MSelection of NSCLC patients to treat with EGFR inhibitors in the era of personalized medicine

2012 ◽  
pp. 18-32
Author(s):  
Rafael Rosell ◽  
Laura Bonanno ◽  
Miquel Taron
Keyword(s):  
Personalized Medicine ◽  
Egfr Inhibitors ◽  
Nsclc Patients

scholarly journals P1.14-61 EGFR Inhibitors Plus Bevacizumab Are Superior Compared to EGFR Inhibitor Monotherapy in Advanced EGFR+ NSCLC Patients with BIM Deletions

2019 ◽  
Vol 14 (10) ◽  
pp. S579
Author(s):  
A.F. Cardona ◽  
O.G. Arrieta ◽  
A. Ruiz-Patiño ◽  
Z.L. Zatarain Barrón ◽  
L.L. Rojas ◽  
...  
Keyword(s):  
Egfr Inhibitors ◽  
Egfr Inhibitor ◽  
Nsclc Patients

Addition of selpercatinib to overcome osimertinib resistance in non-small cell lung cancer (NSCLC) with acquired RET fusion detected in ctDNA at very low allele frequency.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3046-3046
Author(s):  
Leeseul Kim ◽  
Young Kwang Chae ◽  
Chan Mi Jung ◽  
Alice Daeun Lee ◽  
Emma Yu
Keyword(s):  
Allele Frequency ◽  
Treatment Regimen ◽  
Brain Mri ◽  
Acquired Resistance ◽  
Egfr Inhibitors ◽  
Variant Allele ◽  
Leptomeningeal Disease ◽  
Precision Oncology ◽  
Variant Allele Frequency ◽  
Nsclc Patients

3046 Background: Osimertinib, a highly selective third generation EGFR tyrosine kinase inhibitor (TKI) became the standard front-line therapy for EGFR-mutant NSCLC. However, therapeutic options are limited for TKI resistance which commonly occurs. Therefore, overcoming acquired resistance to osimertinib remains an important high unmet need in the field of precision oncology. Herein, we present the first case of advanced adenocarcinoma of the lung that showed notable response with the addition of selpercatinib after acquired resistance to osimertinib monotherapy. Methods: Case presentation. Results: A 37-year-old woman with stage IVB adenocarcinoma of lung with osseous, hepatic and brain metastases initially received one cycle of carboplatin, pemetrexed and pembrolizumab. Based on the EGFR exon19 deletion detected from ctDNA NGS assay (Guardant 360) [variant allele frequency (VAF) 62.7%], the treatment regimen was changed to osimertinib monotherapy (80mg PO daily). Bevacizumab was empirically added given CNS involvement. She maintained overall stable disease for 10 months before subsequent CT showed disease progression. The treatment regimen was switched to atezolizumab, bevacizumab, paclitaxel and carboplatin combination therapy. She tolerated 6 cycles of the regimen in 4 month before a subsequent brain MRI revealed progression of the metastatic brain disease with new leptomeningeal disease. Whole brain radiotherapy was performed and decision was made to start combination TKI treatment of selpercatinib (120mg BID) added to the osimertinib (80mg daily) monotherapy based on her repeat ctDNA NGS assay result showing concurrent acquired CCDC6RET fusion (VAF 0.05%) and EGFR exon 19 deletion (VAF 10.0%). The 6 week follow-up CT demonstrated significant decrease in the largest lung mass (33.95*24.22mm->32.50*16.07mm). Repeat ctDNA NGS assay at one week after selpercatinib use showed disappearance of RET fusion and significant decrease in EGFR clone (VAF 10.0% to 0.05%). Conclusions: It has been reported that co-occurring RET fusions in NSCLC patients with EGFR mutations may contribute to acquired resistance to EGFR inhibitors. Several successful cases of cabozantinib, a non-selective RET inhibitor, or pralsetinib, a selective RET inhibitor combined with EGFR inhibitor, have been reported to aid in overcoming the acquired resistance to EGFR inhibitors. To date, there has been no report of clinical benefit in adding a RET inhibitor based on ctDNA detection of RET fusion with minute variant allele frequency. We for the first time report the case of overcoming acquired resistance to osimertinib by adding selpercatinib, a selective RET inhibitor in NSCLC patients with acquired RET fusion detected in ctDNA at VAF of 0.05%.

Roles of cMET/ErbB3 activation and overexpression in the development of resistance to EGFR inhibitors in NSCLC patients.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 11113-11113
Author(s):  
Myung-Ju Ahn ◽  
Silvia Park ◽  
Jong-Mu Sun ◽  
Jin Seok Ahn ◽  
Keunchil Park ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Mapk Pathway ◽  
Objective Response ◽  
Gene Mutations ◽  
Continuous Variable ◽  
Egfr Inhibitors ◽  
Striking Difference ◽  
Critical Pathway ◽  
Development Of Resistance ◽  
Nsclc Patients

