scholarly journals The Role of De Novo T790M Mutation in The Origin of T790M Resistance Clone and in The Clinical Outcomes For Advanced EGFR-Mutant NSCLC Patients Receiving EGFR-TKIs

2021 ◽  
Author(s):  
Mei-Fang Li ◽  
Jing-Hui Lin ◽  
Jing Zhang ◽  
Yun-Jian Huang ◽  
Sheng-Chi Chen ◽  
...  
Keyword(s):  
Disease Progression ◽  
De Novo ◽  
Resistance Mutation ◽  
Low Frequency ◽  
Third Generation ◽  
Resistance Mutations ◽  
T790m Mutation ◽  
Egfr Mutant ◽  
Nsclc Patients ◽  
Egfr Tkis

Abstract Background: Increasing evidence suggests that de novo T790M mutation occurs at a low frequency in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). However, the effects of this mutation on the formation of T790M resistant clones and efficacy of EGFR tyrosine kinase inhibitors (TKIs) remain unclear. Methods: Fifty-nine treatment-naïve in-patients with advanced EGFR-mutant NSCLC were enrolled in this study between 2017 and 2018. We dynamically monitored T790M mutation in ctDNA of patients before and during treatment with first-generation EGFR-TKIs, which were administered every 2 to 3 months until disease progression. Results: Among the patients, 28.81% (17/59) had a low-frequency de novo T790M mutation, 66.67% (10/15) of them retained T790M mutation and resistance in this group was defined as “selection” resistance. T790M mutation was detected after treatment in 42.3% (11/26) of patients without de novo T790M mutation who experienced disease progression and resistance in this group was defined as “acquisition” resistance. After treatment with third-generation EGFR-TKI, patients with the “selection” T790M resistance mutation had significantly better objective response rate (ORR) and longer progression-free survival (PFS) than those with the “acquisition” T790M resistance mutation. Conclusion: Our study provides evidence that low-frequency de novo T790M mutation is not rare in patients with advanced EGFR-mutant NSCLC. T790M resistance mutations can have two origins: the selection of low-frequency de novo T790M clones or the acquisition of the mutation in initially T790M-negative cells clinically. Since the origin of T790M resistance mutations can affect the efficacy of third-generation EGFR-TKIs, these EGFR-TKIs may be more effective for the treatment of NSCLC patients with “selection” T790M resistance mutations.

The combination of EGFR-TKIs and anlotinib as a first-line therapy for EGFR-mutant advanced non-small cell lung cancer: A multicenter, single-arm, phase II clinical trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9030-9030
Author(s):  
Zhiyong He ◽  
Jinghui Lin ◽  
Yueming He ◽  
Jing Zhang ◽  
Dongyong Yang ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Adverse Events ◽  
Advanced Nsclc ◽  
De Novo ◽  
Egfr Mutations ◽  
Treatment Naïve ◽  
Pre Treatment ◽  
Egfr Mutant ◽  
Nsclc Patients ◽  
Egfr Tkis

