scholarly journals O13‐3: The ratio of T790M to EGFR‐activating mutation predicts response of osimertinib in 1st or 2nd generation EGFR‐TKI‐refractory NSCLC

Respirology ◽  
2021 ◽  
Vol 26 (S3) ◽  
pp. 36-36
Keyword(s):  
2Nd Generation ◽  
Activating Mutation ◽  
Egfr Tki

Antitumor activity of osimertinib in NSCLC harboring EGFR exon 20 insertions.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9030-9030 ◽  
Author(s):  
Jonathan Riess ◽  
Nicolas Floch ◽  
Matthew Martin ◽  
Jonathon Orme ◽  
Anna Staniszewska ◽  
...  
Keyword(s):  
Unmet Need ◽  
Tumor Growth Inhibition ◽  
Drug Discontinuation ◽  
Tumor Shrinkage ◽  
In Vivo Experiments ◽  
Activating Mutation ◽  
Exon 20 ◽  
Egfr Tki ◽  
Egfr Tkis

9030 Background: EGFR exon 20 insertions (Ex20Ins), the 3rd most common EGFR activating mutation, are generally unresponsive to 1st and 2nd generation EGFR-TKIs. Development of EGFR-TKIs that effectively target NSCLC with Ex20Ins mutations represents a major unmet need. Osimertinib is an EGFR TKI approved for the treatment of advanced NSCLC harboring EGFR T790M, but the potential of osimertinib remains to be fully assessed in patients (pts) with Ex20Ins NSCLC. Methods: CRISPR engineered Ex20Ins cell line xenografts representing the two most common Ex20Ins (D770_N771InsSVD and V769_D770InsASV) and pt derived xenograft (PDX) of 3 EGFR Ex20Ins (V769_D770InsASV, M766_A767insASV, H773_V774insNPH) were used for in vivo experiments. Xenografts were treated by oral gavage with vehicle, erlotinib (50 mg/kg/day) or afatinib (20 mg/kg/day), osimertinib metabolite AZ5104 (50 mg/kg/day) and osimertinib (25 mg/kg/day) and assessed for tumor growth inhibition (TGI). Immunoblotting was performed for EGFR and relevant signaling pathways. A pt from whom the V769_D770InsASV Ex20ins PDX was derived was treated on a UC Davis IRB approved protocol with osimertinib at 160 mg PO once-daily (QD). Results: At completion of treatment, QD administration of osimertinib or AZ5104 induced significant TGI in xenografts across the 4 EGFR Ex20ins tested (range 60-95% TGI, p < 0.001 compared to control for all models) that was superior to either afatinib or erlotinib. Robust decrease in p-EGFR, p-ERK, p-Akt, p-Stat3 was observed with osimertinib treatment. The patient corresponding to the V769_D770InsASV Ex20ins PDX treated with osimertinib exhibited clinical improvement and tumor shrinkage; unfortunately he was found to have interstitial pneumonitis that necessitated drug discontinuation. Conclusions: Osimertinib at clinically representative doses has in vivo activity across multiple EGFR Ex20ins that comprising the most common Ex20ins detected in patients (~50% prevalence); metabolite AZ5104 may contribute to efficacy. Tumor shrinkage was observed in a patient with lung cancer harboring an Ex20ins treated for a limited time with osimertinib. Based on this in vivo xenograft and pt data, osimertinib warrants further study in pts with EGFR Ex20ins NSCLC.

The predictive values of mutation patterns, concurrent mutations and efficacy of different generations of EGFR-TKIs in advanced non-small cell lung cancer harboring non-resistant uncommon EGFR mutations.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21612-e21612
Author(s):  
Pengbo Deng ◽  
Jiarong Tan ◽  
Chengping Hu ◽  
Liming Cao ◽  
Huaping Yang ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Egfr Mutations ◽  
Driver Mutations ◽  
Suppressor Genes ◽  
Predictive Values ◽  
2Nd Generation ◽  
Nsclc Patients ◽  
Egfr Tki ◽  
Egfr Tkis

