Clinical Utility of Liquid Biopsy for EGFR Driver, T790M Mutation and EGFR Amplification in Plasma in Patients with Aacquired Resistance to Afatinib

Abstract Background: Cell-free DNA (cfDNA) genotyping in plasma using the cobas EGFR Mutation Test v2 (cobas) is the first liquid biopsy as a companion diagnosis to identify the EGFR T790M mutation (T790M) after the failure of treatment of EGFR-tyrosine kinase inhibitor (TKI) (1st generation, gefitinib [G] and erlotinib [E] and afatinib [A]). This study investigated the clinical utility of a liquid biopsy for patients who acquired resistance to afatinib.Methods: We prospectively collected plasma from 51 patients who had acquired resistance to afatinib between April 2015 and November 2016 to evaluate the frequency of T790M using the cobas and digital droplet PCR (UMIN000025112). Additionally, we retrospectively reviewed 38 patients who tested by cobas in plasma after G/E failure to compare for T790M detection between A and with G/E.Results: The detection rate of EGFR sensitive mutation (EGFR sens.) and T790M in plasma in patients treated with A (A group) as an initial EGFR-TKI was lower than with G/E followed by A (G/E→A), although the differences were not significant (EGFR sens.: 41% (A) vs. 67% (G/E→A), P=0.1867; and T790M: 8% (A) vs. 17% (G/E→A), P=0.5798). In first-line setting, the detection rate for EGFR-sens. and T790M in plasma by cobas was lower in A group than in G/E group, although there was no significant difference (EGFR sens.: 34% (A) vs. 52% (G/E), P=0.2072; and T790M: 10% (A) vs. 27% (G/E), P=0.1161).Conclusion: The detection of EGFR sens. and T790M in plasma by cobas might be insufficient in patients treated with afatinib than with G/E.

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Clinical utility of liquid biopsy for EGFR driver, T790M mutation and EGFR amplification in plasma in patients with acquired resistance to afatinib

10.21203/rs.3.rs-53232/v2 ◽

2020 ◽

Author(s):

Yuko Oya ◽

Tatsuya Yoshida ◽

Kazuhiro Asada ◽

Tetsuya Oguri ◽

Naoki Inui ◽

...

Keyword(s):

Liquid Biopsy ◽

Clinical Utility ◽

Detection Rate ◽

Kinase Inhibitors ◽

Acquired Resistance ◽

First Line ◽

T790m Mutation ◽

Significant Difference ◽

Droplet Pcr ◽

Line Setting

Abstract Background: Cell-free DNA (cfDNA) genotyping in plasma using the cobas EGFR Mutation Test v2 (cobas) is the first liquid biopsy as a companion diagnosis to identify the EGFR T790M mutation (T790M) after the failure of treatment of EGFR-tyrosine kinase inhibitors (TKIs) (1st generation, gefitinib [G] and erlotinib [E] and 2nd generation, afatinib [A]). This study investigated the clinical utility of a liquid biopsy for patients who acquired resistance to afatinib.Methods: We prospectively collected plasma from 51 patients who had acquired resistance to afatinib between April 2015 and November 2016 to evaluate the frequency of T790M by cobas and digital droplet PCR (UMIN000025112). Additionally, we retrospectively reviewed 38 patients who tested by cobas in plasma after G/E failure to compare for T790M detection between A and with G/E.Results: The detection rate of EGFR-driver and T790M in plasma in patients treated with A (A group) as a first-line EGFR-TKI was lower than with G/E followed by A (G/E→A group), although the differences were not significant (EGFR-driver: 41% [A] vs. 67% [G/E→A], P=0.1867; and T790M: 8% [A] vs. 17% [G/E→A], P=0.5798). In first-line setting, the detection rate for EGFR-driver and T790M in plasma by cobas was lower in A group than in G/E group, although there was no significant difference (EGFR-driver: 34% [A] vs. 52% [G/E], P=0.2072; and T790M: 10% [A] vs. 27% [G/E], P=0.1161).Conclusion: The detection of EGFR-driver and T790M in plasma by cobas in patients treated with afatinib might be lower than with G/E in a real-world setting.

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Clinical utility of liquid biopsy for EGFR driver, T790M mutation and EGFR amplification in plasma in patients with acquired resistance to afatinib

BMC Cancer ◽

10.1186/s12885-020-07777-2 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yuko Oya ◽

Tatsuya Yoshida ◽

Kazuhiro Asada ◽

Tetsuya Oguri ◽

Naoki Inui ◽

...

