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EGFR exon 21 L858R as an acquired resistance mechanism to nivolumab in a lung cancer patient originally driver gene-negative.

ABSTRACT: The use of immune checkpoint inhibitors targeting PD-1 and PD-L1 in advanced non-small cell lung cancer (NSCLC) has been one of the most significant improvements in recent years. However the resistance mechanisms of immune checkpoint inhibitors require further investigation. Herein we attempted to determine the possible resistance mechanism of nivolumab in a male smoker with advanced adenosquamous carcinoma. After experiencing disease progression on systematic chemotherapy, he was administered nivolumab as a result of high PD-L1 expression. Larger panel gene detection was performed after the failure of nivolumab treatment to investigate the possible resistance mechanism and a new EGFR exon 21 L858R mutation was detected. After a achieving a response with gefitinib, the patient suffered a rapid relapse and died of tumor progression. This case represents the first time EGFR exon 21 L858R has been detected as an acquired resistance mutation to nivolumab. Patients with high PD-L1 expression may exhibit a poor response to EGFR-tyrosine kinase inhibitors. Large panel gene detection remains the optimal choice when confronted with drug resistance.

SUBMITTER: Xia C

PROVIDER: S-EPMC6501009 | biostudies-literature |

REPOSITORIES: biostudies-literature

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3D radiomics predicts EGFR mutation, exon-19 deletion and exon-21 L858R mutation in lung adenocarcinoma.

Project description:BackgroundTo establish a radiomic approach to identify epidermal growth factor receptor (EGFR) mutation status in lung adenocarcinoma patients based on CT images, and to distinguish exon-19 deletion and exon-21 L858R mutation.MethodsTwo hundred sixty-three patients who underwent pre-surgical contrast-enhanced CT and molecular testing were included, and randomly divided into the training (80%) and test (20%) cohort. Tumor images were three-dimensionally segmented to extract 1,672 radiomic features. Clinical features (age, gender, and smoking history) were added to build classification models together with radiomic features. Subsequently, the top-10 most relevant features were used to establish classifiers. For the classifying tasks including EGFR mutation, exon-19 deletion, and exon-21 L858R mutation, four logistic regression models were established for each task.ResultsThe training and test cohort consisted of 210 and 53 patients, respectively. Among the established models, the highest accuracy and sensitivity among the four models were 75.5% (61.7-86.2%) and 92.9% (76.5-99.1%) to classify EGFR mutation, respectively. The highest specificity values were 86.7% (69.3-96.2%) and 70.4% (49.8-86.3%) to classify exon-19 deletion and exon-21 L858R mutation, respectively.ConclusionsCT radiomics can sensitively identify the presence of EGFR mutation, and increase the certainty of distinguishing exon-19 deletion and exon-21 L858R mutation in lung adenocarcinoma patients. CT radiomics may become a helpful non-invasive biomarker to select EGFR mutation patients for invasive sampling.

| S-EPMC7481623 | biostudies-literature

The benefit of anti-angiogenic therapy in EGFR exon 21 L858R mutant non-small cell lung cancer patients: a retrospective study.

Project description:Patients with epidermal growth factor receptor (EGFR) exon 21 L858R substitution benefit less from standard EGFR tyrosine kinase inhibitor (TKI) treatment, and whether anti-angiogenic therapy was beneficial to the EGFR L858R subpopulation was inconclusive. A retrospective study was conducted to investigate the survival benefit and the target characteristics of the anti-angiogenic agent in the EGFR L858R patients in our center, comparing those treated with or without anti-angiogenic therapy (cohort A and cohort B). At the median follow-up time of 31.0 months vs 32.7 months (cohort A vs. B) respectively, Cohort A (n = 58) had a significantly prolonged median OS compared to Cohort B (n = 101) (60.0 months vs.37.0 months, HR 0.51, p = 0.016). Anti-angiogenic therapy significantly prolonged the OS in patients with liver metastases (NA vs.26.0 months, HR 0.17, p = 0.023) comparing to patients without liver metastases (60.0 months vs.37.0 months, HR 0.63, p = 0.129). For brain metastatic patients, anti-angiogenic treatment tended to improve median OS with (65.0 months vs.35.0 months, HR 0.29, p = 0.068) or without brain radiotherapy (73.0 months vs.29.0 months, HR 0.24, p = 0.171). The grade 3 or more adverse events were manageable and consistent with previous studies. Patients with EGFR L858R mutation treated with anti-angiogenic therapy in their course of treatment had a significantly prolonged OS compared to those who had never received an anti-angiogenic agent. Patients with liver metastases might benefit more from anti-angiogenic therapy than those without.

| S-EPMC9418331 | biostudies-literature

The comparison of EGFR-TKI failure modes and subsequent management between exon 19 deletion and exon 21 L858R mutation in advanced non-small-cell lung cancer.