9030 Background: Currently,EGFR-TKIs are widely accepted as the standard treatment for EGFR- mutant advanced non-small-cell lung cancer (NSCLC); however, acquired resistance is inevitable. Combination therapy is considered as a strategy to overcome the resistance to EGFR-TKIs. Anlotinib, a novel multi-targeting, small-molecule TKI, has shown active to suppress tumor angiogenesis and growth. However, there is still a lack of evidence supporting the use of EGFR-TKIs in combination with anlotinib for the treatment of NSCLC until now. A multi-center, single-arm, phase II clinical trial was therefore designed to examine the efficacy and safety of EGFR-TKIs combined with anlotinib for treatment-naïve, advanced NSCLC patients, and unravel the possible mechanisms. Methods: This study was conducted in 14 research centers in Fujian, China. The main eligibility criteria were stage IV or relapsed nonsquamous NSCLC with EGFR mutations (exon 19 deletion,, and L858R), ECOG score 0-2,and age 20 to 75 years and no previous systemic treatment. Patients with asymptomatic brain metastases were admitted.Eligible patients were given gefitinib (250 mg QD) or icotinib (125 mg TID) in combination with anlotinib (10 mg per day, on days 1‒14; 21 days per cycle) until disease progression. The primary endpoint is progression-free survival (PFS) and safety, and the secondary endpoint is overall survival (OS), objective response rate (ORR) and disease control rate (DCR).Peripheral blood was sampled pre-treatment, once every two months during treatment and after disease progression, and T790M mutation was detected in plasma ctDNA using a droplet digital PCR (ddPCR) assay. Results: Of 60 patients enrolled (August 2, 2018 to May 28, 2020). As of February 1, 2021, 37 patients (61.7%) experienced PFS events and 10 (16.7%) died. The ORR was 78.3%, and the DCR was100%.Median PFS was 13.0 months (95%CI,10.7-15.3).The 5 most common treatment-related adverse events included rash (63.3%), fatigue (55.0%), hypertension (48.3%), diarrhea (33.3%) and hand-foot syndrome (30.0%), and grade 3 adverse events included hypertension (5.0%), rash (1.67%), hypertriglyceridemia (1.67%), vomiting (1.67%) and elevated ALT (1.67%); no grade 4 adverse events or drug-related deaths were observed. Peripheral blood samples were collected from 36 patients pre-treatment, and 30.6% were identified with low-frequency de novo T790M mutations, with the mutation-allele frequency (MAF) ranging from 0.01% to 0.28%. Conclusions: The combination of the first-generation EGFR-TKIs and anlotinib shows impressive ORR and DCR, and acceptable toxicity in treatment-naïve advanced NSCLC patients with activating EGFR mutations, and we observed a high proportion of patients harboring de novo EGFR T790M mutations in this study. Clinical trial information: NCT03720873.

Clinical implications of the T790M mutation in disease characteristics and treatment response in patients with EGFR-mutated NSCLC.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9031-9031
Author(s):  
Daria Gaut ◽  
Myung Shin Sim ◽  
Brian R. Wolf ◽  
Phillip A. Abarca ◽  
James M. Carroll ◽  
...  
Keyword(s):  
Medical Records ◽  
Response Rate ◽  
Kinase Inhibitor ◽  
Resistance Mutation ◽  
Progression Free Survival ◽  
First Line ◽  
T790m Mutation ◽  
Free Survival ◽  
Egfr Mutant ◽  
Nsclc Patients

9031 Background: The secondary T790M mutation accounts for more than 50% of acquired tyrosine kinase inhibitor (TKI) resistance in epidermal growth factor receptor (EGFR)-mutant NSCLC patients. Recent reports suggest this resistance mutation may be more common among patients with longer progression-free survival (PFS) on first-line TKI therapy, but much is still unknown about this resistance mechanism’s association with response to other therapies. Methods: Our group collected medical records from patients who underwent a biopsy for T790M mutation testing in the process of screening for clinical trials involving third generation EGFR inhibitors. Medical records were retrospectively analyzed for demographic data, PFS, best response (BR) to previous therapies, and presence or absence of an acquired T790M mutation. Progression-free survival was estimated using the Kaplan-Meier method and compared across two groups using the log-ranked test followed by univariate and multivariate cox proportional hazard regression analysis. Response rates were compared using Fisher’s exact test. Results: Out of 102 patients who obtained a diagnostic biopsy, 73 patients had a T790M mutation. Patients who later developed a T790M mutation had a longer PFS on first-line TKI therapy (12.0 months in T790M+ vs. 8.0 months in T790M-, p = 0.038, HR 1.66, 95% CI 1.03-2.67), though there was no difference in response rate (75.5% in T790M+ vs 77.3% in T790M-, p = 1.00). T790M+ patients also had a longer PFS on initial chemotherapy treatment (5.0 months in T790M+ vs. 4.0 months in T790M-, p = 0.020, HR 1.97, 95% CI 1.11-3.49) and a higher response rate to chemotherapy (22.7% in T790M+ vs 0% in T790M-, p = 0.033). Median PFS was short (3.0 months) for patients treated with immunotherapy with no difference based on T790M mutation status (p = 0.33). Conclusions: Our study confirms that tumors expressing T790M have a more indolent progression of disease compared to their T790M negative counterparts when treated with both first-line TKI and cytotoxic chemotherapy. This data provides context for therapeutic decision making in EGFR-mutant NSCLC patients.

