c/em\\u003e T790M positive advanced NSCLC patients receiving Osimertinib. \\u003cem\\u003eEGFR\\u003c/em\\u003e active mutations (\\u003cem\\u003eP\\u003c/em\\u003e\\u0026lt;0.001) was significantly associated with overall survival (OS). EGFR T790M AF tended to be related to OS (\\u003cem\\u003eP\\u003c/em\\u003e=0.066). Moreover, high \\u003cem\\u003eEGFR\\u003c/em\\u003e T790M AF (HR: 0.31, 95%CI: 0.10-0.92, \\u003cem\\u003eP\\u003c/em\\u003e=0.035) and \\u003cem\\u003eEGFR\\u003c/em\\u003e active mutations (HR: 2.28, 95%CI: 1.07-4.90, \\u003cem\\u003eP\\u003c/em\\u003e=0.015) were independently predictive factors of OS in multivariate analysis.\\u003c/p\\u003e\\u003cp\\u003eConclusion: \\u003cem\\u003eEGFR\\u003c/em\\u003e T790M AF in ctDNA independently predicted PFS and OS in T790M-positive advanced NSCLC who received Osimertinib after resistance to the first- or second-generation of \\u003cem\\u003eEGFR\\u003c/em\\u003e-TKIs.\\u003c/p\\u003e\",\"manuscriptTitle\":\"The allele frequency of EGFR T790M in ctDNA predicted clinical outcomes of Osimertinib in non-small cell lung cancer patients from a real-world study\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2022-06-15 18:37:00\",\"doi\":\"10.21203/rs.3.rs-1658925/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"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\":\"086301a6-0f14-4781-9f63-7cd0ce6b6f72\",\"owner\":[],\"postedDate\":\"June 15th, 2022\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"posted\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2022-06-15T18:37:01+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2022-06-15 18:37:00\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-1658925\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-1658925\",\"identity\":\"rs-1658925\",\"version\":[\"v1\"]},\"buildId\":\"ApUGefWb6u5IBVtyqm6d5\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}