Non-classic EGFR mutations in a cohort of Dutch EGFR-mutated NSCLC patients and outcomes following EGFR-TKI treatment

9056 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a key treatment for EGFR-mutated non-small-cell lung carcinoma (NSCLC). To date, a biomarker to predict whether NSCLC will exhibit a short- or long-term response to first- or second-generation EGFR-TKIs has not been established for clinical use. Human epidermal growth factor receptor-2 (HER2) aberrations are mechanisms for acquired resistance to EGFR-TKIs; however, their impact on EGFR-TKI therapy outcomes in EGFR-mutant NSCLC has not yet been systematically evaluated. Methods: Patients with advanced NSCLC were prospectively registered from more than 35 institutes (HER2-CS STUDY UMIN 000017003). EGFR mutations or anaplastic lymphoma kinase gene translocations were assessed at each institution using a commercially approved test. HER2 protein expression levels were determined by immunohistochemistry (IHC) using the Ventana I-VIEW PATHWAY anti-HER-2/neu (4B5). The IHC status scoring system applied to gastric cancer was used. Results: Of 1,126 screened patients with NSCLC, 354 (31.8%) had EGFR-mutated tumors, and the HER2 protein statuses were as follows: IHC0 (n = 71, 26%), IHC1+ (n = 148, 53%), IHC2+ (n = 51, 18%), and IHC3+ (n = 7, 3%). The patients’ demographics were almost identical in those with lung tumors harboring EGFR mutations and HER2-IHC2+/3+ (group P) or EGFR mutations and HER2-IHC0/1 (group N). The EGFR-TKI response rates were not different between these groups (Table). However, group P showed significantly shorter time to EGFR-TKI treatment failure than group N (median 19.1 vs. 13.3 months; log rank p = 0.038). Conclusions: These data from a large prospective cohort show that HER2 protein expression in EGFR-mutant NSCLC may have a negative impact on the effect of EGFR-TKIs. A clinical trial of EGFR/HER2-TKIs (e.g., afatinib) is warranted for this population. [Table: see text]

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Dynamic Evaluation of Circulating miRNA Profile in EGFR-Mutated NSCLC Patients Treated with EGFR-TKIs

Cells ◽

10.3390/cells10061520 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1520

Author(s):

Alessandro Leonetti ◽

Mjriam Capula ◽

Roberta Minari ◽

Giulia Mazzaschi ◽

Alessandro Gregori ◽

...

Keyword(s):

Statistical Significance ◽

Dynamic Change ◽

Complete Response ◽

Dynamic Evaluation ◽

Tki Treatment ◽

Nsclc Patients ◽

Egfr Mutated ◽

Egfr Tki ◽

Egfr Tkis

Background: Resistance to EGFR-TKIs constitutes a major challenge for the management of EGFR-mutated NSCLC, and recent evidence suggests that deregulation of specific microRNAs (miRNAs) may influence resistance to targeted agents. In this retrospective study, we explored the role of specific plasmatic miRNAs (miR-21, miR-27a and miR-181a) as a surrogate for predicting EGFR-TKI performance in EGFR-mutated NSCLC patients. Methods: Plasma samples of 39 advanced EGFR-mutated NSCLC patients treated with EGFR-TKIs were collected at different points in time and miRNA levels were assessed by RT-PCR. Results: Higher basal values of miR-21 were reported in patients who achieved a partial/complete response (PR/CR) compared to those with stability/progression of disease (SD/PD) (p = 0.011). Along the same line, patients who experienced a clinical benefit lasting at least six months displayed higher basal levels of circulating miR-21 (p = 0.039). However, dynamic evaluation of miRNA values after two months from the start of EGFR-TKI treatment showed that patients who experienced SD had an increase in miR-21 levels (Fold Change [FC] = 2.6) compared to patients achieving PR/CR (p = 0.029). The same tendency was observed for miR-27a (FC = 3.1) and miR-181a (FC = 2.0), although without reaching statistical significance. Remarkably, preclinical studies showed an increase in miR-21 levels in NSCLC cells that became resistant after exposure to EGFR-TKIs. Conclusions: Our study provides interesting insights on the role of circulating miRNAs, in particular miR-21, and their dynamic change over time in predicting EGFR-TKI response in EGFR-mutated NSCLC.

