Response to osimertinib following treatment with EGF816 in patients with T790M EGFR mutant NSLCLC.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20673-e20673 ◽  
Author(s):  
Kathryn Cecilia Arbour ◽  
Lecia V. Sequist ◽  
Zofia Piotrowska ◽  
Mark G. Kris ◽  
Paul K. Paik ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Cross Resistance ◽  
Third Generation ◽  
Eligibility Criteria ◽  
T790m Mutation ◽  
Previously Treated ◽  
Egfr Mutant ◽  
Egfr Tki ◽  
Egfr T790m ◽  
Egfr Tkis

e20673 Background: Third generation (3rd gen) epidermal growth factor (EGFR) tyrosine kinase inhibitors (TKIs) have been developed to treat EGFR T790M-mediated resistance to EGFR TKIs by inhibiting EGFR T790M, as well as EGFR L858R and EGFR exon 19 deletions. The mechanisms of resistance to third-generation EGFR TKIs are largely unknown and clinical cross-resistance among 3rd gen EGFR TKIs has not been routinely evaluated. Osimertinib is an FDA-approved irreversible 3rd gen EGFR TKI. In patients with EGFR T790M mutant NSCLC, the response rate (ORR) to osimertinib is 61%. EGF816 is a covalent, irreversible, 3rd gen EGFR TKI in clinical development. In early phase data of EGF816, the ORR was 47% and disease control rate was 87% in patients with EGFR T790M mutant NSCLC. To assess clinical cross-resistance between EGF816 and osimertinib, we evaluated the clinical outcomes of patients treated with osimertinib in patients previously treated with EGF816 during the phase I/II trial. Methods: Patients with metastatic EGFR mutant lung adenocarcinoma were identified who were previously treated with EGF816 and received osimertinib after progression of disease on EGF816 (NCT02108964). All patients had documented T790M mutation prior to treatment with EGF816. The best overall response to osimertinib was determined by RECIST 1.1 criteria. Duration of clinical benefit was defined as duration of osimertinib therapy. Results: Fourteen (3 men, 11 women, median age 58 [range 33-77]) patients met eligibility criteria at our centers. The ORR to subsequent osimertinib therapy was 14% (1 CR, 1 PR, 8 SD, 4 POD). Patients continued treatment with osimertinib for a median of 9 months (95% CI 3.8-10.1, [median follow up 11 months, range 1-13 months]). 5 patients are still on osimertinib to date (one patient each 3+, 6+, 8+, 11+, and 12+ months). Conclusions: This series suggests a potentially meaningful clinical benefit for patients with sequential therapy with two different third-generation EGFR inhibitors, emphasizing the importance of understanding resistance mechanisms (genetic alteration of target, bypass signaling, pharmacology, etc.) and raising the possibility of the need for multiple third generation EGFR TKIs in clinical practice.

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 .

Preclinical antitumor activity of oral silibinin-meglumine in combination with erlotinib or gefitinib in the treatment of erlotinib- and gefitinib-resistant EGFR-mutant NSCLC mouse xenografts.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19003-e19003
Author(s):  
Joaquim Bosch-Barrera ◽  
Silvia Cufi ◽  
Alejandro Vazquez-Martin ◽  
Cristina Oliveras-Ferraros ◽  
Bruna Corominas-Faja ◽  
...  
Keyword(s):  
Single Agent ◽  
Water Soluble ◽  
Egfr Mutations ◽  
Soluble Form ◽  
Cross Resistance ◽  
Milk Thistle ◽  
T790m Mutation ◽  
Mesenchymal Transition ◽  
Egfr Mutant ◽  
Egfr T790m

