scholarly journals Real Clinical Practice of Using Afatinib Therapy in NSCLC Patients with an Acquired EGFR T790M Mutation

2018 ◽  
Vol 38 (9) ◽  
pp. 5409-5415 ◽  
Author(s):  
KUNIHIKO MIYAZAKI ◽  
TOMOHIRO TAMURA ◽  
TAKAYUKI KABURAGI ◽  
KAZUHITO SAITO ◽  
MASAHARU INAGAKI ◽  
...  
Keyword(s):  
Clinical Practice ◽  
T790m Mutation ◽  
Nsclc Patients ◽  
Egfr T790m ◽  
Real Clinical Practice

scholarly journals Clinical Characteristics of Osimertinib Responder in Non-Small Cell Lung Cancer Patients with EGFR-T790M Mutation

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 365 ◽  
Author(s):  
Akihiro Yoshimura ◽  
Tadaaki Yamada ◽  
Naoko Okura ◽  
Takayuki Takeda ◽  
Kazuki Hirose ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
T790m Mutation ◽  
Nsclc Patients ◽  
Egfr T790m ◽  
Egfr Tkis

Osimertinib is a mutant-selective EGFR inhibitor that is effective against non-small cell lung cancer (NSCLC) in patients with the EGFR-T790M mutation, who are resistant to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, the factors affecting response to osimertinib treatment are unknown. In this retrospective study, 27 NSCLC patients with the EGFR-T790M mutation were enrolled at five institutions in Japan. Among several parameters tested, the progression-free survival (PFS) associated with the initial EGFR-TKIs was positively correlated with the PFS after osimertinib treatment (p = 0.021). The median PFS following osimertinib treatment and the overall survival (OS) were longer in patients who responded to osimertinib than in those who did not (17.7 months versus 3.5 months, p = 0.009 and 24.2 months versus 13.5 months, p = 0.021, respectively). A multivariate analysis demonstrated that the PFS with initial EGFR-TKIs was significantly related to the PFS with osimertinib treatment (p = 0.035), whereas osimertinib response was significantly related to the PFS and OS with osimertinib treatment (p = 0.016 and p = 0.006, respectively). Our retrospective observations indicate that PFS following the initial EGFR-TKI treatment and the response rate to osimertinib might be promising predictors for effective osimertinib treatment in NSCLC patients with the EGFR-T790M mutation.

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

2018 ◽  
Vol 2 (3) ◽  
pp. 89-96 ◽  
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

The ability of avitinib to penetrate the blood brain barrier and its control of intra-/extra- cranial disease in patients of non-small cell lung cancer (NSCLC) harboring EGFR T790M mutation.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20613-e20613 ◽  
Author(s):  
Hanping Wang ◽  
Li Zhang ◽  
Xin Zheng ◽  
Xiaotong Zhang ◽  
Xiaoyan Si ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Blood Brain Barrier ◽  
Cell Lung Cancer ◽  
Penetration Rate ◽  
Small Cell ◽  
Small Cell Lung ◽  
T790m Mutation ◽  
Nsclc Patients ◽  
Egfr T790m

e20613 Background: Avitinib is an oral, potent, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor selective for T790M resistance mutations. We report the safety, the intracranial/extracranial efficacy, and the blood brain barrier (BBB) penetration rate of Avitinib in non-small cell lung cancer(NSCLC) patients with EGFR T790m mutation. The data come from Peking Union Medical College hospital-a single center of the Phase I, open-label, multicenter study (NCT02330367). Methods: NSCLC Patients with acquired EGFR T790m (+) were enrolled. Patients were orally administered with dose escalating from 150 mg to 300 mg twice daily for 28-continuous-day cycles until disease progression. Blood (2mL) and cerebrospinal fluid (CSF) samples (2ml) were collected for concentration analysis on day 29 in available patients with brain metastases (BM). Tumor response was assessed on day 29 and then every 8 weeks. Results: Sixteen patients were included. Nine patients had asymptomatic BM. The most frequent adverse events were the elevated hepatic transaminases (10/16, 62.5%) and diarrhea (5/16, 31.3%), Most were mild and reversible. 9 Patients (56.3%) achieved Partial Response (PR), 6 (37.5%) achieved Stable Disease (SD). Median Progress Free Survival (PFS) was 253 days (95%CI: 154.8-339.2). Of the 8 evaluable BM patients, intracranial PFS were shorter than extracranial in only two patients. The blood and CSF analysis of 6 BM patients showed the BBB penetration rate were 0.046%-0.146% (Table). Conclusions: Avitinib is well tolerated and efficacious in EGFR T790m(+) NSCLC patients. Its concentration in CSF is low, and the penetrability of BBB is weak. But it still showed a good control of BM. Further studies are proceeding. Clinical trial information: NCT02330367. [Table: see text]