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Tyrosine kinase inhibitors (TKI) treatment of non-small cell lung cancer (NSCLC) patients (p) based on EGFR mutations (m) status in serum only.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e19088 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e19088-e19088

Author(s):

Laia Capdevila ◽

Enric Carcereny ◽

Itziar de Aguirre ◽

Sara Cros ◽

Cristina Queralt ◽

...

Keyword(s):

Kinase Inhibitors ◽

Complete Response ◽

Phase Iii ◽

Egfr Mutations ◽

Molecular Alterations ◽

Former Smokers ◽

Tki Treatment ◽

Ecog Ps ◽

Egfr Mutated ◽

Egfr Tki

e19088 Background: Treatment of EGFR mutated NSCLC p with EGFR TKIs in phase III trials has shown improved efficacy to standard chemotherapy. However, it can be difficult to obtain sufficient tumor tissue for analysis of EGFR m status in a large proportion of p. Nevertheless, so far, no data exists for NSCLC p treated according to EGFR m status in serum alone. Methods: We reviewed our database to identify EGFR mutated p, excluding those for whom status was available in both serum and tissue. We analyzed p treated with an EGFR TKI for whom EGFR m status was known in serum only (status in tissue unknown due to insufficient material). At the same time, we reviewed p in whom EGFR m status in tissue was available over the same period in order to compare clinical characteristics and efficacy parameters: PFS, ORR and overall survival (OS). EGFR m analysis was performed in cell free circulating DNA (cfDNA)isolated from serum and plasma using the QIAmp DNA blood mini kit. Results: 9 p with EGFR m detected in serum and 33 p with EGFR m in tissue were included. In EGFR mutated p in serum, median age 63; male 55.6%; non-smokers 33.3%; former smokers 44.4%; ECOG PS 0-1 66.7%; adenocarcinoma 77.8%; deletion19 33.3%, L858R 66.7%; EGFR TKI treatment in 1st line 44.4%; 2nd or 3rd line 55.6%. ORR: complete response (CR) 22.2%; partial response (PR) 22.2%; stable disease (SD) 22.2%; progressive disease (PD) 11.1%. 2p had poor PS and died prior to evaluation. mPFS 4.7 months (mo). mOS 18 mo. In p with EGFR m in tissue, median age 61; male 36.4%; non-smokers 75.8%; former smokers 24.2%; adenocarcinoma 87.9%; deletion19 75.8%; L858R 24.2%; 1st line 54.5%; 2nd or 3rd line 45.5%. ORR: CR 15.2%; PR 57.6%; SD 12.1%; PD 15.2%. mPFS 8.9 mo. mOS 32.7 mo. The multivariate analysis for OS considering EGFR m in serum differed according to PS (PS 0-1 16.6 mo vs PS > 2 5.2 mo). Conclusions: Obtaining sufficient tissue from NSCLC p for analysis of EGFR m status and other molecular alterations can be difficult. Determination of EGFR m in serum alone is feasible, yields similar results to mutation status in tissue, and could permit us to take treatment decisions.

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Impact of EGFR mutation status on clinical outcome of nintedanib plus docetaxel in patients with previously treated non-small cell lung cancer (NSCLC): Retrospective analysis of Korean nintedanib named-patient usage (NPU) program in NSCLC (KCSG LU14-2).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e20638 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e20638-e20638

Author(s):

Sook-hee Hong ◽

Ho Jung An ◽

Yun-Gyoo Lee ◽

Hoon-Kyo Kim ◽

Seung-Sei Lee ◽

...

Keyword(s):

