Noninvasive detection of acquired T790M mutation in NSCLC patients treated with EGFR-TKI using digital PCR of plasma

TPS9104 Background: EGFR T790M mutation occurs in approximately 50-60% of non-small cell lung cancer adenocarcinoma (NSCLC) patients with acquired EGFR-TKI resistance, based on tumor re-biopsies using an invasive clinical procedure. Recently, Cell free tumor DNA (ctDNA) has emerged as a specific and sensitive blood-based biomarker and studies have demonstrated ctDNA as a feasible and minimally invasive alternative to tissue biopsy. Data on different technology platforms used for EGFR T790M detection in blood in China is limited. We aim to compare the methods currently available in hospital practise, including cobas EGFR Mutation Test (Roche Molecular Systems), super-ARMS, digital PCR and NGS, to compare each platform and clinically validate each as companion diagnostic to osimertinib. Methods: This is an open-label, multi-center study in 250 locally advanced or metastatic NSCLC patients with documented EGFR sensitizing mutation and progression on previous EGFR-TKI. T790M mutation in plasma ctDNA will be tested by four methods: cobas, super-ARMS, digital PCR and NGS in order to evaluate the concordance, sensitivity and specificity of T790M testing in plasma between the cobas test and the other platforms. T790M positive patients by any of the four platforms will receive osimertinib treatment (administered orally as one 80 mg tablet once a day in ASTRIS study, NCT02474355) and the clinical outcomes (PFS, ORR, OS) will be followed. Patients will continue to receive osimertinib until disease progression (PD), as assessed by investigators. Digital PCR and NGS will be used to monitor the molecular evolution of T790M and C797S in plasma from NSCLC patients during osimertinib treatment. NGS will also be used to explore acquired resistance mechanisms before osimertinib treatment and after PD. 23 of planned 250 patients have been enrolled in the study as of January 2017. Clinical trial information: NCT02997501.

Download Full-text

Next-generation sequencing results of brain metastasis in NSCLC patients with acquired EGFR-TKI resistance other than T790M mutation

European Journal of Cancer ◽

10.1016/s0959-8049(16)32815-5 ◽

2016 ◽

Vol 69 ◽

pp. S74-S75

Author(s):

H.Y. Lee ◽

J.H. Kang ◽

J.O. Kim

Keyword(s):

Next Generation Sequencing ◽

Brain Metastasis ◽

Next Generation ◽

T790m Mutation ◽

Tki Resistance ◽

Nsclc Patients ◽

Egfr Tki ◽

Generation Sequencing

Download Full-text

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.

Download Full-text

P05.12 Comparison of next-generation sequencing results between brain metastasis and blood in NSCLC patients with acquired EGFR-TKI resistance other than T790M mutation

Neuro-Oncology ◽

10.1093/neuonc/noy139.338 ◽

2018 ◽

Vol 20 (suppl_3) ◽

pp. iii304-iii305

Author(s):

H Lee ◽

J Kim ◽

J Kang

Keyword(s):

Next Generation Sequencing ◽

Brain Metastasis ◽

Next Generation ◽

T790m Mutation ◽

Tki Resistance ◽

Nsclc Patients ◽

Egfr Tki ◽

Generation Sequencing

Download Full-text

Lungful: An observational prospective study to assess the molecular epidemiology of EGFR mutations upon progression on or after first line EGFR-TKI therapy, in real-life clinical settings in Greece.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e21641 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e21641-e21641

Author(s):

Giannis Socrates Mountzios ◽

Dimitrios Mavroudis ◽

Epaminondas Samantas ◽

Anna Koumarianou ◽

Evangelos Georgios Konstantinos Fergadis ◽

...

Keyword(s):

