Rational application of gefitinib in NSCLC patients with sensitive EGFR mutations based on pharmacokinetics and metabolomics

: 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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68P Comparison of first-generation EGFR-TKIs (gefitinib, erlotinib, and icotinib) as adjuvant therapy in resected NSCLC patients with sensitive EGFR mutations

Journal of Thoracic Oncology ◽

10.1016/s1556-0864(21)01910-9 ◽

2021 ◽

Vol 16 (4) ◽

pp. S732

Author(s):

W. Liang ◽

Q. He ◽

C. Li ◽

H. Liang ◽

B. Cheng ◽

...

Keyword(s):

Adjuvant Therapy ◽

First Generation ◽

Egfr Mutations ◽

Resected Nsclc ◽

Nsclc Patients ◽

Egfr Tkis

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Peptide-Affinity Precipitation of Extracellular Vesicles and Cell-Free DNA Improves Sequencing Performance for the Detection of Pathogenic Mutations in Lung Cancer Patient Plasma

International Journal of Molecular Sciences ◽

10.3390/ijms21239083 ◽

2020 ◽

Vol 21 (23) ◽

pp. 9083

Author(s):

Catherine Taylor ◽

Simi Chacko ◽

Michelle Davey ◽

Jacynthe Lacroix ◽

Alexander MacPherson ◽

...

Keyword(s):

Lung Cancer ◽

Extracellular Vesicles ◽

Liquid Biopsy ◽

Nsclc Patient ◽

Egfr Mutations ◽

Single Nucleotide Variants ◽

Cell Free Dna ◽

Free Dna ◽

Nsclc Patients ◽

Peptide Affinity

Liquid biopsy is a minimally-invasive diagnostic method that may improve access to molecular profiling for non-small cell lung cancer (NSCLC) patients. Although cell-free DNA (cf-DNA) isolation from plasma is the standard liquid biopsy method for detecting DNA mutations in cancer patients, the sensitivity can be highly variable. Vn96 is a peptide with an affinity for both extracellular vesicles (EVs) and circulating cf-DNA. In this study, we evaluated whether peptide-affinity (PA) precipitation of EVs and cf-DNA from NSCLC patient plasma improves the sensitivity of single nucleotide variants (SNVs) detection and compared observed SNVs with those reported in the matched tissue biopsy. NSCLC patient plasma was subjected to either PA precipitation or cell-free methods and total nucleic acid (TNA) was extracted; SNVs were then detected by next-generation sequencing (NGS). PA led to increased recovery of DNA as well as an improvement in NGS sequencing parameters when compared to cf-TNA. Reduced concordance with tissue was observed in PA-TNA (62%) compared to cf-TNA (81%), mainly due to identification of SNVs in PA-TNA that were not observed in tissue. EGFR mutations were detected in PA-TNA with 83% sensitivity and 100% specificity. In conclusion, PA-TNA may improve the detection limits of low-abundance alleles using NGS.

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Longitudinal monitoring of EGFR mutations in plasma predicts outcomes of NSCLC patients treated with EGFR TKIs: Korean Lung Cancer Consortium (KLCC-12-02)

Oncotarget ◽

10.18632/oncotarget.6874 ◽

2016 ◽

Vol 7 (6) ◽

pp. 6984-6993 ◽

Cited By ~ 75

Author(s):

Ji Yun Lee ◽

Xu Qing ◽

Wei Xiumin ◽

Bai Yali ◽

Sangah Chi ◽

...

Keyword(s):

Lung Cancer ◽

Egfr Mutations ◽

Nsclc Patients ◽

Egfr Tkis

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9138 POSTER Frequency of EGFR Mutations in Greek Non-Small-Cell Lung Cancer (NSCLC) Patients

European Journal of Cancer ◽

10.1016/s0959-8049(11)72450-9 ◽

2011 ◽

Vol 47 ◽

pp. S635

Author(s):

G. Nasioulas ◽

C. Efstathiadou ◽

S. Murray ◽

I. Dahabreh

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Egfr Mutations ◽

Small Cell Lung ◽

Nsclc Patients

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Differential responses to therapy in Hispanic NSCLC patients with EGFR, KRAS, or TP53 mutations.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e21027 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e21027-e21027

Author(s):

Fahmin Basher ◽

Diana Saravia ◽

Gilberto Lopes

Keyword(s):