Egfr Mutation ◽

Kinase Inhibitor ◽

Objective Response ◽

Egfr Mutations ◽

Clinical Activity ◽

Good Tolerability ◽

Mutation Status ◽

Tki Treatment ◽

Nsclc Patients ◽

Egfr Tki

e20638 Background: Anti-angiogenic agents have been reported to have clinical activity for NSCLC harboring EGFR mutation (mutEGFR) with/without EGFR Tyrosine kinase inhibitor (TKI). We report clinical outcomes of nintedanib plus docetaxel for refractory NSCLC patients conducted by virtue of Korean NPU program. Methods: Patients with NSCLC were eligible if they failed at least one prior systemic treatment. Docetaxel was administered with 75 or 60mg/m2 on D1 or 37.5mg/m2 on D1, D8 every 3 weeks plus nintedanib 200mg orally twice daily. Nintedanib treatment was continued until disease progression or unacceptable toxicity after 4-6 cycles of combination therapy. Results: Of 62 patients enrolled, 23 patients had activating EGFR mutations (14 in exon19 deletion, 7 exon21 L858R/L861Q, 1 exon20 duplication, and 1 in both exon19 deletion and exon20 T790M) and progressed during prior EGFR-TKI treatment. Of 23 patients, 22 had progressed during or after platinum doublet chemotherapy. Only for 2 patients, EGFR mutation status was unknown. The majority of patients were heavily pretreated, with 43.7% received nintedanib plus docetaxel as ≥ 4th line therapy. 4 patients had prior bevacizumab treatment. Objective response rate (ORR) was 22.9%. Median PFS and OS were 3.9 months (95% CI 3.1-4.6) and 9.5 months (95% CI 5.3-13.7), respectively. Depending on EGFR mutation status, ORR in mutEGFR group was higher than wtEGFR group (30.4% vs 20%, p= 0.50) and median PFS in mutEGFR group was significantly longer than wtEGFR group (6.1 vs 3.3 months, p= 0.008). No treatment related death was reported. Common grade 3/4 adverse events were neutropenia (58.3%) and reversible elevated liver enzyme (18.8%). Conclusions: Taken together, nintedanib plus docetaxel showed meaningful clinical activity with good tolerability for refractory NSCLC patients. Our data suggest that this combination may be a recommendable regimen for EGFR-TKI-resistant mutEGFR NSCLC.

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ERβ localization influenced outcomes of EGFR-TKI treatment in NSCLC patients with EGFR mutations

Scientific Reports ◽

10.1038/srep11392 ◽

2015 ◽

Vol 5 (1) ◽

Cited By ~ 9

Author(s):

Zhijie Wang ◽

Zhenxiang Li ◽

Xiaosheng Ding ◽

Zhirong Shen ◽

Zhentao Liu ◽

...

Keyword(s):

Egfr Mutations ◽

Tki Treatment ◽

Nsclc Patients ◽

Egfr Tki

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Cytokeratin 19 fragment (CYFRA21-1) to predict the efficacy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in non-small cell lung cancer (NSCLC) harboring EGFR mutation.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.10610 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 10610-10610

Author(s):

Kosuke Tanaka ◽

Akito Hata ◽

Reiko Kaji ◽

Shiro Fujita ◽

Jumpei Takeshita ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Egfr Mutation ◽

Predictive Marker ◽

Egfr Mutations ◽

Significant Difference ◽

Nsclc Patients ◽

Egfr Mutated ◽

Egfr Tki ◽

Egfr Tkis

10610 Background: EGFR mutation is independently associated with a favorable response in NSCLC patients receiving EGFR-TKIs, regardless of gender or smoking history. However, recent reports have indicated that squamous cell carcinoma patients harboring EGFR mutations show a worse response to EGFR-TKIs than adenocarcinoma patients. We hypothesized that serum CYFRA21-1 is a predictive marker in EGFR mutated patients treated with EGFR-TKIs. Methods: We retrospectively screened 160 NSCLC patients harboring EGFR mutations (exon 19 deletions, L858R in exon 21, or other minor mutations) who received either gefitinib or erlotinib between 1992 and 2011. Patients were screened for histology, sex, age, smoking status, efficacy of EGFR-TKI and tumor markers (CEA/CYFRA21-1) at initial diagnosis. Results: Out of 160 eligible patients treated with EGFR-TKIs, 77 patients with high CYFRA21-1 level (>2 ng/ml) showed statistically shorter progression-free survival (PFS) than 83 patients with normal CYFRA21-1 level (median PFS 7.5 vs 14.0 months, p=0.006). No significant difference in PFS was observed between high CEA group (>5 ng/ml) and normal CEA group (median PFS 8.6 vs 11.2 months, p=0.2423). Multivariate analysis revealed that high CYFRA21-1 level is independently associated with PFS (HR 1.35; p=0.002) as well as squamous cell carcinoma (HR 1.40; p=0.020) and performance status 2-4 (HR 2.63; p=0.003). No statistically significant difference in overall survival (OS) was observed between high CYFRA21-1 group and normal group (median OS 24.8 vs 39.1 months, p=0.104). Conclusions: High CYFRA level patients have significantly shorter PFS, which may indicate that this subgroup has a larger squamous component and thus less response to EGFR-TKIs. Serum CYFRA21-1 level is a predictive marker of EGFR-TKIs efficacy and EGFR mutated patients can be divided into two subgroups according to CYFRA21-1 level at initial diagnosis.

