osimertinib and alectinib

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Male; Oncogene Proteins, Fusion; Piperidines; Prognosis

Topics: Acrylamides; Aniline Compounds; Antibodies, Monoclonal; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Humans; Immunotherapy; Molecular Targeted Therapy; Nivolumab; Piperazines; Piperidines; Progression-Free Survival

Overall survival in metastatic lung cancer has been dramatically improved with the use of small molecule kinase inhibitors (SMKIs). Quantification of SMKI in cerebrospinal fluid (CSF) can be used to assess penetration of these drugs into the central nervous system. This paper describes an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for quantification of the SMKIs alectinib, lorlatinib and osimertinib in human CSF. Alectinib-d8 and dasatinib-d8 were used as internal standards. Aliquots with 25 µL CSF/30% albumin (9:1,v/v) were mixed with 100 µL internal standard solution consisting of 1 ng/mL dasatinib-d8 and alectinib-d8 in acetonitrile. The analytes were separated by an Acquity UPLC® HSS T3 column (2.1 ×150 mm, 1.8 µm), using gradient elution (ammonium formate pH 4.5, acetonitrile) with a flow rate of 0.400 mL/min. All calibration curves were linear for the concentration range from 2.50 to 250 ng/mL. Within-run and between-run precision varied from 0.72% to 11.7%, with accuracy ranging from 95.3% to 113.2%. For all compounds, a high degree of non-specific binding to the vacutainer was observed. This issue could be countered easily by a combination of pre-coating with BSA solution (30%) in phosphate buffer pH 4.2, and immediate sample mixture with BSA solution after collection. To test the clinical applicability, CSF was collected in seven unique patients using alectinib (n = 1), lorlatinib (n = 2), and osimertinib (n = 4). Measured CSF trough concentrations ranged between 3.37 and 116 ng/mL.

Topics: Chromatography, High Pressure Liquid; Chromatography, Liquid; Dasatinib; Humans; Lactams, Macrocyclic; Reproducibility of Results; Tandem Mass Spectrometry

The echinoderm microtubule associated protein-like 4 gene (EML4) encodes the predominant anaplastic lymphoma kinase (ALK) fusion partner in non-small-cell lung cancer (NSCLC); however, the dynactin subunit 1 (DCTN1)-ALK rearrangement is extremely rare. The co-occurrence of primary epidermal growth factor receptor (EGFR) T790M mutation with EGFR exon 19 deletion (del) in patients with NSCLC is uncommon. Here we report a female lung adenocarcinoma patient with brain metastases and possible coexistence of primary EGFR T790M mutation/EGFR exon 19 del/DCTN1-ALK translocation. The patient received multiline treatment including chemotherapy, antivascular, and targeted therapies. To overcome developed resistance to chemotherapy or targeted therapy to prolong overall survival, the patient's circulating tumor DNA (ctDNA) was dynamically monitored. The patient responded to successive osimertinib and alectinib treatment, and alectinib achieved a nearly complete response for lung and brain lesions after she acquired osimertinib resistance. Furthermore, we summarize 22 published cases of patients with lung adenocarcinoma with concurrent EGFR mutation and ALK rearrangement, including details of clinical characteristics, natural history, and pertinent therapy of this uncommon tumor subtype. This literature review shows that EGFR inhibition was an indispensable aspect of the treatment of patients with EGFR/ALK co-alterations in the pre-alectinib era and that ALK inhibition with crizotinib did not show more eye-catching therapeutic results. Considering the effectiveness achieved by alectinib, this case study provides a new perspective for the treatment of lung cancer brain metastasis patients with concurrent EGFR/ALK mutations.

Topics: Acrylamides; Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Aniline Compounds; Brain; Carbazoles; Carcinoma, Non-Small-Cell Lung; Dynactin Complex; ErbB Receptors; Female; Humans; Lung Neoplasms; Mutation; Piperidines; Protein Kinase Inhibitors