Checkpoint Inhibitors ◽

Egfr Mutations ◽

Comprehensive Cancer Center ◽

Cancer Center ◽

Kras Mutations ◽

Tp53 Mutations ◽

Hispanic Patients ◽

Tumor Mutational Burden ◽

Receive Treatment ◽

Nsclc Patients

e21027 Background: Hispanic (H) patients with non-small cell lung cancer (NSCLC) tend to have more advanced disease at time of diagnosis and less likely to receive treatment compared to non-Hispanic white (NHW) Americans. While survival outcomes do not differ greatly, Hispanic patients tend to have lower response rates to immunotherapy and to targeted therapy with known EGFR mutations. We sought to determine if Hispanic patients with other common mutations present in NSCLC also demonstrate suboptimal responses to therapy compared to NHW patients. Methods: We performed a retrospective review of 468 patients with advanced stage NSCLC at the University of Miami / Sylvester Comprehensive Cancer Center who underwent next-generation sequencing (NGS) for whom treatment outcomes could be identified. Genomic results were obtained from Guardant360 and Foundation One testing in blood or tissue, respectively. Results: In our cohort, 154 patients (33%) were of Hispanic ethnicity, while 279 patients (60%) were NHW. Median age at time of diagnosis was 59, and 50% were male. PD-L1 status was known for 217 patients, with 110 expressing some level of PD-L1. EGFR mutations were present in 25% of all patients, KRAS mutations in 25%, and TP53 mutations in 61%. Average tumor mutational burden was 4.0 in Hispanic patients and 3.6 in NHW patients. We compared outcomes in patients receiving any therapy as well as those specifically receiving immune checkpoint inhibitors (ICI). No differences in OS were observed in our overall patient cohort between H and NHW patients. However, when stratifying patients with EGFR or KRAS mutations, Hispanic patients exhibit significantly shorter OS than their NHW counterparts. In patients with TP53 mutations, we observed no differences between H and NHW outcomes considering all therapy, but Hispanic patients exhibited improved OS with the use of ICI. Conclusions: Our data suggest that the presence of certain mutations in Hispanic patients with advanced NSCLC may serve some prognostic value in predicting responses to therapy, specifically the use of ICI. Further investigation is indicated to determine mechanisms leading to inferior responses after ICI therapy in Hispanic patients.[Table: see text]

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The combination of EGFR-TKIs and anlotinib as a first-line therapy for EGFR-mutant advanced non-small cell lung cancer: A multicenter, single-arm, phase II clinical trial.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.9030 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 9030-9030

Author(s):

Zhiyong He ◽

Jinghui Lin ◽

Yueming He ◽

Jing Zhang ◽

Dongyong Yang ◽

...

Keyword(s):

Clinical Trial ◽

Adverse Events ◽

Advanced Nsclc ◽

De Novo ◽

Egfr Mutations ◽

Treatment Naïve ◽

Pre Treatment ◽

Egfr Mutant ◽

Nsclc Patients ◽

Egfr Tkis

9030 Background: Currently,EGFR-TKIs are widely accepted as the standard treatment for EGFR- mutant advanced non-small-cell lung cancer (NSCLC); however, acquired resistance is inevitable. Combination therapy is considered as a strategy to overcome the resistance to EGFR-TKIs. Anlotinib, a novel multi-targeting, small-molecule TKI, has shown active to suppress tumor angiogenesis and growth. However, there is still a lack of evidence supporting the use of EGFR-TKIs in combination with anlotinib for the treatment of NSCLC until now. A multi-center, single-arm, phase II clinical trial was therefore designed to examine the efficacy and safety of EGFR-TKIs combined with anlotinib for treatment-naïve, advanced NSCLC patients, and unravel the possible mechanisms. Methods: This study was conducted in 14 research centers in Fujian, China. The main eligibility criteria were stage IV or relapsed nonsquamous NSCLC with EGFR mutations (exon 19 deletion,, and L858R), ECOG score 0-2,and age 20 to 75 years and no previous systemic treatment. Patients with asymptomatic brain metastases were admitted.Eligible patients were given gefitinib (250 mg QD) or icotinib (125 mg TID) in combination with anlotinib (10 mg per day, on days 1‒14; 21 days per cycle) until disease progression. The primary endpoint is progression-free survival (PFS) and safety, and the secondary endpoint is overall survival (OS), objective response rate (ORR) and disease control rate (DCR).Peripheral blood was sampled pre-treatment, once every two months during treatment and after disease progression, and T790M mutation was detected in plasma ctDNA using a droplet digital PCR (ddPCR) assay. Results: Of 60 patients enrolled (August 2, 2018 to May 28, 2020). As of February 1, 2021, 37 patients (61.7%) experienced PFS events and 10 (16.7%) died. The ORR was 78.3%, and the DCR was100%.Median PFS was 13.0 months (95%CI,10.7-15.3).The 5 most common treatment-related adverse events included rash (63.3%), fatigue (55.0%), hypertension (48.3%), diarrhea (33.3%) and hand-foot syndrome (30.0%), and grade 3 adverse events included hypertension (5.0%), rash (1.67%), hypertriglyceridemia (1.67%), vomiting (1.67%) and elevated ALT (1.67%); no grade 4 adverse events or drug-related deaths were observed. Peripheral blood samples were collected from 36 patients pre-treatment, and 30.6% were identified with low-frequency de novo T790M mutations, with the mutation-allele frequency (MAF) ranging from 0.01% to 0.28%. Conclusions: The combination of the first-generation EGFR-TKIs and anlotinib shows impressive ORR and DCR, and acceptable toxicity in treatment-naïve advanced NSCLC patients with activating EGFR mutations, and we observed a high proportion of patients harboring de novo EGFR T790M mutations in this study. Clinical trial information: NCT03720873.

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