Circulating tumor DNA profiling of lung cancer patients treated with EGFR inhibitors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23060-e23060
Author(s):  
Sandra Ortiz-Cuaran ◽  
Aurelie Swalduz ◽  
Emma Green ◽  
Virginie Avrillon ◽  
Michael Epstein ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Concordance Rate ◽  
Braf V600e ◽  
Plasma Samples ◽  
Liquid Biopsies ◽  
T790m Mutation ◽  
Invasive Approach ◽  
Nsclc Patients ◽  
Egfr T790m ◽  
Over Time

e23060 Background: The presence of a targetable driver mutation in nearly 50% non-small cell lung cancer (NSCLC) patients has enabled tailoring therapy regimens to improve survival. Serial repeat biopsies can offer an instrumental indication into the longitudinal evolution of cancer. However, tissue biopsies are invasive and can provide insufficient material for molecular testing. Mutation detection in plasma DNA as a “liquid biopsy” has been suggested as non-invasive approach to monitor tumor dynamics over time. Methods: We established an institutional protocol (NCT01511288) for the collection of liquid biopsies from stage IIIB/IV NSCLC patients either untreated, under therapy or progressive on therapy with a TKI. This protocol has included 134 NSCLC patients for whom clinical, pathological and genomic information is collected prospectively. Analyses were performed by Inivata using InVision (enhanced tagged-amplicon sequencing). Results: So far, samples from 50 patients have been analyzed. InVision allowed the detection of driver mutations in 20 plasma samples obtained at diagnosis. Tissue was unavailable for molecular analysis in 8/20 samples. We observed a concordance rate in mached plasma and tissue samples, of 92,3% (n = 12). In plasma samples from patients that relapsed under erlotinib or gefitinib we evidenced the EGFR T790M mutation in 57% of patients, with a concordance rate of 90,9%. Interestingly, analysis of serial samples collected from 3 patients under EGFR-targeted therapy showed the emergence of an EGFR T790M mutation 11 weeks before the radiographic confirmation of progression (P1); differential dynamics in the allelic fractions of mutated clones that reflected the pattern of dissociated tumor response to treatment (P2) and the presence of concomitant EGFR activating and T790M mutations, together with an EGFR C797G, BRAF V600E and KRAS G12D in a patient who progressed under osimertinib (P3). Conclusions: Our preliminary results provide further evidence on the use of liquid biopsies for monitoring disease response, resistance to treatment and tumor heterogeneity. Subsequently, we will evaluate the utility of liquid biopsies in the clinical setting to understand the dynamics of mutant clones over time.

Abstract 760: Detection of EGFR T790M mutation by ddPCR in untreated NSCLC patients: Correlation with clinical outcome

2017 ◽  
Author(s):  
Monica Ganzinelli ◽  
Eliana Rulli ◽  
Elena Tamborini ◽  
Adele Busico ◽  
Giuseppe Lo Russo ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
T790m Mutation ◽  
Nsclc Patients ◽  
Egfr T790m

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.

Novel resistance mechanisms to first-generation EGFR tyrosine kinase inhibitors: A perspective study in NSCLC patients using targeted next generation sequencing.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20576-e20576
Author(s):  
Ying Jin ◽  
Jianjun Zhang ◽  
Ming Chen ◽  
Yang Shao ◽  
Xun Shi ◽  
...  
Keyword(s):  
First Generation ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Egfr Mutations ◽  
T790m Mutation ◽  
Targeted Next Generation Sequencing ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Nsclc Patients ◽  
Egfr T790m

e20576 Background:Patients with non-small-cell lung cancer (NSCLC) harboring sensitive epithelial growth factor receptor (EGFR) mutations invariably develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Identification of actionable mutations conferring drug-resistance can be helpful for guiding the subsequent treatment decision. Currently, the known mechanisms of acquired resistance includes: the secondary gatekeeper EGFR-T790M mutation, activation of members of downstream signaling pathways such as PI3K/AKT/mTOR pathway, activation of bypass signaling such as MET, and changes in tumor histology. However, the mechanisms in the remaining patients are still unknown. Methods:In this prospective study, thirty-one advanced NSCLC patients initially carrying sensitive EGFR mutations and subsequently developing acquired resistance to the first-generation EGFR-TKIs were enrolled. Pre-treatment tumor samples as well as re-biopsies of tumor and plasma when the patients were diagnosed with EGFR-TKI resistance were acquired, followed by mutation profiling using targeted next generation sequencing (NGS) on 416 cancer-related genes. Results: In total, 55% of patients were identified to carry acquired secondary EGFR-T790M mutation. Three patients (~10%) harbor EGFR-T854A mutation, which has been reported as another TKI resistant mutation. 26% and 19% of cases accumulated TP53 and RB1 mutations, respectively. In T790M/T854A-negative cases, 30% of patients acquired MET amplification. Other potential acquired resistance mechanisms includes single nucleotide variants (SNVs) in genes such as SMAD4, DNMT3A, GNAS, ATM, KRAS, PIK3CA and TET2, and copy number variations (CNVs) in genes such as CDK4, MDM2, MYC, RICTOR and ERBB2. Conclusions:The study depicted the genetic landscapes comprehensively in matched pre- and post-EGFR-TKIs samples of NSCLC population resistant to first generation TKI treatments. Our analysis demonstrates new perspectives for further study of resistance and putting forward corresponding relevant tactics against the challenge of disease progression. Clinical trial information: NCT02804217.

Detect T790M in cell free tumor DNA of Chinese advanced non-small cell lung cancer adenocarcinoma patients by different platforms and evaluate clinical outcomes of T790M positive patients with osimertinib monotherapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS9104-TPS9104
Author(s):  
Zhiyong Liang ◽  
Ying Cheng ◽  
Yuan Chen ◽  
Weiping Liu ◽  
You Lu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Digital Pcr ◽  
Small Cell ◽  
Small Cell Lung ◽  
T790m Mutation ◽  
Nsclc Patients ◽  
Egfr Tki ◽  
Tumor Dna ◽  
Egfr T790m

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.

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