Local ablative therapy (LAT) for oligoprogressive, EGFR-mutant, non-small cell lung cancer (NSCLC) after treatment with osimertinib.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20545-e20545 ◽  
Author(s):  
Chul Kim ◽  
Nitin Roper ◽  
Chuong D. Hoang ◽  
Eva Szabo ◽  
Maureen Connolly ◽  
...  
Keyword(s):  
Disease Progression ◽  
Kinase Inhibitors ◽  
Objective Response ◽  
Progression Free Survival ◽  
T790m Mutation ◽  
Tki Treatment ◽  
Egfr Mutant ◽  
A Prospective Study ◽  
Egfr Tki ◽  
Egfr Tkis

e20545 Background: EGFR tyrosine kinase inhibitors (EGFR-TKIs) improve progression-free survival (PFS) in patients with EGFR-mutant NSCLC, but disease progression limits efficacy. Retrospective studies show a survival benefit to LAT in patients with oligoprogressive disease (progression at a limited number of anatomic sites). Methods: This is a prospective study of LAT in patients with oligoprogressive EGFR-mutant NSCLC. Patients with no prior EGFR-TKI therapy (cohort 1) or progression after 1st/2ndgeneration EGFR-TKIs with acquired T790M mutation (cohort 2) receive osimertinib. Upon progression, eligible patients with < = 5 progressing sites undergo LAT and resume osimertinib until disease progression. Patients previously treated with osimertinib qualifying for LAT upon disease progression are also eligible for treatment (cohort 3). Primary endpoint: evaluation of safety and efficacy of reinitiation of osimertinib after LAT (assessed by PFS). Additional goals are assessment of mechanisms of resistance to osimertinib by multi-omics analyses of tumor, blood, and saliva. Results: Between 04/2016 and 01/2017, 15 patients were enrolled (cohort 1: 9, cohort 2: 3, cohort 3: 3). Median age was 57 (range 36-71). Treatment was well tolerated. The most common adverse events (AEs) were rash, diarrhea, thrombocytopenia, and alanine transaminase elevation. Grade 3/4 AEs were observed in 4 (27%) patients. Among evaluable patients, objective response rates prior to LAT in cohorts 1 and 2 were 71% (5/7) and 100% (2/2), respectively, with 6.8 months median PFS (95% CI: 3.4 months-undefined) in cohort 1 and no progressions in cohort 2. To date, 5 patients (33%; cohort 1: 2; cohort 3: 3) had LAT. Two patients with 3 progressing sites underwent a combination of surgery and radiation. Three patients with 1 progressing site underwent surgery alone. Post-LAT PFS and results of molecular analyses will be presented. Conclusions: Patients with EGFR-mutant NSCLC and oligoprogression after EGFR-TKI therapy can be safely treated with LAT. In selected patients, this approach could potentially maximize duration of EGFR-TKI treatment and prevent premature switching to other systemic therapies. Clinical trial information: NCT02759835.

ctDNA resistance landscape of lazertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9601-9601
Author(s):  
Ji-Youn Han ◽  
Myung-Ju Ahn ◽  
Sang-We Kim ◽  
Ki Hyeong Lee ◽  
Eun Kyung Cho ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Resistance Mechanisms ◽  
Third Generation ◽  
Egfr Amplification ◽  
Phase 2 Trial ◽  
Egfr Mutant ◽  
Nsclc Patients ◽  
In Cis ◽  
Egfr Tki ◽  
Egfr Tkis