e19003 Background: Silibinin (SLB), a bioactive flavonolignan isolated from the dried fruits of milk thistle (Silybum marianum), suppresses the resistance to erlotinib (ERL) caused by the EGFR T790M mutation in NSCLC xenograft models. Poor water solubility and low bioavailability might severely limit the efficacy of SLB. The ability of SLB to overcome ERL resistance attributed to mechanisms other than the second-site EGFR mutations remains completely unexplored. Methods: Using PC-9 cells harboring the ERL-sensitizing EGFR exon 19-mutation ΔE746-A750, we developed ERL-refractory derivatives (PC-9 ERL-R) that lacked EGFR T790M mutation. An oral formulation of milk thistle extract enriched (30%) with a water-soluble form of SLB complexed with the excipient amino-sugar meglumine (SLB-m) was explored for its ability to inhibit the growth of PC-9 ERL-R xenografts. Results: In the absence of second-site EGFR mutations or the alternative activation of MET or AXL, acquired cross-resistance to ERL and GEF correlated with enhanced epithelial-to-mesenchymal transition (EMT) features. Single-agent SLB-m significantly decreased the overall tumor volumes of PC-9 ERL-R xenografts, which exhibited enhanced engraftment and faster growth compared with the ERL-/GEF-sensitive PC-9 parental xenografts. Combination treatment with ERL + SLB-m or GEF + SLB-m significantly suppressed tumor growth (> 90%) compared with single-agent treatment. The SLB-m treatment fully inhibited the development of an EMT phenotype in the ERL-/GEF-refractory cells in vitro. Systemic SLB-m treatment significantly affected the expression of EMT-related transcription factors in the ERL-/GEF-refractory xenografts. Conclusions: The oral administration of SLB-m delays tumor progression in ERL-/GEF-refractory EGFR-mutant NSCLC mouse xenografts. Given that the EMT phenomenon is required by a multiplicity of mechanisms of acquired resistance mechanisms to ERL, our data might facilitate the design of clinical trials to test the administration of SLB-m in combination with ERL or GEF in patients with EGFR-mutated tumors that progress to these drugs.

scholarly journals Genomic Profiling Identifies Outcome-Relevant Mechanisms of Innate and Acquired Resistance to Third-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy in Lung Cancer

2019 ◽  
pp. 1-14 ◽  
Author(s):  
Sebastian Michels ◽  
Carina Heydt ◽  
Bianca van Veggel ◽  
Barbara Deschler-Baier ◽  
Nuria Pardo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Third Generation ◽  
Met Amplification ◽  
Epidermal Growth ◽  
Tki Treatment ◽  
Egfr Mutant ◽  
Egfr Tki ◽  
Egfr Tkis

PURPOSE Third-generation epidermal growth factor receptor ( EGFR) tyrosine kinase inhibitors (TKIs) are effective in acquired resistance (AR) to early-generation EGFR TKIs in EGFR-mutant lung cancer. However, efficacy is marked by interindividual heterogeneity. We present the molecular profiles of pretreatment and post-treatment samples from patients treated with third-generation EGFR TKIs and their impact on treatment outcomes. METHODS Using the databases of two lung cancer networks and two lung cancer centers, we molecularly characterized 124 patients with EGFR p.T790M-positive AR to early-generation EGFR TKIs. In 56 patients, correlative analyses of third-generation EGFR TKI treatment outcomes and molecular characteristics were feasible. In addition, matched post-treatment biopsy samples were collected for 29 patients with progression to third-generation EGFR TKIs. RESULTS Co-occurring genetic aberrations were found in 74.4% of EGFR p.T790-positive samples (n = 124). Mutations in TP53 were the most frequent aberrations detected (44.5%; n = 53) and had no significant impact on third-generation EGFR TKI treatment. Mesenchymal-epithelial transition factor ( MET) amplifications were found in 5% of samples (n = 6) and reduced efficacy of third-generation EGFR TKIs significantly (eg, median progression-free survival, 1.0 months; 95% CI, 0.37 to 1.72 v 8.2 months; 95% CI, 1.69 to 14.77 months; P ≤ .001). Genetic changes in the 29 samples with AR to third-generation EGFR TKIs were found in EGFR (eg, p.T790M loss, acquisition of p.C797S or p.G724S) or in other genes (eg, MET amplification, KRAS mutations). CONCLUSION Additional genetic aberrations are frequent in EGFR-mutant lung cancer and may mediate innate and AR to third-generation EGFR TKIs. MET amplification was strongly associated with primary treatment failure and was a common mechanism of AR to third-generation EGFR TKIs. Thus, combining EGFR inhibitors with TKIs targeting common mechanisms of resistance may delay AR.

