- Determination of Somatic Mutations and Tumor Mutation Burden in Plasma by CAPP-Seq during Afatinib Treatment in NSCLC Patients Resistance to Osimertinib. [Journal Article]Sci Rep 2020; 10(1):691SR
- Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were developed to target the EGFR T790M resistance mutation in non-small cell lung cancer (NSCLC) patients resistant to first- or second-generation EGFR-TKIs. To investigate the efficacy of afatinib treatment for EGFR T790M-positive NSCLC patients showing resistance to osimertinib and alterations in somatic…
Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were developed to target the EGFR T790M resistance mutation in non-small cell lung cancer (NSCLC) patients resistant to first- or second-generation EGFR-TKIs. To investigate the efficacy of afatinib treatment for EGFR T790M-positive NSCLC patients showing resistance to osimertinib and alterations in somatic mutations and tumor mutation burden (TMB) in plasma circulating tumor DNA (ctDNA) during afatinib treatment, we conducted a prospective study using Cancer Personalized Profiling by deep Sequencing (CAPP-Seq). Nine NSCLC patients with EGFR T790M mutation who showed resistance to third-generation EGFR-TKIs were enrolled in this study and treated with afatinib. Plasma samples were collected before treatment, 4 weeks after treatment, and at disease progression. The mutation profile and TMB in plasma ctDNA were analyzed by CAPP-Seq. The objective response rate and median progression-free survival associated with afatinib were 0% and 2.0 months, respectively. The C797S mutation-mediated resistance to osimertinib was observed in one patient and following afatinib treatment in two patients; the C797S mutations occurred in the same allele as the T790M mutation. After afatinib treatment, afatinib-sensitive mutant alleles, such as ERBB2, and TMB decreased. We have demonstrated that detection of mutant allele frequency and TMB of ctDNA by CAPP-Seq could help determine the effectiveness of and resistance to afatinib. Although afatinib monotherapy for T790M-positive NSCLC resistant to osimertinib was less effective, the action for multiclonal mutant alleles and TMB might contribute to further treatment strategy.
- Observational Study of Treatment Patterns in Patients with Epidermal Growth Factor Receptor (EGFR) Mutation-Positive Non-Small Cell Lung Cancer After First-Line EGFR-Tyrosine Kinase Inhibitors. [Journal Article]Adv Ther 2020AT
- CONCLUSIONS: Following 1L EGFR-TKI treatment, 19% of patients were tested for EGFR T790M, and most (69%) had no record of receiving any subsequent therapy.
- ONO-7475, a novel AXL inhibitor, suppresses the adaptive resistance to initial EGFR-TKI treatment in EGFR-mutated non-small lung cancer. [Journal Article]Clin Cancer Res 2020CC
- CONCLUSIONS: These results demonstrate that ONO-7475 suppresses the emergence and maintenance of tolerant cells to the initial EGFR-TKIs, osimertinib or dacomitinib, in AXL-overexpressing EGFR-mutated NSCLC cells, suggesting that ONO-7475 and osimertinib is a highly potent combination for initial treatment.
- Abivertinib in patients with T790M-positive advanced NSCLC and its subsequent treatment with osimertinib. [Journal Article]Thorac Cancer 2020TC
- CONCLUSIONS: Abivertinib is a unique novel third-generation EGFR TKI with good tolerance and efficacy in EGFR T790M(+) NSCLC patients. For patients with progressive disease after treatment with abivertinib, osimertinib could be an option for subsequent therapy but further studies are required.Abivertinib is a novel third-generation EGFR TKI targeting the EGFR T790M mutation Abivertinib is well tolerated and efficacious in T790M-positive patients Abivertinib has a unique structure, efficacy, and resistance mechanism compared with osimertinib Osimertinib treatment after AC0010 showed a good response.