9601 Background: While EGFR mutant ( EGFRm) non-small cell lung cancer (NSCLC) patients usually experience improved clinical benefit with EGFR TKIs, most eventually progress. Understanding mechanisms of resistance (MoR) may allow for more personalized treatment. Lazertinib is an irreversible third generation EGFR TKI for which MoR are unknown. Obtaining sufficient tumor tissue for genotyping at progression is often difficult. Therefore, we utilized plasma ctDNA from patients treated with lazertinib to explore MoR. Methods: Plasma samples from 47 NSCLC patients in the phase 2 trial of lazertinib (NCT03046992) were collected at screening and progressive disease (PD) and underwent ctDNA NGS of 74 genes using Guarant360. All patients were positive for an EGFR Ex19del or L858R ( EGFRm) and T790M by tissue testing at screening. Acquired, nonsynonymous, characterized mutations detected in a PD sample but not in the screening sample from the respective patient were considered putative MoR, excluding aneuploidy. Patients with detectable plasma EGFRm and/or T790M at screening were evaluable. Results: ctDNA was detected in 47 (100%) screening samples and 43/45 (96%) PD samples (two failed sequencing). An EGFRm was detected in 85% of patients at screening (n = 40), 38 of which had PD ctDNA results and were included in analysis. T790M was detected in 30 patients at screening and subsequently not detected at PD in 21 of these patients, 55% of all 38 included patients. Among the ten patients with T790M detected at PD, on-target MoR were detected in 7 (18% of all included patients) including EGFR C797S (n = 3, 8%), EGFR amplification (n = 3, 8%), and EGFR T854A (n = 1, 3%). All C797S were in cis with T790M. No on-target MoR were detected in patients without T790M detected at PD. Off-target MoR were seen in 34% of patients (13/38) including mutations in PIK3CA (13%; 2 E545K, 2 E542K, 1 E81K), ERBB2 (5%; 1 D769H, 1 V777L), KRAS (3%; 1 G12C), and BRAF (3%; 1 G469A). Gene amplifications were detected in CCND1 (n = 1, 3%) , CCNE1 (n = 2, 5%) , ERBB2 (n = 1, 3%) , FGFR1 (n = 1, 3%) , MET (n = 4, 11%) , and PIK3CA (n = 1, 3%), with some patients having multiple MoR. Conclusions: The spectrum of MoR identified in this cohort of patients treated with lazertinib is similar to that reported in other third generation EGFR TKIs, but with some differences in frequencies. The most common resistance mechanisms are T790M loss and PIK3CA alterations which may address the mechanism of action. Our findings suggest putative MoR of lazertinib and show that ctDNA NGS is an effective way to identify MoR in patients progressing on targeted therapy. Clinical trial information: NCT03046992 .

scholarly journals Dynamic cfDNA Analysis by NGS in EGFR T790M-Positive Advanced NSCLC Patients Failed to the First-Generation EGFR-TKIs

2021 ◽  
Vol 11 ◽  
Author(s):  
Li Ma ◽  
Haoyang Li ◽  
Dongpo Wang ◽  
Ying Hu ◽  
Mengjun Yu ◽  
...  
Keyword(s):  
First Generation ◽  
Univariate Analysis ◽  
Third Generation ◽  
T790m Mutation ◽  
The Third ◽  
Tki Treatment ◽  
Nsclc Patients ◽  
Next Generation Sequencing Ngs ◽  
Egfr Tkis

PurposeCirculating cell-free DNA (cfDNA) level has been demonstrated to be associated with efficacy in first generation EGFR TKIs in non-small cell lung cancer (NSCLC). However, the role of dynamic cfDNA analysis using next-generation sequencing (NGS) in patients with subsequent third-generation EGFR TKIs remains unclear.MethodsFrom 2016 to 2019, 81 NSCLC patients with EGFR T790M mutation either in tissue or plasma who received third-generation EGFR TKIs treatment were enrolled. CfDNA were sequenced by NGS with a 425-gene panel. The association of clinical characteristics, pretreatment, dynamic cfDNA and T790M level with outcomes in patients treated with the third-generation TKIs were analyzed.ResultsIn univariate analysis, the median PFS of patients with undetectable cfDNA level during treatment was significantly longer than those with detectable cfDNA (16.97 vs. 6.10 months; HR 0.2109; P &lt; 0.0001). The median PFS of patients with undetectable T790M level during treatment was significantly longer than those with detectable T790M (14.1 vs. 4.4 months; HR 0.2192; P &lt; 0.001). Cox hazard proportion model showed that cfDNA clearance was an independent predictor for longer PFS (HR 0.3085; P &lt; 0.001) and longer OS (HR 0.499; P = 0.034). The most common resistant mutations of the third-generation TKIs were EGFR C797S (24%). CDK6 CNV, GRIN2A, BRCA2, EGFR D761N, EGFR Q791H, EGFR V843I, and ERBB4 mutation genes may possibly be new resistant mechanisms.ConclusionsPatients with undetectable cfDNA during the third-generation EGFR TKI treatment have superior clinical outcomes, and dynamic cfDNA analysis by NGS is valuable to explore potential resistant mechanisms.