A phase I dose-escalation study of the HSP90 inhibitor AUY922 and erlotinib for patients with EGFR-mutant lung cancer with acquired resistance (AR) to EGFR tyrosine kinase inhibitors (EGFR TKIs).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3083-3083 ◽  
Author(s):  
Melissa Lynne Johnson ◽  
Helena Alexandra Yu ◽  
Eric M Hart ◽  
Rebekah Worden ◽  
Alfred Rademaker ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase I ◽  
Dose Escalation ◽  
Hsp90 Inhibitor ◽  
Study Entry ◽  
Dose Escalation Study ◽  
Egfr Mutant ◽  
Egfr Tki ◽  
Egfr T790m ◽  
Egfr Tkis

3083 Background: AUY922 is a highly potent, non-geldanamycin analog, HSP90 inhibitor that degrades mutated EGFR and MET. Preclinical studies demonstrate that HSP90 inhibitors have anti-tumor activity in EGFR mutant, EGFR TKI-sensitive and TKI-resistant lung cancer xenograft models. To prevent disease flare after stopping EGFR TKIs in patients (pts) with EGFR mutated lung cancer, erlotinib (E) is often continued with subsequent lines of treatment for AR. This phase I study will determine the maximally tolerated dose (MTD) of AUY922 and E for pts with mutated EGFR and RECIST progression on EGFR TKIs. Methods: All pts have EGFR mutant lung cancer, with development of AR (per Jackman, JCO 2010) after treatment with an EGFR TKI. Pts underwent repeat tumor biopsies after development of AR and prior to study entry. Pts receive AUY922 IV weekly and E oral daily in 28-day cycles, with dose escalation using standard 3+3 design. Pharmacokinetics, serial ophthalmology evaluations and weekly assessment for toxicity are required. Tumor tissue from re-biopsy at study entry is analyzed for EGFR T790M and MET. Results: Since April 2011, 11 pts have been enrolled, in 4 of 5 planned cohorts (AUY922 25 mg/m2 + E 75 mg; AUY922 25 mg/m2+ E 150 mg; AUY922 37.5 mg/m2+ E 150 mg; AUY922 55 mg/m2+E 150 mg). Prior to developing AR, pts were treated with EGFR TKIs for a median of 9 months (range 8-32). Of 9 pts with tissue analyzed thus far, 6 had EGFR T790M. Pts have received a median of two cycles (range 1-7), and 5 remain on study. There have been no dose-limiting toxicities. Adverse events reported in ≥ 20% of pts were diarrhea, nausea, vomiting, fatigue, and rash, all graded 1 or 2. No cardiovascular, renal or hepatic toxicities have been observed. Three pts have reported “flashing lights” and 2 pts transient night blindness, all grade 1. Dose escalation continues. No partial responses have been seen in 6 evaluable pts, 4 patients have confirmed stable disease at 8 wks. Conclusions: AUY922 and E is a well-tolerated combination at dose levels up to AUY922 55 mg/m2+ E 150 mg. Further dose-escalation, MTD, and correlation with markers of AR will be reported. Supported by Novartis, Inc.

scholarly journals CM93, a novel covalent small molecule inhibitor targeting lung cancer with mutant EGFR

2020 ◽  
Author(s):  
Qiwei Wang ◽  
Jing Ni ◽  
Tao Jiang ◽  
Hwan Geun Choi ◽  
Tinghu Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastases ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Third Generation ◽  
T790m Mutation ◽  
Activating Mutations ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Egfr Mutant ◽  
Egfr Tki

AbstractEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have provided successful targeted therapies for patients with EGFR-mutant non-small-cell lung cancer (NSCLC). Osimertinib (AZD9291) is a third-generation irreversible EGFR TKI that has received regulatory approval for overcoming resistance mediated by the EGFR T790M mutation as well as a first-line treatment targeting EGFR activating mutations. However, a significant fraction of patients cannot tolerate the adverse effect associated with AZD9291. In addition, brain metastases are common in patients with NSCLN and remain a major clinical challenge. Here, we report the development of a novel third-generation EGFR TKI, CM93. Compared to AZD9291, CM93 exhibits improved lung cancer targeting and brain penetration and has demonstrated promising antitumor efficacy in mouse models of both EGFR-mutant NSCLC orthotopic and brain metastases. In addition, we find that CM93 confers superior safety benefits in mice. Our results demonstrate that further evaluations of CM93 in clinical studies for patients with EGFR-mutant NSCLC and brain metastases are warranted.

scholarly journals Anlotinib can overcome acquired resistance to EGFR-TKIs via FGFR1 signalling in non-small cell lung cancer without harboring EGFR T790M mutation

2020 ◽  
Author(s):  
Zengzhi Lian ◽  
Wenwen Du ◽  
Yang Zhang ◽  
Yulong Fu ◽  
Ting Liu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Acquired Resistance ◽  
Xenograft Model ◽  
T790m Mutation ◽  
Mouse Xenograft ◽  
Cycle Arrest ◽  
Mouse Xenograft Model ◽  
Egfr Tki ◽  
Egfr T790m ◽  
Egfr Tkis