Keyword(s):

Liquid Biopsy ◽

Clinical Utility ◽

Detection Rate ◽

Kinase Inhibitors ◽

Acquired Resistance ◽

First Line ◽

T790m Mutation ◽

Significant Difference ◽

Droplet Pcr ◽

Line Setting

Abstract Background Cell-free DNA (cfDNA) genotyping in plasma using the cobas EGFR Mutation Test v2 (cobas) is the first liquid biopsy as a companion diagnosis to identify the EGFR T790M mutation (T790M) after the failure of treatment of EGFR-tyrosine kinase inhibitors (TKIs) (1st generation, gefitinib [G] and erlotinib [E] and 2nd generation, afatinib [A]). This study investigated the clinical utility of a liquid biopsy for patients who acquired resistance to afatinib. Methods We prospectively collected plasma from 51 patients who had acquired resistance to afatinib between April 2015 and November 2016 to evaluate the frequency of T790M by cobas and digital droplet PCR (UMIN000025112). Additionally, we retrospectively reviewed 38 patients who tested by cobas in plasma after G/E failure to compare for T790M detection between A and with G/E. Results The detection rate of EGFR-driver and T790M in plasma in patients treated with A (A group) as a first-line EGFR-TKI was lower than with G/E followed by A (G/E→A group), although the differences were not significant (EGFR-driver: 41% [A] vs. 67% [G/E→A], P=0.1867; and T790M: 8% [A] vs. 17% [G/E→A], P=0.5798). In first-line setting, the detection rate for EGFR-driver and T790M in plasma by cobas was lower in A group than in G/E group, although there was no significant difference (EGFR-driver: 34% [A] vs. 52% [G/E], P=0.2072; and T790M: 10% [A] vs. 27% [G/E], P=0.1161). Conclusion The detection of EGFR-driver and T790M in plasma by cobas in patients treated with afatinib might be lower than with G/E in a real-world setting.

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Triple Trouble: A Case of Multiple Resistance Mechanisms after First Generation EGFR-TKI in NSCLC

Case Reports in Oncology ◽

10.1159/000502214 ◽

2019 ◽

Vol 12 (2) ◽

pp. 625-630 ◽

Cited By ~ 2

Author(s):

Mike Ralki ◽

Brigitte Maes ◽

Karin Pat ◽

Jokke Wynants ◽

Kristof Cuppens

Keyword(s):

Kinase Inhibitor ◽

Acquired Resistance ◽

Growth Factor Receptor ◽

Standard Of Care ◽

Resistance Mechanisms ◽

First Line ◽

T790m Mutation ◽

Her2 Mutation ◽

Egfr Mutant ◽

Egfr Tki

Epidermal growth factor receptor (EGFR)-targeted therapy has become standard of care in advanced stages EGFR-mutant non-small cell lung cancer. Acquired resistance to first-line EGFR-tyrosine kinase inhibitor (TKI) and subsequent disease progression is a common problem and mostly due to a secondary mutation (T790M) in EGFR. We report a case of a patient with EGFR-mutated lung adenocarcinoma who developed a complex resistance profile: T790M mutation, HER2 mutation and HER2 amplification after first-line EGFR-TKI. This patient was safely treated with a combination of osimertinib and trastuzumab and achieved a clinically meaningful and clear molecular response.This is the first reported case of acquired resistance to first-line EGFR-TKI based on three resistance mechanisms, treated with molecular targeted combination therapy.

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KRAS mutational status and sensitivity to a reversible epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in EGFR wild type (WT) advanced non-small cell lung cancer (NSCLC) patients (pts).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e18023 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e18023-e18023

Author(s):

Giulio Metro ◽

Simona Duranti ◽

Rita Chiari ◽

Chiara Bennati ◽

Carmen Molica ◽

...