Detecting T790M mutation of tissue and plasma ctDNA samples by ARMS in EGFR-mutant NSCLC patients after disease progression.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20625-e20625 ◽  
Author(s):  
Ya-Lan Wu ◽  
Rui-Zhan Tong ◽  
Yan Zhang ◽  
Bin-Bin Hu ◽  
Ke Zhen ◽  
...  
Keyword(s):  
Disease Progression ◽  
New Technologies ◽  
Clinical Care ◽  
Common Mechanism ◽  
T790m Mutation ◽  
Clinical Resistance ◽  
Positive Rate ◽  
Egfr Mutant ◽  
Egfr Tkis ◽  
Tissue Test

e20625 Background: T790M mutation is the most common mechanism of acquired EGFR TKI resistance. The use of T790M-targeted EGFR TKIs needs re-biopsy to confirm the existence of sensitive mutation. People wonder whether blood can replace tissue to diagnose acquired T790M mutation. Methods: We performed a prospective study in our institution (West China Hospital, Chengdu, China) between 2014 and 2016. Patients were eligible if they have advanced EGFR-mutant NSCLC, clinical resistance to EGFR TKIs, and were undergoing a re-biopsy for EGFR genotyping as part of their routine clinical care. We used ARMS to sequence EGFR of tissue and blood sample. Blood collection was performed within 2 weeks of the repeat biopsy. Measurement of diagnostic concordance among two different methods was done using cohen’s kappa, and the McNemar test used to judge significance. All statistical analysis was performed with the use of SPSS 20.0. Results: Forty-five patients were enrolled in this study. Thirty-eight patients received tissue test, thirty-one patients received plasma ctDNA test, and twenty-four patients received both tissue and plasma ctDNA tests. 26/38 (38.4%) reported positive T790M mutation by tissue test, and 13/31 (41.9%) by plasma ctDNA test. In 24 patients received both tissue and plasma ctDNA tests, 10/24 (41.7%) were concordant for T790M mutation status (κ = 0.006, p = 0.013). The positive rate of T790M mutation is 70.8% by tissue test, and 37.5% by plasma ctDNA test. In 17 patients reported positive T790M mutation by tissue test, 7/17 (41.2%) also reported positive T790M mutation by plasma ctDNA test, and 3 of the 7 positive ctDNA tests (42.9%) reported weakly positive T790M mutation. In the other 7 patients reported negative T790M mutation by tissue test, 2/7 (28.6%) reported positive T790M mutation by plasma ctDNA test. Conclusions: The positive rate of ARMS in our study is high than that of some reported new technologies. The level of plasma ctDNA was reported to relate to prognosis. Hence, plasma ctDNA cannot fully replace tissue to diagnose acquired T790M mutation after disease progression. It is important and significant to develop new technology to improve the safety of tissue biopsy.

Disease monitoring and TKI resistance mutations of EGFR mutation-positive NSCLC patients via circulating tumor DNA.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21627-e21627
Author(s):  
Corinna Woestmann ◽  
Christine Ju ◽  
Bernd Hinzmann ◽  
Stephanie J. Yaung ◽  
Michael Thomas ◽  
...  
Keyword(s):  
Disease Progression ◽  
Liquid Biopsy ◽  
Kinase Inhibitors ◽  
Outcome Data ◽  
Egfr Mutations ◽  
Driver Mutations ◽  
Plasma Samples ◽  
Resistance Mutations ◽  
T790m Mutation ◽  
Nsclc Patients

e21627 Background: 15–40% of NSCLC adenocarcinoma patients harbor EGFR sensitizing mutations. Tyrosine kinase inhibitors (TKI) provide significant clinical benefit in this population, yet all patients will develop resistance. Liquid biopsy has been demonstrated to reliably identify tumor associated somatic EGFR mutations. Quantitative assessment of mutated EGFR driven tumors could potentially be used to monitor disease progression, to assess therapeutic response, and to identify resistance mechanisms. Methods: 106 longitudinal plasma samples from 16 NSCLC patients who were treated with osimertinib as either first line or second line therapy were collected. A series of plasma samples collected during treatment and at the time of disease progression were analyzed with the AVENIO ctDNA Surveillance kit*. Mutations at each time point were identified and reported by the AVENIO software v2.0*. The mutation profile of each patient at different timepoints along with the treatment journey was examined in combination with clinical outcome data. Results: EGFR sensitizing mutations were detected in all plasma samples by sequencing except in 3 cases. Patients responsive to anti-EGFR therapy showed a rapid decrease of EGFR driver mutations to non-detectable levels. Meanwhile, patients who had stable disease or rapid disease progression had stable or slightly decreasing ctDNA levels after receiving the treatment. One patient had a MET amplification, FBXL7 SNV, and EGFR T790M detected at the time of disease progression which were not detected at baseline. One patient had both EGFR L858R and T790M mutations. This patient progressed very quickly on erlotinib. Detection of the T790M mutation decreased upon osimertinib administration, however, the L858R mutation level stayed the same. TP53 mutations were elevated in 3 patients at the time of progression, and could potentially be related to anti-EGFR resistance. Conclusions: This study clearly demonstrated that liquid biopsy could identify resistance mutations beyond EGFR prior to clinical progression. Plasma samples collected prior to or at disease progression could facilitate identification of novel resistant mutations to TKI therapy. Further studies to demonstrate the clinical utility of serial blood EGFR testing in NSCLC management are necessary. *For Research Use Only. Not for use in diagnostic procedures.