11113 Background: Multifaceted efforts in the molecular and cellular research of lung cancer revealed many critical pathway dysregulations due genetic and epigenetic alterations to alter balances in signal transduction leading to carcinogenesis. Methods: US guided FNAs or pleural fluid were collected from 44 NSCLC patients enrolled in on-going prospective study involving EGFR inhibitors (gefitinib, erlotinib, or afatinib) and evaluated for EGFR as well as other various receptor tyrosine kinases (RTKs, i.e. ErbB2, ErbB3, cMET, IGF1R, ALK, etc) and downstream AKT and MAPK pathway proteins for their level of expression and activation in order to 1) Compare objective response rate according to the expression/activation of RTK and pathway proteins; 2) Evaluate the modulation of the RTK and pathway proteins during the treatment of EGFRi; 3) Correlate between activating EGFR gene mutations and RTK activation in patients treated with EGFRi. Results: Majority of patients over-expressed EGFR. While not overexpressed, varying and significant levels of cMET and ErbB3 were found and quantitated in each patient. A striking difference in PFS was observed with respect to relative levels of cMET to EGFR in pretreatment FNA. Regardless of EGFR mutation status, patients with higher levels of EGFR to cMET (or higher E/M-Index) showed superior PFS. With an increase in cMET involvement (or decrease in E/M-Index; continuous variable), NSCLC patients exhibited worse clinical outcome with reduction in PFS (as shown in the Table). Furthermore, patients with shorter PFS (< 8 months) had significantly higher levels of total and phosphorylated ErbB3 (67% positive) than patients with longer PFS (>8 months, 27% positive). Conclusions: This study clearly demonstrates the critical roles of cMET and ErbB3 in resistance to EGFR inhibitors in NSCLC patients. E/M-Index and activation may serve as predictive markers for treatment selection with EGFRi and cMETi, and should be validated in prospective clinical studies. [Table: see text]

scholarly journals Outcome of EGFR inhibitors treatment in advanced NSCLC patients, not enrolled in clinical trials

Neoplasma ◽  
2017 ◽  
Vol 64 (02) ◽  
pp. 253-261 ◽  
Author(s):  
M. Mencoboni ◽  
R. A. Filiberti ◽  
P. Taveggia ◽  
A. Bruzzone ◽  
A. Garuti ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Advanced Nsclc ◽  
Egfr Inhibitors ◽  
Nsclc Patients

scholarly journals EGFR Inhibitors Plus Bevacizumab are Superior Than EGFR Inhibitors Alone as First-Line Setting in Advanced NSCLC With EGFR Mutations and BIM Deletion Polymorphisms (BIM-CLICaP)

2021 ◽  
pp. 839-848
Author(s):  
Andrés F. Cardona ◽  
Camila Ordóñez-Reyes ◽  
Alejandro Ruiz-Patiño ◽  
Juan Esteban Garcia-Robledo ◽  
Lucia Zatarain Barron ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Overall Survival ◽  
Advanced Nsclc ◽  
Egfr Inhibitors ◽  
Egfr Mutations ◽  
First Line ◽  
Chain Reaction ◽  
Polymerase Chain ◽  
Nsclc Patients ◽  
Egfr Tkis

PURPOSE BIM activation is essential for epidermal growth factor receptor ( EGFR)-tyrosine kinase inhibitor (TKI)–triggered apoptosis in EGFR-mutant non–small-cell lung cancer (NSCLC). A deletion in the intron two of the BIM gene results in generation of alternatively spliced isoforms that impairs their apoptotic response to TKIs, conferring the NSCLC cells intrinsic resistance to these medications. Patients with both alterations have poor clinical evolution. The current study aimed to investigate the clinical efficacy and tolerability of EGFR-TKIs plus bevacizumab (Bev) versus EGFR-TKIs alone as first-line treatment in advanced NSCLC patients with EGFR mutations and BIM deletions ( BIMdel). MATERIALS AND METHODS A retrospective analysis was conducted. BIMdel was detected using polymerase chain reaction analysis and direct sequencing of DNA. BIM protein expression was investigated by immunohistochemistry, and BIM mRNA levels by reverse transcriptase-polymerase chain reaction. Clinical characteristics, overall survival, progression-free survival (PFS), overall response rate (ORR), and treatment-related adverse events were compared between both groups. RESULTS Thirty-three patients were included; 15 received EGFR-TKIs, and 18 received EGFR-TKIs plus Bev. The median age was 63 years, with a majority of recruited female patients. All included individuals had an Eastern Cooperative Oncology Group performance score of 2 or less. The addition of Bev resulted in a significantly higher ORR (94.4% v 40%, P > .001). Median PFS was longer with the use of the combination therapy (11.12 v 7.87 months; P = .001). Median overall survival tended to be longer in the EGFR-TKIs plus Bev (30.9 v 25.4 months; P = .06) but failed to reach statistical significance. Response in terms of both partial and complete as well as overall favorably affected PFS. CONCLUSION EGFR-TKIs plus Bev conferred a significantly higher ORR and PFS in advanced NSCLC patients with EGFR mutation and BIMdel. Further prospective studies are needed to validate these findings.

