Osimertinib in UntreatedEGFR-Mutated Advanced Non–Small-Cell Lung Cancer

New England Journal of Medicine, Journal Year: 2017, Volume and Issue: 378(2), P. 113 - 125

Published: Nov. 18, 2017

Osimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI–sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR-TKIs in patients previously untreated, mutation–positive advanced non–small-cell lung cancer (NSCLC).

Language: Английский

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Non–Small Cell Lung Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology

Journal of the National Comprehensive Cancer Network, Journal Year: 2022, Volume and Issue: 20(5), P. 497 - 530

Published: May 1, 2022

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommended management patients with NSCLC, including diagnosis, primary treatment, surveillance relapse, and subsequent treatment. Patients metastatic lung cancer who are eligible targeted therapies or immunotherapies now surviving longer. This selection from the NSCLC focuses on actionable mutations.

Language: Английский

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Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer

British Journal of Cancer, Journal Year: 2019, Volume and Issue: 121(9), P. 725 - 737

Published: Sept. 29, 2019

Abstract Osimertinib is an irreversible, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that highly selective for EGFR- activating mutations as well the EGFR T790M mutation in patients with advanced non-small cell lung cancer (NSCLC) oncogene addiction. Despite documented efficacy of osimertinib first- and second-line settings, inevitably develop resistance, no further clear-cut therapeutic options to date other than chemotherapy locally ablative therapy selected individuals. On account high degree tumour heterogeneity adaptive cellular signalling pathways NSCLC, acquired resistance heterogeneous, encompassing - dependent EGFR-independent mechanisms. Furthermore, data from repeat plasma genotyping analyses have highlighted differences frequency preponderance mechanisms when administered a front-line versus setting, underlying discrepancies selection pressure clonal evolution. This review summarises molecular mutated including MET/HER2 amplification, activation RAS–mitogen-activated protein (MAPK) or RAS–phosphatidylinositol 3-kinase (PI3K) pathways, novel fusion events histological/phenotypic transformation, discussing current evidence regarding potential new approaches counteract resistance.

Language: Английский

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Systemic Therapy for Locally Advanced and Metastatic Non–Small Cell Lung Cancer

JAMA, Journal Year: 2019, Volume and Issue: 322(8), P. 764 - 764

Published: Aug. 27, 2019

Importance

Non–small cell lung cancer remains the leading cause of death in United States. Until last decade, 5-year overall survival rate for patients with metastatic non–small was less than 5%. Improved understanding biology has resulted development new biomarker–targeted therapies and led to improvements advanced or disease.

Observations

Systemic therapy is selected according presence specific biomarkers. Therefore, all should undergo molecular testing relevant mutations expression protein PD-L1 (programmed ligand 1). Molecular alterations that predict response treatment (eg,EGFRmutations,ALKrearrangements,ROS1rearrangements, andBRAFV600E mutations) are present approximately 30% cancer. Targeted these improves progression-free compared cytotoxic chemotherapy. For example, somatic activating theEGFRgene 20% Tyrosine kinase inhibitors such as gefitinib, erlotinib, afatinib improve susceptibleEGFRmutations. In overexpression ALK protein, significantly better crizotinib (a tyrosine inhibitor) combination pemetrexed either cisplatin carboplatin (platinum-based chemotherapy) (74% vs 45%, respectively;P < .001) (median, 10.9 months 7.0 months;P .001). Subsequent generations have improved agents. without biomarkers indicating susceptibility targeted treatments, immune checkpoint inhibitor–containing regimens monotherapy chemotherapy superior alone. These advances biomarker-directed survival. currently exceeds 25% among whose tumors high (tumor proportion score ≥50%) 40% withALK-positive tumors.

Conclusions Relevance

subtypes more newer empirical

Language: Английский

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Properties of FDA-approved small molecule protein kinase inhibitors

Pharmacological Research, Journal Year: 2019, Volume and Issue: 144, P. 19 - 50

Published: March 13, 2019

Language: Английский

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Investigating Novel Resistance Mechanisms to Third-Generation EGFR Tyrosine Kinase Inhibitor Osimertinib in Non–Small Cell Lung Cancer Patients

Clinical Cancer Research, Journal Year: 2018, Volume and Issue: 24(13), P. 3097 - 3107

