scholarly journals Successful treatment of a patient with NSCLC carrying uncommon compound EGFR G719X and S768I mutations using osimertinib: A case report

2020 ◽  
Vol 48 (6) ◽  
pp. 030006052092879
Author(s):  
Yangyang Cai ◽  
Yizhuo Wang ◽  
Jingnan Sun ◽  
Xu Wang ◽  
Yinghui Xu ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Postoperative Outcome ◽  
Postoperative Recurrence ◽  
Small Cell Lung ◽  
Epidermal Growth ◽  
First And Second Generation ◽  
Egfr Tkis

The discovery of epidermal growth factor receptor ( EGFR) somatic mutations and the availability of tyrosine kinase inhibitors (TKIs) as targeted therapies have altered the therapeutic prospects of advanced non-small-cell lung cancer (NSCLC). G719X and S768I are uncommon mutations, and they often exist as compound mutations. A few reports have described the efficacy of first- and second-generation EGFR-TKIs. However, the efficacy of osimertinib in patients with these uncommon compound mutations is unknown. In this study, we reported the postoperative outcome of a patient with NSCLC and uncommon compound EGFR G719X and S768I mutations. After postoperative recurrence, the patient was treated with osimertinib, and an excellent and long-lasting clinical response was achieved. The patient has taken osimertinib for 31.0 months and exhibited a partial response, and her follow-up is ongoing.

scholarly journals Clinical Definition of Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small-Cell Lung Cancer

2010 ◽  
Vol 28 (2) ◽  
pp. 357-360 ◽  
Author(s):  
David Jackman ◽  
William Pao ◽  
Gregory J. Riely ◽  
Jeffrey A. Engelman ◽  
Mark G. Kris ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Somatic Mutations ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Small Cell Lung ◽  
Epidermal Growth ◽  
Definition Of ◽  
Egfr Tki ◽  
Egfr Tkis

Ten percent of North American patients with non–small-cell lung cancer have tumors with somatic mutations in the gene for the epidermal growth factor receptor (EGFR). Approximately 70% of patients whose lung cancers harbor somatic mutations in exons encoding the tyrosine kinase domain of EGFR experience significant tumor regressions when treated with the EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib. However, the overwhelming majority of these patients inevitably acquire resistance to either drug. Currently, the clinical definition of such secondary or acquired resistance is not clear. We propose the following criteria be used to define more precisely acquired resistance to EGFR TKIs. All patients should have the following criteria: previous treatment with a single-agent EGFR TKI (eg, gefitinib or erlotinib); either or both of the following: a tumor that harbors an EGFR mutation known to be associated with drug sensitivity or objective clinical benefit from treatment with an EGFR TKI; systemic progression of disease (Response Evaluation Criteria in Solid Tumors [RECIST] or WHO) while on continuous treatment with gefitinib or erlotinib within the last 30 days; and no intervening systemic therapy between cessation of gefitinib or erlotinib and initiation of new therapy. The relatively simple definition proposed here will lead to a more uniform approach to investigating the problem of acquired resistance to EGFR TKIs in this unique patient population. These guidelines should minimize reporting of false-positive and false-negative activity in these clinical trials and would facilitate the identification of agents that truly overcome acquired resistance to gefitinib and erlotinib.

Insulin-like growth factor-1 receptor/epidermal growth factor receptor (EGFR) heterodimerization and resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13032-13032 ◽  
Author(s):  
F. Morgillo ◽  
W. K. Hong ◽  
H. Lee
Keyword(s):  
Lung Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Small Cell Lung ◽  
Epidermal Growth ◽  
Induced Apoptosis ◽  
Egfr Tkis

13032 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been used to treat lung cancers, but resistance to these agents has been observed. This study was designed to investigate whether the insulin-like growth factor (IGF)-mediated signaling pathway induces resistance to the EGFR TKIs in lung cancer. Methods: The antitumor activities and action mechanisms of EGFR inhibitors (erlotinib, gefinitib, cetuximab), single or in combination with IGF-IR inhibitors, were assessed in vitro in a subset of non-small-cell lung cancer (NSCLC) cell lines by the MTT assay, flow cytometry-based TUNEL assay, soft agar, confocal microscopy, metabolic labeling, coimmunoprecipitation, and northern and western blot analyses, and in vivo in animal models. Correlation of EGFR and IGF-1R expression was assessed using lung tissues from patients with NSCLC. Results: EGFR TKI inhibited the proliferation and anchorage-dependent and -independent colony-forming ability of NSCLC cells, which induced apoptosis, only when IGF-1R signaling was blocked. Treatment with EGFR TKIs, but not with the EGFR antibody, induced EGFR:IGF-1R heterodimerization on cell surface and activation of the IGF-1R, resulting in the stimulation of PI3K/Akt/ mTOR pathway, promoting the de novo protein biosynthesis of survivin and EGFR, resulting in the survival of NSCLC cells. When IGF-IR and mTOR were blocked, treatment of EGFR-TKIs induced apoptosis in NSCLC cells, resulting in suppression of the NSCLC tumor growth. When we tested the expression of IGF-R and EGFR in human lung tissue, 9/14 tumor samples exhibited increased expression of EGFR and 7/9 samples showed a correlative increases in IGF-IR protein levels compared to their paired normal counterparts. Conclusions: These findings suggest that simultaneous targeting of EGFR and IGF-1R signaling pathways might be an effective therapeutic strategy against NSCLC. No significant financial relationships to disclose.

scholarly journals Real-world clinical outcomes of first-generation and second-generation epidermal growth factor receptor tyrosine kinase inhibitors in a large cohort of European non-small-cell lung cancer patients

ESMO Open ◽  
2020 ◽  
Vol 5 (6) ◽  
pp. e001011
Author(s):  
Adam Pluzanski ◽  
Maciej Krzakowski ◽  
Dariusz Kowalski ◽  
Rafal Dziadziuszko
Keyword(s):  
Real World ◽  
First Generation ◽  
Second Generation ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Small Cell ◽  
Small Cell Lung ◽  
First Line ◽  
Epidermal Growth ◽  
Egfr Tkis

BackgroundFirst-generation or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are commonly used in EGFR-mutation-positive advanced non-small-cell lung cancer (NSCLC) with no relevant differences in efficacy in randomised clinical trials (RCTs). Patients enrolled to RCTs may differ from NSCLC population in everyday practice. Limited real-world experience (RWE) exists on efficacy of EGFR TKIs in European patient cohorts.Patients and methodsIn this retrospective study, real-world data of all patients who started first-line EGFR TKIs between 2012 and 2016 in Poland were analysed. The main endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoints were an objective response rate and toxicity.ResultsA total of 620 treatment-naive EGFR mutated patients with stage III/IV NSCLC were analysed with follow-up time of 24.5 months. A significantly longer median PFS (p=0.005) and higher 1-year OS rate (p=0.004) for afatinib (16.4 months and 78.2%) vs gefitinib (10.3 months and 69.1%) and erlotinib (12.1 months and 71.6%) were observed. In multivariate analysis toxicity was predictive for PFS and OS. In patients with adverse events (AEs) versus those without AEs, improved median PFS (13.6 months vs 8.8 months) and median OS (23.6 vs 15.5 months) were observed. Median OS in the group with AE of grades 3–4 and those with AE of grades 1–2 were 42.1 months and 23.4 months, respectively.ConclusionThis study represents the largest RWE of first-line TKI therapy in a European country with longer survival of patients receiving second-generation TKI. We confirmed in everyday practice the role of toxicity as a marker of clinical benefit.

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