Molecular agents targeting the epidermal growth factor receptor (EGFR)-, anaplastic lymphoma kinase (ALK)- or c-ros oncogene 1 (ROS1) alterations have revolutionized the treatment of oncogene-driven non-small-cell lung cancer (NSCLC). However, the emergence of acquired resistance remains a significant challenge, limiting the wider clinical success of these molecular targeted therapies. In this study, we investigated the efficacy of various molecular targeted agents, including erlotinib, alectinib, and crizotinib, combined with anti-vascular endothelial growth factor receptor (VEGFR) 2 therapy. The combination of VEGFR2 blockade with molecular targeted agents enhanced the anti-tumor effects of these agents in xenograft mouse models of EGFR-, ALK-, or ROS1-altered NSCLC. The numbers of CD31-positive blood vessels were significantly lower in the tumors of mice treated with an anti-VEGFR2 antibody combined with molecular targeted agents compared with in those of mice treated with molecular targeted agents alone, implying the antiangiogenic effects of VEGFR2 blockade. Additionally, the combination therapies exerted more potent antiproliferative effects in vitro in EGFR-, ALK-, or ROS1-altered NSCLC cells, implying that VEGFR2 inhibition also has direct anti-tumor effects on cancer cells. Furthermore, VEGFR2 expression was induced following exposure to molecular targeted agents, implying the importance of VEGFR2 signaling in NSCLC patients undergoing molecular targeted therapy. In conclusion, VEGFR2 inhibition enhanced the anti-tumor effects of molecular targeted agents in various oncogene-driven NSCLC models, not only by inhibiting tumor angiogenesis but also by exerting direct antiproliferative effects on cancer cells. Hence, combination therapy with anti-VEGFR2 antibodies and molecular targeted agents could serve as a promising treatment strategy for oncogene-driven NSCLC.

Topics: A549 Cells; Acrylamides; Anaplastic Lymphoma Kinase; Angiogenesis Inhibitors; Aniline Compounds; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Combined Modality Therapy; Crizotinib; Drug Synergism; Erlotinib Hydrochloride; Female; Genes, erbB-1; Heterografts; Humans; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Targeted Therapy; Mutation; Neovascularization, Pathologic; Oncogenes; Piperidines; Platelet Endothelial Cell Adhesion Molecule-1; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Ramucirumab; Random Allocation; Signal Transduction; Vascular Endothelial Growth Factor Receptor-2

Routine therapeutic drug monitoring is a promising approach for the rational use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and anaplastic lymphoma kinase (ALK) inhibitors. The purpose of this study was to develop and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of 5 EGFR-TKIs (afatinib, dacomitinib, erlotinib, gefitinib, and osimertinib) and 3 ALK inhibitors (alectinib, ceritinib, and crizotinib).. A 100-mL aliquot of serum was diluted with 100 μL of 1% aqueous ammonia containing internal standards and then purified using the supported liquid extraction method. LC-MS/MS was conducted in positive ionization mode, and the method was validated according to published guidelines.. Calibration curves were linear across concentration ranges examined. The intra- and interassay accuracies were 90.7%-110.7% and 94.7%-107.6%, respectively. All intra- and interassay imprecision values were ≤10.1%. The EGFR-TKIs and ALK inhibitors examined in this study, except osimertinib, which could be stored on ice for at least 5 hours, were stable at room temperature for 3 hours. For the internal standard-normalized matrix factors, the mean recovery and percent coefficient of variation values ranged between 54%-112% and 1.7%-11.7%, respectively. This method successfully determined serum concentrations of afatinib, alectinib, erlotinib, gefitinib, and osimertinib in clinical samples. Serum levels of kinase inhibitors consistently reflected those reported in previous studies.. An LC-MS/MS method suitable for the simultaneous determination of 5 EGFR-TKIs and 3 ALK inhibitors in serum was developed and validated. The newly developed method enabled the determination of 5 of 8 target drugs examined in clinical samples. However, a large number of clinical samples need to be analyzed to verify the usefulness of the method.

Topics: Acrylamides; Afatinib; Aniline Compounds; Carbazoles; Chromatography, Liquid; Crizotinib; Erlotinib Hydrochloride; Gefitinib; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Quinazolinones; Sulfones; Tandem Mass Spectrometry

Leptomeningeal carcinomatosis (LMC) occurs frequently in anaplastic lymphoma kinase (ALK)-rearranged NSCLC and develops acquired resistance to ALK tyrosine kinase inhibitors (ALK TKIs). This study aimed to clarify the resistance mechanism to alectinib, a second-generation ALK TKI, in LMC and test a novel therapeutic strategy.. We induced alectinib resistance in an LMC mouse model with ALK-rearranged NSCLC cell line, A925LPE3, by continuous oral alectinib treatment, established A925L/AR cells. Resistance mechanisms were analyzed using several assays, including Western blot and receptor tyrosine kinase array. We also measured amphiregulin (AREG) concentrations in cerebrospinal fluid from patients with ALK-rearranged NSCLC with alectinib-refractory LMC by enzyme-linked immunosorbent assay.. A925L/AR cells were moderately resistant to various ALK TKIs, such as alectinib, crizotinib, ceritinib, and lorlatinib, compared with parental cells in vitro. A925L/AR cells acquired the resistance by EGFR activation resulting from AREG overexpression caused by decreased expression of microRNA-449a. EGFR TKIs and anti-EGFR antibody resensitized A925L/AR cells to alectinib in vitro. In the LMC model with A925L/AR cells, combined treatment with alectinib and EGFR TKIs, such as erlotinib and osimertinib, successfully controlled progression of LMC. Mass spectrometry imaging showed accumulation of the EGFR TKIs in the tumor lesions. Moreover, notably higher AREG levels were detected in cerebrospinal fluid of patients with alectinib-resistant ALK-rearranged NSCLC with LMC (n = 4), compared with patients with EGFR-mutated NSCLC with EGFR TKI-resistant LMC (n = 30), or patients without LMC (n = 24).. These findings indicate the potential of novel therapies targeting both ALK and EGFR for the treatment of ALK TKI-resistant LMC in ALK-rearranged NSCLC.

