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JTO Clinical and Research Reports Dec 2023To compare the performance of droplet digital polymerase chain reaction (ddPCR) and plasma next-generation sequencing (NGS) in detecting clearance of plasma EGFR (pEGFR)...
Brief Report: Droplet Digital Polymerase Chain Reaction Versus Plasma Next-Generation Sequencing in Detecting Clearance of Plasma EGFR Mutations and Carcinoembryonic Antigen Levels as a Surrogate Measure.
INTRODUCTION
To compare the performance of droplet digital polymerase chain reaction (ddPCR) and plasma next-generation sequencing (NGS) in detecting clearance of plasma EGFR (pEGFR) mutations.
METHODS
Patients with treatment-naive advanced EGFR-mutated lung cancer treated with first-line tyrosine kinase inhibitors (TKIs) were included. pEGFR were measured at baseline and first response assessment using ddPCR and NGS. Clearance of pEGFR was defined as undetectable levels after a positive baseline result. Results were correlated with time-to-treatment failure (TTF). In exploratory analysis, corresponding change in carcinoembryonic antigen (CEA) levels was evaluated.
RESULTS
Between January 1, 2020, and December 31, 2021, 27 patients were recruited. Ex19del comprised 74% (20 of 27) and L858R 26% (seven of 27). Osimertinib was used in 59% (16 of 27), dacomitinib 4% (one of 27), and gefitinib/erlotinib 37% (10 of 27). Sensitivity of ddPCR and NGS in detecting pEGFR mutation at baseline was 70% (19 of 27) and 78% (21 of 27), respectively ( = 0.16). All patients with detectable pEGFR by ddPCR were detected by NGS.At a median of 8 (range 3-24) weeks post-TKI initiation, clearance of pEGFR was achieved in 68% (13 of 19) and 71% (15 of 21) using ddPCR and NGS, respectively. Concordance between ddPCR and NGS was 79% (kappa = 0.513, = 0.013). Clearance of pEGFR was associated with longer median TTF (not reached versus 6 months, = 0.03) and median decrease in CEA levels by 70% from baseline.In another cohort of 124 patients, decrease in CEA levels by greater than 70% within 90 days of TKI initiation was associated with doubling of both TTF and overall survival.
CONCLUSIONS
Plasma NGS trended toward higher sensitivity than ddPCR in detecting pEGFR, although both had similar concordance in detecting pEGFR clearance. Our results support using NGS at diagnosis and interchangeability of NGS and ddPCR for monitoring, whereas CEA could be explored as a surrogate for pEGFR clearance.
PubMed: 38162173
DOI: 10.1016/j.jtocrr.2023.100599 -
Lung Feb 2024This study investigated the safety and efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) re-administration after recovery from...
Efficacy and Safety of Re-administration of Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor (EGFR-TKI) After EGFR-TKI-Induced Interstitial Lung Disease (CS-Lung-005).
PURPOSE
This study investigated the safety and efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) re-administration after recovery from EGFR-TKI-induced interstitial lung disease (ILD).
METHODS
This multicenter retrospective study collected data from consecutive advanced NSCLC patients who underwent EGFR-TKI re-administration after recovery from EGFR-TKI-induced ILD.
RESULTS
Fifty-eight patients were registered. The grades of initial TKI-induced ILD were grade 1 to 4. TKIs used for re-administration were erlotinib for 15 patients, osimertinib for 15, gefitinib for 14, afatinib for 13 patients, and dacomitinib for 1 patient. ILD recurred in 13 patients (22.4%), comprising 3 patients with grade 1, 6 patients with grade 2, and 4 patients with grade 3. No significant associations were found between ILD recurrence and age, smoking history, performance status, time from initial ILD to TKI re-administration, or concomitant corticosteroid use. However, the incidence of ILD recurrence was high in cases of repeated use of gefitinib or erlotinib or first time use of osimertinib at TKI re-administration. The ILD recurrence rate was lowest in patients treated with first time use of gefitinib (8%) or erlotinib (8%), followed by patients treated with repeated use of osimertinib (9%). The response rate, median progression-free survival by TKI re-administration, and median overall survival were 55%, 9.6 and 84.8 months, respectively.
CONCLUSION
This study showed that EGFR-TKI re-administration is a feasible and effective treatment for patients who recovered from EGFR-TKI-induced ILD. Our results indicate that re-administration of EGFR-TKI is an important option for long-term prognosis after recovery from EGFR-TKI-induced ILD.
Topics: Humans; Acrylamides; Aniline Compounds; Antineoplastic Agents; ErbB Receptors; Erlotinib Hydrochloride; Gefitinib; Indoles; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Pyrimidines; Retrospective Studies; Tyrosine Kinase Inhibitors
PubMed: 38265672
DOI: 10.1007/s00408-023-00669-9 -
Biomedicine & Pharmacotherapy =... Jul 2024The lesson from many studies investigating the efficacy of targeted therapy in glioblastoma (GBM) showed that a future perspective should be focused on combining...