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EGFR-TKI after disease progression with central nervous system metastasis in advanced non-small cell lung cancer with EGFR mutations.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e19083 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e19083-e19083

Author(s):

Takashi Sone ◽

Kazuo Kasahara ◽

Koji Kurokawa ◽

Asao Sakai ◽

Toshiyuki Kita ◽

...

Keyword(s):

Good Prognosis ◽

Egfr Mutations ◽

Group Differences ◽

Cns Metastasis ◽

Free Treatment ◽

Never Smokers ◽

Tki Treatment ◽

A Prospective Study ◽

Nsclc Patients ◽

Egfr Tki

e19083 Background: Several retrospective studies have reported that continued treatment with EGFR-TKI after developing progressive disease (PD) by RECIST improved survival compared to TKI-free treatment in NSCLC patients with EGFR mutations. However, it is unclear which patients would benefit from EGFR-TKI after PD. We hypothesized that patients with CNS progression only, without systemic deterioration, would show a good prognosis with EGFR-TKI after PD. Methods: In order to clarify the survival benefits in patients treated by EGFR-TKI after developing PD, particularly patients with CNS metastasis alone, NSCLC patients with EGFR mutations who were treated with EGFR-TKI and showed progression were analyzed retrospectively. The patients were categorized into two groups: patients continuing with EGFR-TKI treatment after progression (continuation group) and patients switched to chemotherapy or BSC (discontinuation group). Patients were also classified into two groups by site of progression: patients who showed deterioration involving only CNS metastasis (CNS group) and patients who showed progression of the primary lesion, lymph nodes, bone, liver, adrenal glands, CNS, or other sites (systemic group). Differences in post-EGFR-TKI progression survival (PPS) and overall survival were compared between the groups. Results: A total of 75 patients, including 54 women, 56 never smokers, 73 patients with adenocarcinomas, and 57 patients with good PS (0, 1), were analyzed. There were 40 patients with deletions in exon 19, 29 patients with L858R, and 6 with minor mutations. The continuation group (n=36) had a significantly longer PPS than the discontinuation group (n=39) (16.2 m vs. 8.5 m, p<0.01). Although it was not significant, the CNS group (n=14) showed longer PPS than the systemic group (n=61) (17.3 m vs. 9.2 m, p=0.10). The PPS of 9 patients (continuation and CNS groups) was 21.0 m, while PPS of 34 patients (discontinuation and systemic group) was 7.2 m. Conclusions: In this retrospective analysis, continued treatment with EGFR-TKI after PD resulted in longer PPS. A prospective study of patients with progression involving only CNS metastasis treated with EGFR-TKI is needed.

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SHP2 Inhibition Benefits Epidermal Growth Factor Receptor mutated Non-Small Cell Lung Cancer Therapy

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557520666201127104104 ◽

2020 ◽

Vol 20 ◽

Author(s):

Leiming Xia ◽

Lu Wen ◽

Siying Wang

Keyword(s):

Stem Cells ◽

Synergistic Effects ◽

Growth Factor Receptor ◽

Egfr Mutations ◽

Combination Strategies ◽

Lung Cancer Therapy ◽

Src Homology ◽

Nsclc Patients ◽

Egfr Mutated ◽

Egfr Tkis

: EGFR-TKIs are facing a big challenge of everlasting activated EGFR mutations which lack of effective binding sites, this barrier confers the dark sides that largely limited the outcome of NSCLC patients in clinic. Combination strategies show impressive anti-tumor efficacy comparing with EGFR-TKI mono-treatment, especially targeting both stem cells and non-stem cells. SHP2 (Src homology 2-containing phosphotyrosine phosphatase 2) plays an important role in regulating various malignant biology through hyper-activating intracellular pathways due to either over expression or catalytical mutation. Some pathways that SHP2 involved in were overlaps with EGFR downstream, and others were not subject to EGFR. Interestingly, SHP2 suppression was reported that can destroy the stemness of cancer. Therefore, we hypothesize SHP2 inhibitor might be an promising drug that could synergistically enhance or sensitize the anti-tumor efficacy of EGFR-TKIs in EGFR mutated NSCLC patients. Here, we summarized the mechanisms of SHP2 in regulating EGFR mutated NSCLC patients, attempted to reveal the potential synergistic effects of SHP2 inhibitor combined with EGFR-TKIs.