Topics: Acrylamides; Amphiregulin; Anaplastic Lymphoma Kinase; Aniline Compounds; Animals; Carbazoles; Cell Line, Tumor; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Lung Neoplasms; Meningeal Carcinomatosis; Mice; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

Topics: Acrylamides; Amphiregulin; Aniline Compounds; Carbazoles; Humans; Lung Neoplasms; Meningeal Carcinomatosis; Piperidines; Receptor Protein-Tyrosine Kinases

Topics: Acrylamides; Amphiregulin; Aniline Compounds; Carbazoles; Humans; Lung Neoplasms; Meningeal Carcinomatosis; Piperidines; Receptor Protein-Tyrosine Kinases

Topics: Acrylamides; Afatinib; Aminopyridines; Anaplastic Lymphoma Kinase; Aniline Compounds; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; B7-H1 Antigen; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; ErbB Receptors; Gefitinib; Hope; Humans; Lactams; Lung; Lung Neoplasms; Piperidines; Programmed Cell Death 1 Receptor; Pyrazoles; Quinazolinones; Survival Analysis

Guidelines recommend testing for multiple biomarkers in non-small cell lung cancer (NSCLC) tumors. Blood-based liquid biopsy analyzing cell-free DNA (cfDNA) could be used in addition to tumor biopsy genotyping, especially if tissue/time are limiting.. To investigate the clinical utility of early cfDNA analysis (Guardant360® CDx) in treatment-naïve NSCLC patients.. A prospective cohort of treatment-naïve patients with metastatic NSCLC who underwent tumor and cfDNA analysis between 12/2018 and 2/2019 were included.. Ten patients were included: 6 males, median age 70.5 years (range 48-87), 8 prior smokers. Liquid biopsy was sent when cancer cells were detected in the biopsy specimen. Median time from diagnosis to receiving the report on the last biomarker from the tumor biopsy was 20 days (range 9-34); median time from blood draw to receiving the cfDNA findings was 9 days (range 7-12). The median difference between the cfDNA and the tumor analysis reports was 20 days (range 9-28). Actionable biomarkers were identified in four patients by both the biopsy analysis and the cfDNA analysis (2cases with EGFR mutations, one with ROS1 fusion, and one with EML4-ALK fusion for whom the biopsy analysis also identified an EGFR mutation not detected in the cfDNA analysis). Overall, eight patients received treatment (2 died before treatment initiation). Three patients received biomarker-based treatment (1 osimertinib, 1 alectinib, and 1 crizotinib).. These findings suggest that cfDNA analysis should be ordered by the pulmonologists early in the evaluation of patients with NSCLC, which might complement the tumor biopsy.

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aged, 80 and over; Aniline Compounds; Antineoplastic Agents; Biomarkers, Tumor; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; DNA, Neoplasm; Female; Genotyping Techniques; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Prospective Studies

The development and full validation of a sensitive and selective ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method are described for the simultaneous analysis of afatinib, alectinib, crizotinib and osimertinib in human lithium heparinized plasma. Afatinib-d6, crizotinib-d5 and erlotinib-d6 were used as internal standards. Given osimertinib's instability in plasma and whole blood at ambient temperature, samples should be solely processed on ice (T = 0 °C). Chromatographic separation was obtained on an Acquity UPLC ® BEH C18; 2.1 × 50 mm, 1.7 μm column, which was eluted with 0.400 mL/minute flow on a linear gradient, consisting of 10 mM ammonium formate (pH 4.5) and acetonitrile. Calibration curves for all compounds were linear for concentration ranges of 1.00 to 100 ng/mL for afatinib and 10.0 to 1000 ng/mL for alectinib, crizotinib and osimertinib, herewith validating the lower limits of quantification at 1.00 ng/mL for afatinib and 10.0 ng/mL for alectinib, crizotinib and osimertinib. Within-run and between-run precision measurements fell within 10.2%, with accuracy ranging from 89.2 to 110%.

Topics: Acrylamides; Afatinib; Aniline Compounds; Carbazoles; Chromatography, High Pressure Liquid; Crizotinib; Drug Stability; Humans; Limit of Detection; Linear Models; Male; Middle Aged; Piperazines; Piperidines; Reproducibility of Results; Tandem Mass Spectrometry