scholarly journals 172P: Antacid and de novo brain metastases in EGFR-mutant NSCLC patients treated with first-line, first-generation EGFR-TKIs

2016 ◽  
Vol 11 (4) ◽  
pp. S132
Author(s):  
Y.-M. Chen ◽  
M.-C. Lin ◽  
C.-H. Lai ◽  
W.-F. Fang ◽  
H.-C. Chang ◽  
...  
Keyword(s):  
Brain Metastases ◽  
First Generation ◽  
De Novo ◽  
First Line ◽  
Egfr Mutant ◽  
Nsclc Patients ◽  
Egfr Tkis

Non-invasive and quantitative analysis for EGFR T790M mutation in the patients with advanced non-small cell lung cancer received EGFR-TKI therapy.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19101-e19101
Author(s):  
Rui Chen ◽  
Tongtong An ◽  
Jie Wang ◽  
Hua Bai ◽  
Zhijie Wang ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Low Frequency ◽  
Digital Pcr ◽  
T790m Mutation ◽  
Frequency Group ◽  
Pre Treatment ◽  
Nsclc Patients ◽  
Wild Group ◽  
Egfr T790m ◽  
Egfr Tkis

e19101 Background: Approximately 50% of advanced non-small cell lung cancer (A-NSCLC) patients with EGFR sensitive mutation who develop acquired resistance to EGFR-TKIs reportedly have a secondary EGFR T790M mutation. Establishing a dynamical, quantitative and noninvasive detection system of EGFR T790M mutation in process of disease therapy for NSCLC is critical to personalized targeted therapy. Methods: 135 A-NSCLC patients with EGFR mutation who received EGFR-TKIs and presented acquired resistance (PFS≥6 months) were included into this study. All patients provided the plasma samples for molecular analysis when disease progressed. 109 patients of them had matched TKI-naive plasma. T790M mutation was measured qualitatively and quantitatively by ARMS and Digital PCR (DggPCR), respectively. Association of T790M mutation with clinical charateristics were evaluated. Results: DgPCR was more sensitive than ARMs to detect T790M mutation in plasma [pre-treatment 29.4% (32/109) VS 5.5% (6/109); post-treatment: 43.0% (58/135) VS 25.2% (34/135)]. 32 patients with pre-treatment T790M mutation predicted shorter PFS and OS compared with 77 T790 M negative patients (PFS, F 12.7 VS 9.2 months, P=0.004, GOS, F 27.0 VS 18.8 months, P=0.002). Patients with or without post-treatment T790M mutation have no significantly different PFS and OS. However, quantified the ratio of copy number of mutant T790M to wild-type by DgPCR, patients were divided into high-frequency groups (≥5%), low-frequency group (0%-5%) and wild-group (0%) according to the number of positive signals observed from DgPCR results. 12 patients in high-frequency group showed shorter PFS and OS compared with wild group and low-frequency group (PFS 9.5 VS 11.9 months, P=0.033, G9.5 VS 13.6 months, P=0.028, GOS, F 18.5 VS 21.2 months, P=0.044, 18.5 VS 28.8 months, P=0.001). Conclusions: Non-invisive and quantitative detection of T790m mutation by digital PCR is feasible in clinical practice. High contents of T790M when disease progression after EGFR-TKIs therapy predicted poor prognosis.

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