The lesson from many studies investigating the efficacy of targeted therapy in glioblastoma (GBM) showed that a future perspective should be focused on combining multiple target treatments. Our research aimed to assess the efficacy of drug combinations against glioblastoma stem cells (GSCs). Patient-derived cells U3042, U3009, and U3039 were obtained from the Human Glioblastoma Cell Culture resource. Additionally, the study was conducted on a GBM commercial U251 cell line. Gene expression analysis related to receptor tyrosine kinases (RTKs), stem cell markers and genes associated with significant molecular targets was performed, and selected proteins encoded by these genes were assessed using the immunofluorescence and flow cytometry methods. The cytotoxicity studies were preceded by analyzing the expression of specific proteins that serve as targets for selected drugs. The cytotoxicity study using the MTS assay was conducted to evaluate the effects of selected drugs/candidates in monotherapy and combinations. The most cytotoxic compounds for U3042 cells were Disulfiram combined with Copper gluconate (DSF/Cu), Dacomitinib, and Foretinib with IC values of 52.37 nM, 4.38 µM, and 4.54 µM after 24 h incubation, respectively. Interactions were assessed using SynergyFinder Plus software. The analysis enabled the identification of the most effective drug combinations against patient-derived GSCs. Our findings indicate that the most promising drug combinations are Dacomitinib and Foretinib, Dacomitinib and DSF/Cu, and Foretinib and AZD3759. Since most tested combinations have not been previously examined against glioblastoma stem-like cells, these results can shed new light on designing the therapeutic approach to target the GSC population.
Topics: Humans; Glioblastoma; Neoplastic Stem Cells; Drug Repositioning; Protein Kinase Inhibitors; Cell Line, Tumor; Receptor Protein-Tyrosine Kinases; Brain Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Antineoplastic Agents; Cell Survival
PubMed: 38876048
DOI: 10.1016/j.biopha.2024.116892 -
Heliyon May 2024A775_G776insYVMA, the typical and predominant exon 20 insertion variant in non-small cell lung cancer, exhibits relative insensitivity to covalent -targeted tyrosine...
A775_G776insYVMA, the typical and predominant exon 20 insertion variant in non-small cell lung cancer, exhibits relative insensitivity to covalent -targeted tyrosine kinase inhibitors. However, other less common insertions have shown better responses to -targeted inhibitors. M774delinsWLV is a rare exon 20 insertion subtype and its clinical sensitivity to -targeted inhibitors remains unclear. Furthermore, there is a lack of current studies to elucidate its structure and predict its sensitivity to -targeted tyrosine kinase inhibitors. Herein, we presented a case of non-small cell lung cancer harboring M774delinsWLV who derived favorable response and significant survival benefit from -targeted tyrosine kinase inhibitors. A 60-year-old male with metastatic lung adenocarcinoma carrying M774delinsWLV received pyrotinib monotherapy as first-line treatment. After rapid disease progression at three months, sequential combination therapy with pyrotinib and bevacizumab yielded promising antitumor activity and sustained progression-free survival benefits for nearly a year. Subsequent dacomitinib monotherapy displayed significant activity against this uncommon insertion, resulting in a rapid decrease in tumor markers and partial response, along with progression-free survival of one year. The molecular simulation revealed no significant differences in the overall protein structure and binding pocket region between M774delinsWLV and the wild type. Drug binding dynamics simulation indicated that dacomitinib exhibited the most potent binding activity compared to afatinib, pyrotinib and poziotinib. Conclusively, dacomitinib exhibited promising efficacy against the rare exon 20 insertion M774delinsWLV. Extensive investigation is needed to elucidate the effects of -targeted tyrosine kinase inhibitors on non-small cell lung cancer with different insertion subtypes.
PubMed: 38707278
DOI: 10.1016/j.heliyon.2024.e30312 -
Frontiers in Oncology 2024Front-line therapy with an EGFR tyrosine kinase inhibitor (TKI) is the standard of care for treating patients with advanced nonsquamous NSCLC with the common sensitizing...
BACKGROUND
Front-line therapy with an EGFR tyrosine kinase inhibitor (TKI) is the standard of care for treating patients with advanced nonsquamous NSCLC with the common sensitizing exon 19 deletion and exon 21 L858R point mutations. However, EGFR TKI resistance inevitably develops. The optimal subsequent therapy remains to be identified, although platinum-containing chemotherapy regimens are often administered. Our objectives were to describe baseline characteristics, survival, and subsequent treatment patterns for patients with advanced nonsquamous NSCLC with exon 19 deletion or L858R mutation who received a platinum-based combination regimen after front-line EGFR TKI therapy.
METHODS
This retrospective study used a nationwide electronic health record-derived deidentified database to select adult patients with advanced nonsquamous NSCLC, evidence of exon 19 deletion or L858R mutation, and ECOG performance status of 0-2 who initiated platinum-containing chemotherapy, with or without concomitant immunotherapy, from 1-January-2011 to 30-June-2020 following receipt of any EGFR TKI as first-line therapy or, alternatively, a first- or second-generation EGFR TKI (erlotinib, afatinib, gefitinib, dacomitinib) as first-line therapy followed by the third-generation EGFR TKI osimertinib as second-line therapy. Data cut-off was 30-June-2022. The Kaplan-Meier method was used to estimate overall survival (OS) after initiation of pemetrexed-platinum (n=119) or any platinum-based combination regimen (platinum cohort; n=311).
RESULTS
The two cohorts included two-thirds women (65%-66%) and 57%-58% nonsmokers; median ages were 66 and 65 years in pemetrexed-platinum and platinum cohorts, respectively. Median OS was 10.3 months (95% CI, 8.1-13.9) from pemetrexed-platinum initiation and 12.4 months (95% CI, 10.2-15.2) from platinum initiation; 12-month survival rates were 48% and 51%, respectively; 260 patients (84%) had died by the end of the study.
CONCLUSION
The suboptimal survival outcomes recorded in this study demonstrate the unmet need to identify more effective subsequent treatment regimens for patients with -mutated advanced nonsquamous NSCLC after EGFR TKI resistance develops.
PubMed: 38699642
DOI: 10.3389/fonc.2024.1285280