Molecular Epidemiology ◽

Second Generation ◽

Egfr Mutation ◽

Locally Advanced ◽

Real Life ◽

Egfr Mutations ◽

Liquid Biopsies ◽

T790m Mutation ◽

Nsclc Patients ◽

Egfr Tki

e21641 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the gold standard 1st line strategy for non-small-cell lung cancer (NSCLC) patients with activating EGFR mutations (EGFRm), associated with improved survival outcomes and quality of life compared to chemotherapy. Despite the high response rate with first- and second- generation TKIs, most patients develop resistance to treatment and progress. The acquisition of T790M mutation in exon 20 is considered the most common resistance mechanism. This study aims to investigate the molecular epidemiology of EGFR resistance mutations, focusing on T790M in EGFRm NSCLC patients treated with TKIs. Methods: The study included patients with locally advanced/metastatic EGFRm NSCLC who have progressed on or after 1st line treatment with first- or second- generation TKI. Samples either from plasma-based liquid biopsy and/or tissue re-biopsy were analysed using the Cobas EGFR Mutation Test v2. All patients signed informed consent and were enrolled between July 2017 and September 2019. Statistical analyses were performed using SAS software, Version 9.4. Results: Ninety-six eligible patients were enrolled. At the time of progression, T790M mutation was detected in 16.7%of the patients using plasma-based liquid biopsies. Among patients with negative T790M result, in plasma, tissue re-biopsy was performed in 22,7% with evaluable/valid results in 72.2% of them. T790M mutation was identified in 38.5% of re-biopsy samples. According to Cobas EGFR Mutation test results (combined plasma and tissue), T790M mutation was identified in 21.9% of the patients. Of T790M-positive patients 42.9% had previously received first and 57.1% second generation EGFR-TKI. Conclusions: Results from this study in real world clinical setting in Greece, show that EGFR-T790M acquired resistance positivity rate in plasma is lower compared to previous reports. Moreover, these data underline the challenges of implementing precision medicine using tissue re-biopsy in advanced/metastatic NSCLC. Clinical trial information: D133FR00126. [Table: see text]

Download Full-text

A digital PCR assay development to detect EGFR T790M mutation in NSCLC patients

Frontiers in Laboratory Medicine ◽

10.1016/j.flm.2018.08.002 ◽

2018 ◽

Vol 2 (3) ◽

pp. 89-96 ◽

Cited By ~ 2

Author(s):

Ruifeng Zhou ◽

Yiran Cai ◽

Zhaoliang Li ◽

Shuangye Shen ◽

Mozhou Sha ◽

...

Keyword(s):

Digital Pcr ◽

Assay Development ◽

Pcr Assay ◽

T790m Mutation ◽

Nsclc Patients ◽

Egfr T790m

Download Full-text

Osimertinib in previously EGFR-TKI treated non-small cell lung cancer (NSCLC) patients without T790M mutation: Real-world evidence.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e21631 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e21631-e21631

Author(s):

Yung-Hung Luo ◽

Han Liu ◽

Jason A. Wampfler ◽

Henry D. Tazelaar ◽

Yalun Li ◽

...

Keyword(s):

Treatment Failure ◽

Real World ◽

Survival Benefit ◽

T790m Mutation ◽

Risk Of Death ◽

Tki Treatment ◽

Egfr Mutant ◽

Nsclc Patients ◽

Risk Of Treatment ◽

Egfr Tki

e21631 Background: The efficacy of osimertinib in previously EGFR-TKI treated NSCLC patients without T790M mutation remains unclear in real-world practice. We investigated whether osimertinib can provide survival benefit in EGFR-mutant patients without T790M mutation after 1st/2nd generation TKI treatment. Methods: Between January 1, 2009, and March 31, 2019, 417 patients had stage III-IV NSCLC harboring EGFR mutation and 154 out of 417 patients receiving osimertinib as≥2nd-line EGFR-TKI treatment were identified at Mayo Clinic. The time to treatment failure of osimertinib was analyzed by the Kaplan-Meier (KM) estimates. The risk of death post diagnosis was analyzed by Cox proportional hazard models. Results: Among 417 EGFR-mutant patients, higher risk of death was found in patients with age above 65 years, non-adenocarcinoma, no surgery treatment, no radiation treatment, non-exon 19 deletion/exon 21 L858R mutation, higher ECOG PS (2-4), PD-L1 expression of 50% or more, bone metastasis, live metastasis, and adrenal metastasis (all p < 0.05). Moreover, osimertinib as ≥2nd-line TKI treatment in patients with or without T790M revealed lower risk of death compared to 1st/2nd generation TKI treatment without subsequent osimertinib (HR = 0.33; 0.46, and p = 0.0002; 0.0232, respectively). However, among patients receiving osimertinib as ≥2nd-line TKI treatment, patients with T790M did not have superior survival than those without (p = 0.2803). Among 154 patients receiving osimertinib, a higher risk of treatment failure for osimertinib was found in male (HR = 1.72; p = 0.0327), patients with 1st-line TKI duration ≤12 months (HR = 2.16; p = 0.0019), BMI drop > 10% (HR = 1.85; p = 0.0207), PD-L1 levels of 50% or more (HR = 4.28; p = 0.0008), and 1st-line TKI with afatinib (HR = 2.19; p = 0.0136). Nonetheless, osimertinib as ≥2nd-line TKI in patients without 790M mutation did not have higher risk of treatment failure than those with T790M (p = 0.1236). Conclusions: This is the first study to demonstrate that osimertinib can provide similar survival benefit in previously EGFR-TKI treated NSCLC patients without T790M mutation as those with T790M in real-world practice. Additionally, EGFR-mutant patients with PD-L1 expression ≥50% had a higher risk of treatment failure for osimertinib and worse overall survival than those with PD-L1 expression < 50% and may potentially gain benefit from optimizing treatment strategies including immunotherapy.

