osimertinib and icotinib

Gefitinib, osimertinib and icotinib are the most commonly used tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) with EGFR mutation. Therapeutic drug monitoring (TDM) for these TKIs has become a standard and essential procedure. Dried plasma spots (DPS) was choosen for microsampling strategies for TDM, allowing easy and cost-effective logistics in many settings. This study developd and validated an assay for the simultaneous quantitative determination of gefitinib, osimertinib and icotinib in DPS by online solid-phase extraction-liquid chromatography-tandem mass spectrometry (online SPE-LC-MS) system. The TKIs were extracted from DPS with methanol and enriched on a Welch Polar-RP SPE column (30 × 4.6 mm, 5 µm), followed by separation on Waters X Bridge C18 analytical column(4.6 × 100 mm, 3.5 µm). The method achieved LLOQ of 2 ng mL

Topics: Carcinoma, Non-Small-Cell Lung; Chromatography, High Pressure Liquid; Drug Monitoring; Gefitinib; Humans; Lung Neoplasms; Tandem Mass Spectrometry

As numerous studies have reported the concentration-exposure relationships of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), therapeutic drug monitoring is a promising approach in lung cancer treatment, aiming to avoid treatment failure or toxicity. A new method for the simultaneous analysis of five EGFR-TKIs (afatinib, erlotinib, gefitinib, icotinib and osimertinib) and their metabolites in human plasma samples was developed and validated using liquid chromatography-tandem mass spectrometry (LC-MS/MS).. The proposed method showed satisfactory results in terms of linearity, sensitivity, specificity, precision (intra- and inter-day coefficients of variation ranged from 1.1 to 13.9%), and accuracy (from 93.3 to 111.1%). The IS-normalized matrix factors were below 15%. The sensitivity and linearity were highly appropriate for the expected concentrations according to the analysis of samples from non-small cell lung caner (NSCLC) patients who received EGFR-TKIs.. The proposed method showed an acceptable reproducibility, high sensitivity and selectivity, and low matrix effects. This method could be significant for monitoring plasma concentrations of the mentioned EGFR-TKIs in NSCLC patients, aiming to improve the efficacy and safety of targeted therapies.

Topics: Acrylamides; Afatinib; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Chromatography, Liquid; Crown Ethers; Erlotinib Hydrochloride; Gefitinib; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Quinazolines; Reproducibility of Results; Tandem Mass Spectrometry

This study profiled the somatic genes mutations and the copy number variations (CNVs) in cerebrospinal fluid (CSF)-circulating tumor DNA (ctDNA) from patients with neoplastic meningitis (NM).. A total of 62 CSF ctDNA samples were collected from 58 NM patients for the next generation sequencing. The data were bioinformatically analyzed by (Database for Annotation, Visualization and Integrated Discovery) DAVID software.. The most common mutated gene was TP53 (54/62; 87.10%), followed by EGFR (44/62; 70.97%), PTEN (39/62; 62.90%), CDKN2A (32/62; 51.61%), APC (27/62: 43.55%), TET2 (27/62; 43.55%), GNAQ (18/62; 29.03%), NOTCH1 (17/62; 27.42%), VHL (17/62; 27.42%), FLT3 (16/62; 25.81%), PTCH1 (15/62; 24.19%), BRCA2 (13/62; 20.97%), KDR (10/62; 16.13%), KIT (9/62; 14.52%), MLH1 (9/62; 14.52%), ATM (8/62; 12.90%), CBL (8/62; 12.90%), and DNMT3A (7/62; 11.29%). The mutated genes were enriched in the PI3K-Akt signaling pathway by the KEGG pathway analysis. Furthermore, the CNVs of these genes were also identified in these 62 samples. The mutated genes in CSF samples receiving intrathecal chemotherapy and systemic therapy were enriched in the ERK1/2 signaling pathway.. This study identified genes mutations in all CSF ctDNA samples, indicating that these mutated genes may be acted as a kind of biomarker for diagnosis of NM, and these mutated genes may affect meningeal metastasis through PI3K-Akt signaling pathway.

Topics: Acrylamides; Adult; Aged; Aniline Compounds; Antineoplastic Agents; Circulating Tumor DNA; Class I Phosphatidylinositol 3-Kinases; Crown Ethers; DNA Copy Number Variations; Female; Genes, erbB-1; High-Throughput Nucleotide Sequencing; Humans; Karnofsky Performance Status; Lung Neoplasms; Male; Meningeal Neoplasms; Middle Aged; Mutation; Mutation Rate; Proto-Oncogene Proteins c-akt; Quinazolines; Young Adult

A 61-year-old Chinese woman was diagnosed as primary pulmonary adenocarcinoma of left superior lobe with epidermal growth factor receptor (EGFR) 19 del mutation positive. Treatment with icotinib was given, but her disease progressed after 6 months remission. CT-guide needle biopsy for the new lesion in inferior lobe of left lung demonstrated intrapulmonary metastasis, and EGFR gene panel by Amplification Refractory Mutation System Polymerase Chain Reaction (ARMS-PCR) confirmed EGFR T790M mutation. Treatment with osimertinib was initiated. After 2 months remission, the disease progressed. Re-biopsy was performed for the tumor in the inferior lobe of left lung, and ARMS-PCR demonstrated no other gene mutation except EGFR 19 del. Icotinib was re-challenged, but disease progressed continuously. Bevacizumab was added, and partial response was achieved after 2-cycle of combination therapy. The non-small cell lung cancer (NSCLC) in this case maintained EGFR activating mutation and lost EGFR T790M mutation was a genetic change after osimertinib treatment. This case suggests the re-challenge of the first-generation EGFR-TKIs combined with bevacizumab may overcome the tumor resistance and prolong survival of NSCLC patient.