e21612 Background: The efficacy of EGFR-TKIs in patients with non-resistant uncommon EGFR mutations is controversial. The predictive values of mutation patterns, the presence of concurrent mutations and the choice of different generations of EGFR-TKI have not been well elucidated. Methods: We retrospectively enrolled 190 NSCLC patients with non-resistant uncommon EGFR mutations, defined as mutations other than single L858R, 19del, T790M or 20ins. Among them, 72 were advanced/recurrent patients who received 1st (N = 55) or 2nd generation (N = 17) EGFR-TKIs as first-line therapy and with retrievable PFS data; therefore, were enrolled for subsequent survival analyses. Results: Patients were categorized according mutation patterns: group1 patients harboring EGFR uncommon mutation in combination with EGFR 19 del/L858R; group 2 patients harboring single or complex EGFR uncommon mutations. Our analyses revealed that the median PFS (mPFS) of group 1 was significantly longer than those in groups 2 (14.65months vs 8.05 months; P = 0.004). Next, we investigated whether the presence of concurrent mutations in tumor suppressor genes or oncogenes would affect PFS. The mPFS of patients with no concurrent mutation, patients with concurrent tumor-suppressor genes mutations and patients with concurrent oncogenic driver mutations were 13.57m, 8.05m and 16.92m, respectively (p = 0.04). Patients with no concurrent mutation had a significantly longer mPFS than patients with concurrent tumor-suppressor genes mutations (p = 0.013). Collectively, multivariate analysis revealed that patients receiving 2nd generation TKI (p = 0.006, HR:0.277,95%CI:0.112-0.688) and coexist with 19del/L858R (p < 0.001, HR: 0.148,95% CI:0.065-0.333) were independently associated with favorable PFS; while concurrent TP53 mutation was independently associated with worse PFS (p = 0.008, HR: 2.530,95% CI:1.270-5.042). Conclusions: Our study revealed NSCLC patients harboring non-resistant uncommon EGFR mutations in combination with 19del/L858R were associated with favorable PFS. The presence of concurrent tumor-suppressor genes mutations especially TP53 is associated with worse prognosis. Patients treated with 2nd generation EGFR-TKI showed a longer PFS than those treated with 1st generation TKI.

scholarly journals EP1.01-72 Treatment Outcome of 2nd Generation EGFR-TKI for Non-Small Cell Lung Cancer

2019 ◽  
Vol 14 (10) ◽  
pp. S939-S940
Author(s):  
T. Kondo ◽  
Y. Nakahara ◽  
R. Usui ◽  
S. Murakami ◽  
T. Kato ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Treatment Outcome ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
2Nd Generation ◽  
Egfr Tki

scholarly journals Ratio of T790M to EGFR-activating mutation predicts response of osimertinib in 1st or 2nd - generation EGFR-TKI-refractory NSCLC

2021 ◽  
Author(s):  
Motohiro Tamiya ◽  
Akihiro Tamiya ◽  
Norio Okamoto ◽  
Yoshihiko Taniguchi ◽  
Kazumi Nishino ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
T790m Mutation ◽  
Biopsy Tissue ◽  
Group Methods ◽  
Activating Mutation ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Epidermal Growth ◽  
Response Group ◽  
Egfr Tki

Abstract Background: Afatinib followed by osimertinib (Afa group) may reportedly provide better outcomes for T790M-positive non-small cell lung cancer (NSCLC) than 1st-generation (G) epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) (1st-G group). Methods: We studied 111 consecutive patients with T790M mutation-positive NSCLC who were treated with osimertinib after progression following 1st- or 2nd-G EGFR-TKI between March 28, 2016 and March 31, 2018. We analyzed T790M ratio with the re-biopsy tissue, obtained after EGFR-TKI resistance using droplet digital polymerase chain reaction, and investigate whether afatinib prifies the T790M mutation more than 1st-G EGFR-TKI.Results: Among the 60 patients with preserved re-biopsy tissues, we analyzed 38 patients whose re-biopsy tissue had adequate DNA content. Eleven patients in the Afa group had 81.8% of response rate, and 27 patients in the 1st-G group had 85.2% with RR. The mean T790M ratio was 0.3643. The T790M ratio in those with response of the osimertinib group was significantly higher than in those with non-response group (p=0.0272) and was similar in the Afa and 1st-G group (p=0.9693).Conclusion: T790M ratio significantly correlated with osimertinib response and T790M ratio was similar between the 1st and 2nd -G EGFR-TKIs in 1st or 2nd -G EGFR-TKI-refractory tumors.

scholarly journals P3.02b-064 Time to EGFR-TKI Treatment for Patients with Advanced NSCLC and EGFR Activating Mutation in a Tertiary Cancer Center