Download Full-text

Abstract A131: Comparison of next-generation sequencing results between brain metastasis and blood in NSCLC patients with acquired EGFR-TKI resistance other than T790M mutation

10.1158/1535-7163.targ-17-a131 ◽

2018 ◽

Author(s):

Hee Yeon Lee ◽

Jeong-Oh Kim ◽

Jin-Hyoung Kang

Keyword(s):

Next Generation Sequencing ◽

Brain Metastasis ◽

Next Generation ◽

T790m Mutation ◽

Tki Resistance ◽

Nsclc Patients ◽

Egfr Tki ◽

Generation Sequencing

Download Full-text

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

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e19101 ◽

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.

Download Full-text

Correlation between re-biopsy site and detection of T790M mutation in NSCLC patients treated with EGFR TKI.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e20620 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e20620-e20620

Author(s):

Fumie Shigematsu ◽

Yoshihito Kogure ◽

Hideo Saka ◽

Arisa Yamada ◽

Akane Ishida ◽

...

Keyword(s):

Kinase Inhibitor ◽

Smoking Status ◽

Stage Iv ◽

Progression Free Survival ◽

Primary Lesion ◽

T790m Mutation ◽

Biopsy Site ◽

Median Period ◽

Nsclc Patients ◽

Egfr Tki

e20620 Background: Re-biopsy is important to decide the treatment after EGFR-tyrosine kinase inhibitor (TKI) failure in non-small cell lung cancer (NSCLC) patients. We hypothesized that the T790M mutation in EGFR might show heterogeneity depending on the re-biopsy site. Methods: NSCLC patients who had received initial EGFR-TKI since January 2009 to December 2016, at any stage and recurrence after surgery and at any line of treatment, were included. Results: In total, 128 patients were included. Median age at EGFR-TKI therapy initiation was 73 (range, 38–97) years; 67% patients were female, all were Asian, 56% had never smoked, and 99% had adenocarcinoma. Of total 128 patients, 109 showed progressive disease. Median progression-free survival (PFS) was 10 (0.56–57) months. Median period since EGFR-TKI failure until the first re-biopsy was 197 (0–1322) days. Re-biopsy was performed 50 times in 42 patients; the number of T790M positive, negative, and pathologically negative patients was 20, 17, and 5, respectively, and the number of re-biopsies in these patients was 20, 22, and 8, respectively. Median PFS was longer in T790M positive patients than in negative patients significantly (17 [11–24] vs. 7.6 [4.3–11] months, P = 0.007). Characteristics such as gender, smoking status, proportion of stage IV, time between EGFR-TKI failure and first re-biopsy, and number of biopsies did not affect the T790M status in the biopsies. T790M positive group had more exon 19 deletions than negative group significantly (75% vs. 23%, P = 0.012). Biopsies at primary lesion, distant, and pleural effusion (PE) were 25% vs. 50%, 60% vs. 36%, and 15% vs. 14%, respectively, in the T790M positive vs. negative groups. Compared with the biopsy-site at diagnosis, the site was same as before in 35% vs. 50% cases (primary lesion [20% vs. 45%], distant [10% vs. 4.5%], and PE [5% vs. 0%]) and was new in 55% vs. 41% cases (distant lesions [45% vs. 27%] and PE [10% vs. 14%]) in the T790M positive vs. negative groups, respectively. Conclusions: In NSCLC patients treated with EGFR-TKI, re-biopsy was performed in distant lesions more frequently in the T790M positive cases than in negative cases. However, the T790M status was not correlated with the re-biopsy site.

Download Full-text