Abstract Background Although many studies have defined mechanisms of resistance to EGFR-TKIs, acquired resistance remains the major limitation of monotherapy with EGFR-TKIs. Therefore, there is an urgent need to develop effective therapeutic interventions to overcome acquired resistance. Methods Cell viability was analysed using CCK‐8 assay. EGFR T790M mutation was sequenced on a HiSeq 4000 platform. mRNA from HCC827 and HCC827 gefitinib-resistant (GR) cells was analysed by genome analyser-based deep sequencing. The effect of anlotinib on apoptosis and cell cycle arrest of HCC827 GR was detected by fluorescence-activated cell sorting (FACS) analysis. A mouse xenograft model was used to assess the killing effect of anlotinib on HCC827 GR cells. Results Here we found the T790M mutation in the PC-9 gefitinib-resistant (GR) cell line but not in the HCC827 GR cell line. Interestingly, anlotinib could suppress the growth of HCC827 GR cells by inhibiting FGFR1 in vitro and in a mouse xenograft model. Moreover, FGFR1 was overexpressed in HCC827 GR cells, and the knockdown of FGFR1 reversed gefitinib resistance in HCC827 GR cells. Furthermore, anlotinib induced apoptosis and cell cycle arrest in HCC827 GR cells by increasing the activity of Caspase-3 and decreasing the expression of Cyclin D1. Conclusion FGFR1 overexpression is one of the mechanisms of EGFR-TKI acquired resistance and anlotinib can suppresses the growth of EGFR-TKI-resistant NSCLC cells without T790M mutation.

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.

scholarly journals Next-generation sequencing of tissue and circulating tumor DNA: Resistance mechanisms to EGFR targeted therapy in a cohort of patients with advanced non-small cell lung cancer

2020 ◽  
Author(s):  
Yujun Zhang ◽  
Liwen Xiong ◽  
Fangfang Xie ◽  
Xiaoxuan Zheng ◽  
Ying Li ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Genetic Alterations ◽  
Third Generation ◽  
T790m Mutation ◽  
Epidermal Growth ◽  
Tki Treatment ◽  
Egfr Tki ◽  
Egfr Tkis

Abstract Background Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) has been considered as an effective treatment in epidermal growth factor receptor-mutant (EGFR-mutant) advanced non-small cell lung cancer (NSCLC). However, most patients develop acquired resistance eventually. Here, we compared and analyzed the genetic alterations between tissue assay and circulating tumor DNA (ctDNA), and further explored the resistance mechanisms after EGFR-TKI treatment. Methods Amplification refractory mutation system-polymerase chain reaction (ARMS-PCR), Cobas® ARMS-PCR and next-generation sequencing (NGS) were performed on tissue samples after pathological diagnosis. Digital droplet PCR (ddPCR) and NGS were performed on plasma samples. The association between genetic alterations and clinical outcomes was analyzed retrospectively. Results Thirty-seven patients were included. The success rate of re-biopsy was 91.89% (34/37). The total detection rate of EGFR T790M was 62.16% (23/37) and the consistency between tissue and ctDNA was 78.26% (18/23). Thirty-four patients were analyzed retrospectively. Twenty-four patients harbored concomitant mutations. Moreover, tissue re-biopsy at resistance showed 21 patients (21/34, 61.76%) had concomitant T790M mutation, 4 with MET amplification and 4 with PIK3CA mutation. Patients with T790M mutation (p = 0.010 & p = 0.017) or third-generation EGFR-TKI treatment (p < 0.0001 & p = 0.073) showed better progression-free survival (PFS) and overall survival (OS). Interestingly, concomitant genetic alterations were significantly associated with a worse prognosis for patients with T790M mutation receiving third-generation EGFR-TKIs (p = 0.037). Conclusions Multi-platforms are feasible and highly consistent for re-biopsy after EGFR-TKI resistance. Concomitant genetic alterations may be associated with a poor prognosis for patients with T790M mutation after third-generation EGFR-TKIs. Trial Registration: The clinical trial registration was carried out on ClinicalTrials.gov. (NCT03309462), registered on September 1st 2017. https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S0007G1B&selectaction=Edit&uid=U0001WUU&ts=2&cx=frpicv

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