Keyword(s):

Advanced Nsclc ◽

Kinase Inhibitor ◽

Growth Factor Receptor ◽

Progression Free Survival ◽

Distinct Subgroup ◽

Mutational Status ◽

Significant Difference ◽

Never Smokers ◽

Line Setting ◽

Egfr Tki

e18023 Background: Treatment with a reversible EGFR-TKI may benefit pts with EGFR WT advanced NSCLC, though to a much lesser extent than pts carrying an activating mutation in the EGFR gene. We assessed whether KRAS mutational status would help predict sensitivity to gefitinib or erlotinib in EGFR WT advanced NSCLC pts. Methods: Sixty-seven EGFR WT, advanced NSCLC pts treated with a reversible EGFR-TKI in any line setting were included. Pts were treated from May 2005 to March 2011 at the Medical Oncology of the Perugia Hospital. EGFR (exons 18 to 21) and KRAS (codons 12, 13 and 61) genes were amplified by nested PCR and sequenced in both sense and antisense directions. Results: Median age was 60 years (39-84); 52 pts (77.6%) were PS 0 or 1; 58 pts (86.6%) belonged to the non-squamous subtype and 22 pts (32.8%) were never-smokers. Eighteen pts (26.8%) were KRAS mutant (MUT), of which 14 pts at codon 12 (COD 12 MUT) and 4 pts at codon 13 (COD 13 MUT). Overall, 11 pts (16.4%) responded to treatment and 8 pts (11.9%) achieved stable disease, for a disease control rate of 28.3%. At a median follow-up of 25.2 months, median progression-free survival (PFS) and overall survival (OS) were 2.9 and 29.5 months, respectively. When analyzed according to KRAS status, a significantly shorter PFS was noted for the EGFR WT/KRAS MUT subgroup (N=18) compared with the EGFR WT/KRAS WT population (N=49) (1.6 vs. 3.0 months, respectively, p=0.04). However, no significant difference was observed between the two groups in terms of OS (18.0 vs. 34.8 months, respectively, p=0.42). Within the EGFR WT/KRAS MUT subrgoup a significantly longer PFS was reported for COD 12 MUT pts compared with COD 13 MUT pts (1.7 vs 0.7 months, respectively, p=0.04). Similarly, KRAS COD 12 MUT pts experienced a statistically significant superior OS compared with COD 13 MUT pts (36.2 vs 7.4 months, respectively, p=0.003). Conclusions: EGFR WT/KRAS MUT pts appear to be more resistant to treatment with a reversible EGFR-TKI, the greatest resistance occurring in COD 13 MUT pts. KRAS COD 12 MUT pts may represent a clinically distinct subgroup of KRAS mutants with a particularly favorable prognosis.

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Anlotinib Hydrochloride Combined With EGFR-Tyrosine Kinase Inhibitor (TKI) in Treating Advanced NSCLC Patients With Acquired Resistance to EGFR-TKI

Case Medical Research ◽

10.31525/ct1-nct04007835 ◽

2019 ◽

Author(s):

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Advanced Nsclc ◽

Kinase Inhibitor ◽

Acquired Resistance ◽

Egfr Tyrosine Kinase Inhibitor ◽

Egfr Tyrosine Kinase ◽

Nsclc Patients ◽

Egfr Tki

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P34.06 The Clinical Utility of Liquid Biopsy by Digital Droplet PCR in Patients with Advanced NSCLC

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2021.01.697 ◽

2021 ◽

Vol 16 (3) ◽

pp. S417

Author(s):

V. Lamberts ◽

M. Aldea ◽

L. Mezquita ◽

C. Jovelet ◽

D. Vasseur ◽

...

Keyword(s):

Liquid Biopsy ◽

Clinical Utility ◽

Advanced Nsclc ◽

Digital Droplet Pcr ◽

Droplet Pcr

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Efficacy of gefitinib combined with bevacizumab versus gefitinib in advanced EGFR L858R NSCLC.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e21185 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e21185-e21185

Author(s):

Xinmin Zhao ◽

Xianghua Wu ◽

Huijie Wang ◽

Hui Yu ◽

Si Sun ◽

...