2017 ◽  
Vol 12 (1) ◽  
pp. S1229
Author(s):  
Jennifer Le Guévelou ◽  
Audrey Dugué ◽  
Nicolas Richard ◽  
Catherine Dubos ◽  
Pascal Dô ◽  
...  
Keyword(s):  
Advanced Nsclc ◽  
Cancer Center ◽  
Activating Mutation ◽  
Tki Treatment ◽  
Egfr Tki ◽  
Tertiary Cancer Center

scholarly journals Treatment (tx) patterns in patients (pts) with lung cancer starting 1st or 2nd generation (1G/2G) EGFR-TKI: A US insurance claims database analysis

2018 ◽  
Vol 29 ◽  
pp. ix156-ix157 ◽  
Author(s):  
J.E. Gray ◽  
B. Thakrar ◽  
P. Sun ◽  
S. Maclachlan ◽  
N. Chehab ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Insurance Claims ◽  
Database Analysis ◽  
Claims Database ◽  
2Nd Generation ◽  
Egfr Tki

Circulating tumor DNA profiling to reveal heterogeneity of EGFR-TKI resistance mechanisms in lung adenocarcinoma patients.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11527-11527
Author(s):  
Rongrong Chen ◽  
Jun Zhao ◽  
Xingsheng Hu ◽  
Pingping Dai ◽  
Yuting Yi ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Liquid Biopsy ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Single Nucleotide Variants ◽  
Molecular Abnormalities ◽  
Activating Mutation ◽  
Tki Resistance ◽  
Egfr Tki ◽  
Tumor Dna

11527 Background: EGFR-TKI therapy has significantly improved prognosis of NSCLC patients with EGFR sensitive mutation. However, almost all patients ultimately develop PD while receiving TKI treatment. Circulating tumor DNA (ctDNA) is promising as a minimally-invasive liquid biopsy for comprehensive analysis of molecular abnormalities. Methods: A total of 254 advanced lung adenocarcinoma patients with signs of EGFR-TKI resistance were enrolled in the study. ctDNA was analyzed using next-generation sequencing based ER-Seq method, which enables simultaneously assess single-nucleotide variants, insertions/deletions, rearrangements, and somatic copy-number alterations across 59 genes. Results: ctDNA profiling was possible for all patients, 172 patients had ≥ 1 ctDNA alteration(s). Median number of plasma somatic mutations was 2, predominantly located in EGFR and TP53, with MET, ERBB2 and PIK3CA followed. Of that, 30.6% of mutations detected in ctDNA were at a frequency below 1%. In exploring the mechanisms of TKI-resistance, we found TKI-sensitizing mutations were not detected in plasma of 138 patients (54.3%). Known mechanisms such as EGFR T790M/C797S mutation, activating mutations of PI3K- AKT- mTOR signaling, amplification of MET, activating mutation / amplification of ERBB2, activating mutation of KRAS, BRAF or mutations in EGFR EX20 other than T790M/C797S were identified in 59, 16, 8, 7, 3, 2, and 2 patients respectively. T790M/C797S was detected in 50.8% of patients with plasma positive for TKI-sensitizing mutations. Of note, C797S was only detected in patients treated with AZD9291. EGFR amplification were identified in 15 patients, though whether it would result in TKI-resistance was still controversial. Co-occurrence of resistance mechanisms were observed in 22 patients including 13 patients without TKI-sensitizing mutations. Conclusions: There was a high frequency of inter and intra-patient heterogeneity of resistance mechanisms after EGFR TKI therapy. ctDNA can be used as a ‘liquid biopsy’ to facilitate the broad exploration of potential resistance mechanisms.

TKI-Resistenzen beim EGFR-positiven NSCLC

2019 ◽  
Vol 10 (05) ◽  
pp. 216-216
Author(s):  
Susanne Krome
Keyword(s):  
Liquid Biopsy ◽  
Invasives Monitoring ◽  
Egfr Tki

EGFR-Tyrosinkinase-Inhibitoren (EGFR-TKI) haben zu einem Paradigmenwechsel in der Behandlungsstrategie für nicht-kleinzellige Bronchialkarzinome (NSCLC) geführt und gehören inzwischen zum Standard. Dabei ist es auch wichtig, primäre und erworbene Resistenzen zu überwinden. Eine aktuelle Studie mit 116 Patienten ergab unterschiedliche Resistenz-Mechanismen für TKI der 1./2. und der 3. Generation. Die Liquid Biopsy ist nach Ansicht der Autoren eine Option für ein nicht-invasives Monitoring der molekularen Veränderungen unter der EGFR-Therapie. Ein Review beschäftigte sich mit den Resistenzmechanismen und der Liquid Biopsy als Instrument für die Therapieplanung und -monitoring.

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