Published: March 5, 2018

Purpose: The third-generation EGFR tyrosine kinase inhibitor osimertinib is approved to treat patients with T790M-positive non-small cell lung cancer (NSCLC) who have developed resistance earlier-generation drugs. Acquired C797S mutation has been reported mediate in some patients. However, the remaining mechanisms are largely unknown.Experimental Design: We performed profiling using targeted next-generation sequencing (NGS) for 416 cancer-relevant genes on 93 osimertinib-resistant patients' samples, mainly cell-free DNAs (cfDNAs), and matched pretreatment samples of 12 In vitro experiments were conducted functionally study secondary mutations identified.Results:EGFR G796/C797, L792, L718/G719 identified 24.7%, 10.8%, 9.7% cases, respectively, certain coexisting one patient different prevalence. L792 L718 mutants markedly increased half inhibitory concentration (IC50) vitro, among which L718Q conferred greatest osimertinib, as well gefitinib when not T790M. Further analysis confirmed that these acquired during treatment. Alterations parallel or downstream oncogenes such MET, KRAS, PIK3CA also discovered, potentially contributing osimertinib-resistance without mutations.Conclusions: present comprehensive profiles a large cohort cfDNA. Besides C797 mutations, novel residues confer resistance, both vivo, great clinical pharmaceutical relevance. Clin Cancer Res; 24(13); 3097-107. ©2018 AACR.

Language: Английский

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Small molecule inhibitors targeting the EGFR/ErbB family of protein-tyrosine kinases in human cancers

Pharmacological Research, Journal Year: 2018, Volume and Issue: 139, P. 395 - 411

Published: Nov. 27, 2018

Language: Английский

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Engineered T Cell Therapy for Cancer in the Clinic

Frontiers in Immunology, Journal Year: 2019, Volume and Issue: 10

Published: Oct. 11, 2019

T cells play a key role in cell-mediated immunity, and strategies to genetically modify cells, including chimeric antigen receptor (CAR) cell therapy (TCR) therapy, have achieved substantial advances the treatment of malignant tumors. In clinical trials, CAR-T TCR-T therapies produced encouraging outcomes, thereby demonstrating their therapeutic potential mitigating tumor development. This article summarizes current applications trials worldwide. It is predicted that engineered immunotherapies will become safe, well-tolerated effective therapeutics bring hope cancer patients.

Language: Английский

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EGFR in Cancer: Signaling Mechanisms, Drugs, and Acquired Resistance

Cancers, Journal Year: 2021, Volume and Issue: 13(11), P. 2748 - 2748

Published: June 1, 2021

The epidermal growth factor receptor (EGFR) has served as the founding member of large family receptors harboring intrinsic tyrosine kinase function. High abundance EGFR and internal deletions are frequently observed in brain tumors, whereas point mutations small insertions within domain common lung cancer. For these reasons its preferred heterodimer partner, HER2/ERBB2, became popular targets anti-cancer therapies. Nevertheless, research keeps revealing unexpected observations, which reviewed herein. Once activated by a ligand, initiates time-dependent series molecular switches comprising downregulation cohort microRNAs, up-regulation newly synthesized mRNAs, covalent protein modifications, collectively controlling phenotype-determining genes. In addition to long non-coding RNAs circular play critical roles signaling. Along with driver mutations, drives metastasis many ways. Paracrine loops tumor stromal cells enable fuel invasion across tissue barriers, survival clusters circulating cells, well colonization distant organs. We conclude listing all clinically approved drugs targeting either or HER2. Because emergence drug resistance is nearly inevitable, we discuss major evasion mechanisms.

Language: Английский

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Lung Cancers: Molecular Characterization, Clonal Heterogeneity and Evolution, and Cancer Stem Cells

Cancers, Journal Year: 2018, Volume and Issue: 10(8), P. 248 - 248

Published: July 27, 2018

Lung cancer causes the largest number of cancer-related deaths in world. Most (85%) lung cancers are classified as non-small-cell (NSCLC) and small-cell (15%) (SCLC). The 5-year survival rate for NSCLC patients remains very low (about 16% at 5 years). two predominant histological phenotypes adenocarcinoma (ADC) squamous cell carcinoma (LSQCC). ADCs display several recurrent genetic alterations, including: KRAS, BRAF EGFR mutations; mutations amplifications oncogenes, including ERBB2, MET, FGFR1 FGFR2; fusion oncogenes involving ALK, ROS1, Neuregulin1 (NRG1) RET. In LSQCC TP53, FGFR1, FGFR2, FGFR3, DDR2 genes PI3K pathway have been detected, quantitative gene abnormalities PTEN CDKN2A. Developments characterization molecular provided a strong rationale new therapeutic options understanding mechanisms drug resistance. However, complexity genomes is particularly high, shown by deep-sequencing studies supporting heterogeneity tumors cellular level, with sub-clones exhibiting different combinations mutations. Molecular performed on during treatment phenomenon clonal evolution, thus occurrence temporal tumor heterogeneity.

Language: Английский

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