Keyword(s):

Liquid Biopsy ◽

Therapeutic Option ◽

Objective Response ◽

Acquired Resistance ◽

Response To Treatment ◽

Control Group ◽

Special Cases ◽

Significant Difference ◽

Experimental Group ◽

Egfr Tkis

e21185 Background: 60-80% of EGFR+ NSCLC could benefit from the treatment of EGFR TKIs. However, as a result of acquired resistance, median progression-free survival (PFS) associated with EGFR-TKIs monotherapy was rarely longer than 11 months. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) play an important role in the angiogenesis and progression of NSCLC. The combination of EGFR-TKIs and anti-vascular drugs that inhibit the EGFR and VEGF/VEGFR pathways may be a potential therapeutic option for EGFR-mutant NSCLC. The purpose of our study was to evaluate whether gefitinib combined with bevacizumab is associated with an increased PFS benefit compared with gefitinib alone. Methods: This study is a randomized, open-controlled, single-center study. A total of 43 advanced non-squamous NSCLC patients with EGFR L858R mutations were enrolled, including 24 in the experimental group and 19 in the control group. The experimental group received gefitinib combined with bevacizumab (gefitinib 250 mg, QD+bevacizumab 7.5 mg/kg, Q3W), and the control group received gefitinib monotherapy (250 mg, QD). Response to treatment was evaluated after one month of the treatment, followed by once every two months, and adverse events were graded. The primary endpoint was PFS, and secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DOR), overall survival (OS), and safety and tolerability evaluation. Samples at baseline (tissue or liquid biopsy), 43 days after treatment (liquid biopsy), and disease progression were subjected to genomic (139-gene NGS panel) profiling. Results: As of December 31, 2020, 22 patients were evaluable (12 for experimental group, 10 for control group). The ORR of the experimental group and the control group were 42% vs 60%, respectively, with no significant difference (experimental group: CR = 0, PR = 5, SD = 7, PD = 0; control group: CR = 0, PR = 6, SD = 4, PD = 0). Main adverse reactions included skin rash (n = 16), diarrhea (n = 24), hypertension (n = 2), proteinuria (n = 1). Other special cases developed fever, nausea and vomiting, elevated platelets, conjunctivitis, back pain, which were manageable. 36 patients with baseline liquid biopsy samples can be evaluated (33 plasma and 3 pleural fluid samples). Of these, EGFR L858R were detectable in 86% (n = 31) of patients. The most common co-mutated gene was TP53 (57%), followed by DNMT3A (49%) and TET2 (17%). Mutation profiles were comparable between the two groups. Conclusions: Compared to gefitinib monotherapy, gefitinib combined with bevacizumab in the treatment of non-squamous NSCLC with EGFR L858R showed similar efficacy and safety profiles.

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Efficacy and Acquired Resistance of EGFR-TKI Combined with Chemotherapy as First-Line Treatment for Chinese Patients with Advanced Non-Small Cell Lung Cancer in a Real-world Setting

10.21203/rs.3.rs-121107/v1 ◽

2020 ◽

Author(s):

Qianqian Wang ◽

Wen Gao ◽

Fangyan Gao ◽

Shidai Jin ◽

Tianyu Qu ◽

...

Keyword(s):

Egfr Mutation ◽

Advanced Nsclc ◽

Acquired Resistance ◽

Small Cell ◽

Combination Group ◽

Monotherapy Group ◽

Small Cell Lung ◽

T790m Mutation ◽

Nsclc Patients ◽

Egfr Tki

Abstract Background To compare the benefits and explore the cause of acquired resistance of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and its combination with chemotherapy in advanced non-small-cell lung cancer (NSCLC) patients harboring EGFR mutation in a real-life setting.Methods This retrospective analysis included 117 advanced NSCLC patients with EGFR mutation who underwent next-generation sequencing (NGS) prior to treatment. The combination group included 50 patients who received the regimen of EGFR-TKI combined with chemotherapy, while the EGFR-TKI monotherapy group included 67 patients treated with TKI only. The primary endpoint of this study was progression-free survival (PFS); the secondary endpoints were overall survival (OS), response rate, and toxicity.Results The median PFS was significantly longer in the combination group than in the EGFR-TKI monotherapy group (19.00 months [95% CI, 14.674-23.326] vs. 11.70 months [95% CI, 10.807-12.593], p = 0.000). Subgroup analysis showed a similar trend of results. The median OS was not reached in the combination group and was 38.50 (95% CI, 35.300-41.700) months in the EGFR-TKI monotherapy group (p = 0.586). Patients in the combination group were more likely to experience adverse events, most of which showed the severity of grade 1 or 2. T790M mutation remains the main reason for acquired resistance, and the frequency of T790M mutation was similar between the two groups (p = 0.898). Conclusions Compared with EGFR-TKI monotherapy, EGFR-TKI combined with chemotherapy significantly improved PFS in advanced NSCLC patients with EGFR mutation, with acceptable toxicity.

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