Project description:Background: Advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion (19 Del) and exon 21 L858R mutation (L858R) might be distinct diseases. Therefore, it is necessary to take EGFR mutation subgroups into consideration for making choices of subsequent treatment after tyrosine kinase inhibitors (TKIs) failure. Patients and methods: 174 patients who developed to EGFR-TKI failure were categorized into three cohorts of dramatic progression, gradual progression and local progression. Chi-square was used to compare the distribution of failure modes between 19 Del and L858R. Kaplan-Meier method and Cox Regression were performed for analyses of survival in different subsequent treatments. Results: The distribution of EGFR-TKI failure modes showed no significant difference between 19 Del and L858R. Patients in gradual progression had a longer progression-free survival (PFS) and overall survival (OS) compared with other failure modes in whole population, 19 Del cohort and L858R cohort. 19 Del patients with dramatic progression would obtain survival benefit from chemotherapy, while those with gradual progression got no survival benefit neither from chemotherapy nor previous TKI continuation. However, patients with dramatic or gradual progression would benefit from previous TKI continuation in L858R cohort. Conclusion: For advanced EGFR-positive NSCLC patients with acquired resistance to EGFR-TKI, subsequent treatment should be personalized according to EGFR-TKI failure modes & EGFR mutation subtypes.

| S-EPMC5556650 | biostudies-literature

Osimertinib <i>vs.</i> afatinib as first-line treatment for patients with metastatic non-small cell lung cancer with an <i>EGFR</i> exon 19 deletion or exon 21 L858R mutation.

Project description:BackgroundThe optimal treatment sequencing for patients with metastatic epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) remains a subject of debate. In the United States, osimertinib is the preferred EGFR tyrosine kinase inhibitor (TKI) in the first-line setting. However, small retrospective studies suggest that alternative EGFR TKI sequencing strategies may produce similar outcomes. This study aimed to compare the outcomes of patients with metastatic NSCLC harboring an EGFR exon 19 deletion or exon 21 L858R mutation treated with osimertinib vs. afatinib as first-line therapy.MethodsThis retrospective, single-institution study examined 86 patients with metastatic EGFR-mutant NSCLC treated with either afatinib (n=15) or osimertinib (n=71) in the first-line setting. The primary outcome was progression-free survival (PFS), and secondary endpoints included time on EGFR TKI, overall survival (OS), and the incidence of adverse events (AEs).ResultsThere was no difference in the PFS (median: 27.9 vs. 29.0 months, P=0.75), OS (P=0.18), and the median time on first-line EGFR TKI (23.9 vs. 15.2 months, P=0.10) between the afatinib and osimertinib groups, respectively. The number of AEs was also similar between the two treatment groups (P=0.17).ConclusionsIn this real-world retrospective study, there were no differences in PFS or OS between patients treated with afatinib or osimertinib in the first-line setting. These findings should be further investigated in larger prospective studies.

| S-EPMC10713299 | biostudies-literature

Emerging a Novel VOPP1-EGFR Fusion Coexistent With T790M as an Acquired Resistance Mechanism to Prior Icotinib and Sensitive to Osimertinib in a Patient With EGFR L858R Lung Adenocarcinoma: A Case Report.

Project description:BackgroundEpidermal growth factor receptor (EGFR) fusions are rare genomic events in non-small-cell lung cancer (NSCLC). Clinical support and evidence to guide management are absent for NSCLC patients harboring EGFR fusion.Case presentationIn this case report, we describe a 69-year-old female who received right lobectomy and was diagnosed with pathological stage IIIA lung adenocarcinoma harboring EGFR L858R. Twenty months later he had recurrent disease in the liver, lung, and bone, and was treated with icotinib. A novel vesicular overexpressed in cancer pro-survival protein 1 (VOPP1)-EGFR fusion gene coexistent with T790M were identified by next-generation sequencing using pericardial effusion and blood samples after icotinib treatment, which led to progression after icotinib six months and suggested a potential resistance mechanism. Subsequently, the patient was switched to osimertinib treatment, which resulted in a progression-free survival interval of more than 11 months.ConclusionsThe present results suggested that acquired VOPP1-EGFR fusion gene with T790M potentially serve an additional resistance mechanism to first-generation EGFR tyrosine kinase inhibitors in EGFR-mutated NSCLC. And the present case increases the evidence supporting use of osimertinib for treatment of NSCLC patients harboring EGFR fusion.

| S-EPMC8727519 | biostudies-literature

Association of mutant EGFR L858R and exon 19 concentration in circulating cell-free DNA using droplet digital PCR with response to EGFR-TKIs in NSCLC.