- IGF2 autocrine-mediated IGF1R activation is a clinically relevant mechanism of osimertinib resistance in lung cancer. [Journal Article]Mol Cancer Res 2020MC
- EGFR-mutated lung cancer accounts for a significant proportion of lung cancer cases worldwide. For these cases, osimertinib, a third-generation EGFR tyrosine kinase inhibitor, is extensively used as a 1st or 2nd line treatment. However, lung cancer cells acquire resistance to osimertinib in 1-2 years. Thus, a thorough clarification of resistance mechanisms to osimertinib is highly anticipated. Re…
EGFR-mutated lung cancer accounts for a significant proportion of lung cancer cases worldwide. For these cases, osimertinib, a third-generation EGFR tyrosine kinase inhibitor, is extensively used as a 1st or 2nd line treatment. However, lung cancer cells acquire resistance to osimertinib in 1-2 years. Thus, a thorough clarification of resistance mechanisms to osimertinib is highly anticipated. Recent next-generation sequencing (NGS) of lung cancer samples identified several genetically defined resistance mechanisms to osimertinib, such as EGFR C797S or MET amplification. However, non-genetically defined mechanisms are not well evaluated. For thorough clarification of osimertinib resistance, both genetic and non-genetic mechanisms are essential. By using our comprehensive protein phosphorylation array, we detected IGF1R bypass pathway activation after EGFR abolishment. Both of our established lung cancer cells and patient-derived lung cancer cells demonstrated IGF2 autocrine-mediated IGF1R pathway activation as a mechanism of osimertinib resistance. Notably, this resistance mechanism was not detected by a previously performed NGS, highlighting the essential roles of living cancer cells for thorough clarification of resistance mechanisms. Interestingly, the immunohistochemical analysis confirmed the increased IGF2 expression in lung cancer patients who were treated with osimertinib and met the established clinical definition of acquired resistance. The findings highlight the crucial roles of cell-autonomous ligands expression in osimertinib resistance. Here, we report for the first time the IGF2 autocrine-mediated IGF1R activation as a non-genetic mechanism of osimertinib resistance in lung cancer at a clinically relevant level. Implications: Using comprehensive protein phosphorylation array and patient-derived lung cancer cells, we found that IGF2 autocrine-mediated IGF1R pathway activation is a clinically relevant and common mechanism of acquired resistance to osimertinib.
- Front-Line Therapy in Advanced Non-Small Cell Lung Cancer With Sensitive Epidermal Growth Factor Receptor Mutations: a Network Meta-Analysis. [Review]Clin Ther 2020CT
- CONCLUSIONS: Osimertinib seemed to be a better option as upfront therapy for EGFR-mutant NSCLC in terms of efficacy and tolerability.
- Osimertinib in patients with advanced/metastatic epidermal growth factor receptor T790M mutation-positive non-small cell lung cancer - the Belgian ASTRIS data. [Journal Article]Acta Clin Belg 2020; :1-8AC
- CONCLUSIONS: We here demonstrate the effectiveness of osimertinib in a real-world setting in Belgian patients with locally advanced or metastatic T790M-positive NSCLC who had received previous EGFR-TKI treatment. No new safety signals were identified.
- Osimertinib and dihydroartemisinin: a novel drug combination targeting head and neck squamous cell carcinoma. [Journal Article]Ann Transl Med 2019; 7(22):651AT
- CONCLUSIONS: The results illustrate that the combinatory therapy of osimertinib and DHA, as a repurposing anticancer drug, could be a novel therapeutic strategy for recurrent and/or metastatic HNSCC patients. The findings strongly indicate that a clinical trial is warranted to confirm the benefit of the combination.
- Venous Sinus Stenting for Transverse Sinus Stenosis Associated with Leptomeningeal Carcinomatosis in a Patient with Epidermal Growth Factor Receptor-Mutated Lung Cancer: A Case Report. [Journal Article]Am J Case Rep 2020; 21:e918488AJ
- CONCLUSIONS: Venous sinus stenting can offer an effective palliative interventional option for symptom relief of severe headache and visual symptoms, even in the end stage of malignancy.
New Search Next
- Osimertinib treatment for patients with EGFR exon 20 mutation positive non-small cell lung cancer. [Journal Article]Lung Cancer 2019; 141:9-13LC
- CONCLUSIONS: Osimertinib has limited antitumor activity in patients with EGFR exon 20 mutated NSCLC, with an ORR of 5 %.