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Crown Ethers; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Middle Aged; Quinazolines; Tomography, X-Ray Computed; Treatment Outcome

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have been emerged as the standard selection in non-small cell lung cancer (NSCLC) patients with EGFR sensitive mutations. However, primary or acquired resistance to EGFR-TKIs seems inevitable, especially to third-generation TKIs, which has appeared absence of effective solutions so far.. Here we reported a NSCLC patient with EGFR sensitive mutation of deletion within EGFR exon 19, who had been resistant to icotinib and AZD9291 successively after a period of 18 months response duration. Next-generation sequencing (NGS) technique using plasma sample suggested an acquired EGFR Leu792H mutation, rather than C797S one. Interestingly, the patient obtained another 8 months of disease-free duration with symptoms greatly relieved after repeating icotinib administration. The overall survival of the patient has been thirty-six months and still in the extension.. The presentation of the case may provide some selective therapeutic thoughts for NSCLC patients with acquired EGFR Leu792H mutation suffering resistance to the third-generation TKIs.

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Alleles; Amino Acid Substitution; Aniline Compounds; Antineoplastic Agents; Biomarkers; Brain Neoplasms; Combined Modality Therapy; Crown Ethers; ErbB Receptors; Humans; Magnetic Resonance Imaging; Male; Mutation; Neoplasm Metastasis; Neoplasm Staging; Quinazolines; Retreatment; Tomography, X-Ray Computed; Treatment Outcome

Topics: Acrylamides; Aged; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Crown Ethers; ErbB Receptors; Female; Humans; Lung Neoplasms; Mutation; Quinazolines

The epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer has been successfully treated with tyrosine kinase inhibitors (TKIs). Acquired resistance becomes a tough issue when patients fail to respond to the third-generation TKI osimertinib. This study aimed to report a case baring acquired EGFR L858R/L718Q mutation in the central nervous system induced by osimertinib, which was successfully overcome using afatinib.. A 65-year-old female patient was diagnosed with stage IV non-small-cell lung adenocarcinoma with synchronic brain metastasis in February 2015. Before and during treatment, 416 tumor-related genes were monitored dynamically by liquid biopsies using next-generation sequencing, and the treatment strategy was decided according to the gene status. At baseline, an EGFR L858R mutation in exon 21 was detected, so treatment with icotinib was started. After 8 months, she experienced disease progression with leptomeningeal metastasis and switched to osimertinib based on an acquired EGFR T790 M mutation. After 9 months, her disease progressed and an EGFR L718Q mutation was found in the cerebrospinal fluid. The patient was then challenged with afatinib, and her disease was under control for 4 months. In January 2017, the patient passed away, with an overall survival time of 23 months, 15 months after leptomeningeal metastasis.. The acquired EGFR L718Q mutation in the cerebrospinal fluid resulted in subsequent resistance to osimertinib and could be partly overcome using afatinib, indicating a promising treatment option in the clinic.

Topics: Acrylamides; Afatinib; Aged; Aniline Compounds; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crown Ethers; Disease Progression; Drug Resistance, Neoplasm; ErbB Receptors; Fatal Outcome; Female; Follow-Up Studies; Humans; Lung Neoplasms; Meningeal Carcinomatosis; Mutation; Protein Kinase Inhibitors; Quinazolines

The efficacy of osimertinib was compromised by the development of resistance mechanisms, such as MET amplification. However, cohort studies of osimertinib resistance mechanism, and the correlation of MET and progression-free survival (PFS) after osimertinib resistance have been poorly investigated.. This study was carried out to study the acquired MET amplification after osimertinib resistance in advanced lung adenocarcinoma patients, and interrogate the correlation of clinical prognosis and MET amplification.. We performed capture-based sequencing on longitudinal plasma and tissue samples obtained before osimertinib treatment and after resistance development from lung adenocarcinoma patients to investigate the underlying resistance mechanism. We also investigated the correlation of MET amplification and patient prognosis after osimertinib resistance using Kaplan-Meier analysis.. Paired biopsies before osimertinib treatment and after the resistance development revealed underlying resistance mechanisms. In addition, a cohort of 13 patients who developed disease progression after osimertinib resistance was investigated. Patients with MET amplification after osimertinib resistance commonly had inferior median progression-free survival (mPFS) than patients without MET amplification appearance or increase (3.5 months vs. 9.9 months, p = .117). Patients in MET amplification group also displayed poor median overall survival (mOS) compared to MET amplification negative group (15.6 months vs. 30.7 months, p = .885). Furthermore, combinatorial treatment of first/third-generation EGFR-TKI and crizotinib was efficaciously administrated into two patients with newly acquired MET amplification after osimertinib resistance. Partial responses were achieved by them, both clinically and radiographically.. We investigated the osimertinib resistance mechanism in a small cohort of lung adenocarcinoma patients, and demonstrated MET amplification was correlated with inferior PFS/OS after osimertinib treatment. Moreover, we reported the first clinical evidence of efficacy generated by combination of first-generation EGFR-TKI icotinib and crizotinib after the resistance to osimertinib.

Topics: Acrylamides; Adenocarcinoma of Lung; Adult; Aged; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Carcinogenesis; Cohort Studies; Crizotinib; Crown Ethers; Drug Resistance, Neoplasm; ErbB Receptors; Female; Gene Amplification; High-Throughput Nucleotide Sequencing; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Piperazines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Quinazolines; Survival Analysis