Project description:The present study aimed to determine the diagnostic concordance of plasma epidermal growth factor receptor (EGFR) mutation using droplet digital polymerase chain reaction (ddPCR) with tumor tissue samples and the predictive clinical significance of plasma EGFR mutation concentration. Plasma DNA samples from patients with non-small cell lung cancer (NSCLC) were analyzed for EGFR exon 21 codon 858 (L858R) mutation, deletion of exon 19 (ex19del) and exon 20 codon 790 (T790M) mutation using ddPCR. Firstly, the mutations in the plasma samples were compared with the matched tumor samples to determine the concordance. Secondly, image examination follow-ups were analyzed to assess the association between plasma EGFR mutation concentration and patients' response to EGFR-tyrosine kinase inhibitors (TKIs). A total of 51 patients with NSCLC were enrolled, including 48 newly diagnosed patients. Compared with tumor tissue samples, the sensitivity and specificity of ddPCR were 76.19% (16/21) and 96.55% (28/29) for mutant L858R, and 88.89% (8/9) and 100% (41/41) for ex19del, respectively. No patient exhibited the T790M mutation in the tumor tissue or plasma samples. Furthermore, 5 patients with the L858R mutation and 4 patients with ex19del in plasma and tumor tissue samples had been followed up with image examination for ≥3 months following EGFR-TKI treatment. The baseline mutant EGFR concentrations were positively correlated with a reduction in tumor burden (Spearman's r=0.7000, P=0.0358). When analyzed separately, ex19del concentrations (Spearman's r=1.0000, P<0.0001) were also positively correlated with the reduction, while mutant L858R concentrations were not (Spearman's r=0.7000, P=0.1881). In the present study, detection of plasma EGFR mutations using ddPCR exhibited sufficient concordance with tumor tissue sample results. Baseline plasma mutant EGFR and ex19del concentrations were significantly and positively correlated with response to EGFR-TKIs.

| S-EPMC5530088 | biostudies-other

Clinical utility of liquid biopsy for EGFR driver, T790M mutation and EGFR amplification in plasma in patients with acquired resistance to afatinib.

Project description:BackgroundCell-free DNA (cfDNA) genotyping in plasma using the cobas EGFR Mutation Test v2 (cobas) is the first liquid biopsy as a companion diagnosis to identify the EGFR T790M mutation (T790M) after the failure of treatment of EGFR-tyrosine kinase inhibitors (TKIs) (1st generation, gefitinib [G] and erlotinib [E] and 2nd generation, afatinib [A]). This study investigated the clinical utility of a liquid biopsy for patients who acquired resistance to afatinib.MethodsWe prospectively collected plasma from 51 patients who had acquired resistance to afatinib between April 2015 and November 2016 to evaluate the frequency of T790M by cobas and digital droplet PCR (UMIN000025112). Additionally, we retrospectively reviewed 38 patients who tested by cobas in plasma after G/E failure to compare for T790M detection between A and with G/E.ResultsThe detection rate of EGFR-driver and T790M in plasma in patients treated with A (A group) as a first-line EGFR-TKI was lower than with G/E followed by A (G/E→A group), although the differences were not significant (EGFR-driver: 41% [A] vs. 67% [G/E→A], P=0.1867; and T790M: 8% [A] vs. 17% [G/E→A], P=0.5798). In first-line setting, the detection rate for EGFR-driver and T790M in plasma by cobas was lower in A group than in G/E group, although there was no significant difference (EGFR-driver: 34% [A] vs. 52% [G/E], P=0.2072; and T790M: 10% [A] vs. 27% [G/E], P=0.1161).ConclusionThe detection of EGFR-driver and T790M in plasma by cobas in patients treated with afatinib might be lower than with G/E in a real-world setting.

| S-EPMC7802126 | biostudies-literature

Spotlight on Furmonertinib (Alflutinib, AST2818). The Swiss Army Knife (del19, L858R, T790M, Exon 20 Insertions, "uncommon-G719X, S768I, L861Q") Among the Third-Generation EGFR TKIs?