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Detection of EGFR Activating and Resistance Mutations by Droplet Digital PCR in Sputum of EGFR-Mutated NSCLC Patients

Clinical Medicine Insights Oncology ◽

10.1177/1179554921993072 ◽

2021 ◽

Vol 15 ◽

pp. 117955492199307

Author(s):

Klaus Hackner ◽

Anna Buder ◽

Maximilian J Hochmair ◽

Matthaeus Strieder ◽

Christina Grech ◽

...

Keyword(s):

Stable Disease ◽

Progressive Disease ◽

Kinase Inhibitor ◽

Diagnostic Yield ◽

Resistance Mutation ◽

Egfr Mutations ◽

Plasma Samples ◽

Percent Agreement ◽

Nsclc Patients ◽

Egfr Mutated

Background: Proof of the T790M resistance mutation is mandatory if patients with EGFR-mutated non-small cell lung cancer (NSCLC) progress under first- or second-generation tyrosine kinase inhibitor therapy. In addition to rebiopsy, analysis of plasma circulating tumor DNA is used to detect T790M resistance mutation. We studied whether sputum is another feasible specimen for detection of EGFR mutations. Methods: Twenty-eight patients with advanced EGFR-mutated NSCLC were included during stable and/or progressive disease. The initial activating EGFR mutations (exon 19 deletions or L858R mutations) at stable disease and at progressive disease (together with T790M) were assessed in simultaneously collected plasma and sputum samples and detected by droplet digital polymerase chain reaction (ddPCR). Results: Activating EGFR mutations were detected in 47% of the plasma samples and 41% of sputum samples during stable disease, and in 57% of plasma samples and 64% of sputum samples during progressive disease. T790M was detected in 44% of the plasma samples and 66% of the sputum samples at progressive disease. In ddPCR T790M-negative results for both specimens (plasma and sputum), negativity was confirmed by rebiopsy in 5 samples. Concordance rate of plasma and sputum for T790M was 0.86, with a positive percent agreement of 1.0 and a negative percent agreement of 0.80. Conclusions: We demonstrated that EGFR mutation analysis with ddPCR is feasible in sputum samples. Combination of plasma and sputum analyses for detection of T790M in NSCLC patients with progressive disease increases the diagnostic yield compared with molecular plasma analysis alone.

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Molecular and Clinical Features of EGFR-TKI-Associated Lung Injury

International Journal of Molecular Sciences ◽

10.3390/ijms22020792 ◽

2021 ◽

Vol 22 (2) ◽

pp. 792

Author(s):

Tohru Ohmori ◽

Toshimitsu Yamaoka ◽

Koichi Ando ◽

Sojiro Kusumoto ◽

Yasunari Kishino ◽

...

Keyword(s):

Lung Injury ◽

Tyrosine Kinase ◽

Performance Status ◽

Cytotoxic Agents ◽

Egfr Mutations ◽

Poor Performance Status ◽

Chronic Obstructive ◽

Tki Treatment ◽

Egfr Tki ◽

Egfr Tkis

The tyrosine kinase activity of epidermal growth factor receptors (EGFRs) plays critical roles in cell proliferation, regeneration, tumorigenesis, and anticancer resistance. Non-small-cell lung cancer patients who responded to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) and obtained survival benefits had somatic EGFR mutations. EGFR-TKI-related adverse events (AEs) are usually tolerable and manageable, although serious AEs, including lung injury (specifically, interstitial lung disease (ILD), causing 58% of EGFR-TKI treatment-related deaths), occur infrequently. The etiopathogenesis of EGFR-TKI-induced ILD remains unknown. Risk factors, such as tobacco exposure, pre-existing lung fibrosis, chronic obstructive pulmonary disease, and poor performance status, indicate that lung inflammatory circumstances may worsen with EGFR-TKI treatment because of impaired epithelial healing of lung injuries. There is limited evidence from preclinical and clinical studies of the mechanisms underlying EGFR-TKI-induced ILD in the available literature. Herein, we evaluated the relationship between EGFR-TKIs and AEs, especially ILD. Recent reports on mechanisms inducing lung injury or resistance in cytokine-rich circumstances were reviewed. We discussed the relevance of cytotoxic agents or immunotherapeutic agents in combination with EGFR-TKIs as a potential mechanism of EGFR-TKI-related lung injury and reviewed recent developments in diagnostics and therapeutics that facilitate recovery from lung injury or overcoming resistance to anti-EGFR treatment.

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