Project description:Osimertinib, a third-generation (3G) epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is now considered the standard of care for the first-line (1L) treatment of advanced EGFR+ NSCLC due to statistically significant improved progression-free survival (PFS) and overall survival (OS) compared with first-generation (1G) treatment from the FLAURA trial. Recently two other 3G EGFR TKIs (aumolertinib and furmonertinib) have been approved in China for treatment of EGFR T790M+ NSCLC. Randomized Phase 3 trials of these two 3G EGFR TKIs have also demonstrated PFS over gefitinib respectively. Among these two Chinese home-grown, 3G EGFR TKIs, furmonertinib seems to most closely resemble osimertinib in terms of dosing regimen, efficacy and adverse events profile. In this article, we reviewed the clinical activity and adverse events of furmonertinib at 80 mg daily (approved dose), potential usage of 160 mg daily for CNS metastasis in EGFR+ NSCLC, and usage of 160 mg or 240 mg daily in EGFR exon20 insertion positive (EGFRex20ins+) NSCLC patients.

| S-EPMC9617553 | biostudies-literature

Differential MicroRNA Expression between EGFR T790M and L858R Mutated Lung Cancer.

Project description:BACKGROUND:MicroRNAs (miRNAs) are short, non-coding RNAs that mediate post-transcriptional gene regulation. They are commonly deregulated in human malignancies, including non-small cell lung cancer (NSCLC). The aim of this study is to investigate miRNA expression in T790M-mutated NSCLC resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. METHODS:Six cases of resected NSCLC harboring the T790M mutation were examined. We performed miRNA time polymerase chain reaction (PCR) array profiling using EGFR T790M-mutated NSCLC and L858R-mutated NSCLC. Once identified, miRNAs that were differentially expressed between the two groups were validated by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS:miRNA PCR array profiling revealed three up-regulated miRNAs whose expression levels were altered 4.0-fold or more in the EGFR T790M mutation group than in the L858R group: miR-1 (fold change, 4.384), miR-196a (fold change, 4.138), and miR-124 (fold change, 4.132). The three differentially expressed miRNAs were validated by qRT-PCR, and they were found to be overexpressed in the T790M group relative to L858R group. In particular, expression levels of miR-1 and miR-124 were significantly higher in the T790M group (p-value of miR-1 = .004, miR-124 = .007, miR-196a = .096). CONCLUSIONS:MiR-1, miR-124, and miR-196a are overexpressed in EGFR T790M mutated NSCLC.

| S-EPMC6166019 | biostudies-literature

Comparative assessment of NOIR-SS and ddPCR for ctDNA detection of EGFR L858R mutations in advanced L858R-positive lung adenocarcinomas.

Project description:Genotyping epidermal growth factor receptor (EGFR) is an essential process to indicate lung adenocarcinoma patients for the most appropriate treatment. Liquid biopsy using circulating tumor DNA (ctDNA) potentially complements the use of tumor tissue biopsy for identifying genotype-specific mutations in cancer cells. We assessed the performance of a high-fidelity sequencing method that uses molecular barcodes called the nonoverlapping integrated read sequencing system (NOIR-SS) for detecting EGFR L858R-mutated alleles in 33 advanced or recurrent patients with L858R mutation-positive lung adenocarcinoma revealed by matched tissue biopsy. We compared NOIR-SS with site-specific droplet digital PCR (ddPCR), which was taken as the reference, in terms of sensitivity and ability to quantify L858R variant allele fractions (VAFs). NOIR-SS and ddPCR had sensitivities of 87.9% (29/33) and 78.8% (26/33) for detecting L858R alleles, respectively. The VAFs measured by each assay were strongly correlated. Notably, one specimen was positive with a VAF of 30.12% for NOIR-SS but marginally positive with that of 0.05% for ddPCR because of a previously poorly recognized mechanism: two-base substitution-induced L858R (c.2573_2574delinsGA). These results indicate that NOIR-SS is a useful method for detecting ctDNA, potentially overcoming a limitation of ddPCR which highly depends on the binding ability of primers to specific targeting sequences.

| S-EPMC8298558 | biostudies-literature

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