Efficacy and Safety of EGFR Inhibitors in the Treatment of EGFRPositive NSCLC Patients: A Meta-analysis

2020 ◽  
Vol 15 ◽  
Author(s):  
Amit Dang ◽  
Sumit Dang ◽  
Vallish BN
Keyword(s):  
Subgroup Analysis ◽  
Objective Response ◽  
Nonsmall Cell Lung Cancer ◽  
Egfr Inhibitors ◽  
Egfr Mutations ◽  
Controlled Trials ◽  
Cochrane Central Register ◽  
Targeted Chemotherapy ◽  
Egfr Inhibitor ◽  
Nsclc Patients

Background:: We compared the response rates, survival rates, and safety profile of epidermal growth factor receptor (EGFR) inhibitors with non-targeted chemotherapy and older EGFR inhibitors when used to treat advanced nonsmall cell lung cancer (NSCLC) patients with activating EGFR mutations. Methods:: We searched PubMed, Cochrane Central Register of Controlled Trials, and clinicaltrial.gov for randomized controlled trials published until 11-Feb-2020. Treatment outcomes were compared between EGFR inhibitor and pooled comparator; a subgroup analysis compared outcomes between EGFR inhibitor and non-targeted chemotherapy, and between newer and older EGFR inhibitors. Results:: Twenty-one studies with 4,250 unique patients were included. Significantly higher objective response rate (ORR) (odds ratio (OR) 2.28; 95% CI 2.00-2.61), higher disease control rate (DCR) (OR 2.3; 95% CI 1.88-3.06), and longer progression-free survival (PFS) (Hazard ratio (HR) 0.56; 95% CI 0.52-0.60) were observed in the EGFR inhibitor group compared to the pooled comparator group. Subgroup analysis revealed that the ORR, DCR, and PFS were significantly higher with EGFR inhibitors than non-targeted chemotherapy, and only PFS (and not ORR and DCR) was significantly longer with newer EGFR inhibitors than the older EGFR inhibitors. Overall survival (OS) was not significantly different between EGFR inhibitors and pooled comparator (HR 0.91; 95% CI 0.83-1.00) as well as in either of the subgroup analyses. Adverse events ≥ grade 3 and treatment discontinuation were significantly higher with non-targeted chemotherapy compared to the EGFR inhibitors. Conclusions:: The benefits of prolongations of ORR, DCR, and PFS might not imply significantly improved OS after therapy with EGFR inhibitors when compared with non-targeted chemotherapy or older EGFR inhibitors.

Ligands of EGFR and the insulin-like growth factor family as serum biomarkers for response to EGFR-inhibitors in patients with advanced NSCLC

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8100-8100
Author(s):  
M. A. Vollebergh ◽  
I. Kappers ◽  
M. M. van den Heuvel ◽  
J. C. Buning-Kager ◽  
C. M. Korse ◽  
...  
Keyword(s):  
Overall Survival ◽  
Growth Factor ◽  
Proportional Hazards ◽  
Transforming Growth Factor ◽  
Advanced Nsclc ◽  
Egfr Inhibitors ◽  
Control Group ◽  
Insulin Like Growth Factor ◽  
Transforming Growth Factor Α ◽  
Nsclc Patients

8100 Background: To determine whether concentrations of transforming growth factor α (TGFa), amphiregulin (ARG), both ligands of the epidermal growth factor receptor (EGFR), insulin-like growth factor 1(IGF1) or IGF-binding protein 3 (IGFBP3) measured in serum of advanced non-small cell lung cancer (NSCLC) patients are predictive of EGFR-inhibitors (EGFRi) response. Methods: We assessed serum levels of marker candidates using ELISA (TGA and ARG) and chemiluminescent (IGF1 and IGFBP3) assays. Sixty-one advanced NSCLC patients treated with EGFRi (gefitinib or erlotinib, >14 days) were matched for gender, age and histology to a control group of 63 EGFRi-untreated advanced NSCLC patients. We dichotomized marker levels at the 20th, 50th or 80th percentile and evaluated whether the effect of EGFRi treatment on overall survival (OS) differed by marker level based on multivariate proportional hazards regression with an interaction term. We adjusted for gender, smoking, stage, histology and prior chemotherapy. Results: While 6-months OS did not appreciably differ between 50 EGFRi treated and 50 control patients whose TGFa levels were below the 80th percentile (39% vs. 54%, multivariate HR 0.78, 95% CI 0.45–1.34, p=0.359), it was substantially worse for 11 EGFRi treated patients compared with 13 control patients whose TGFa levels were high (9% vs. 42%, multivariate HR 2.38, 95% CI 0.87–6.52, p=0.092). The difference of EGFRi effects by TGFa level was statistically significant (interaction p=0.033). There was no evidence that EGFRi treatment effects differed by levels of ARG, IGF1 and IGFBP3. Patients with high concentrations of IGFBP3 (above the median) had significantly longer OS than patients with low IGFBP3 concentrations, independent of treatment (HR 0.46, 95% CI 0.29–0.73, p=0.001). Conclusions: This is the first study in NSCLC patients of Caucasian origin in which serum concentrations of TGFa are predictive for EGFR-inhibitor response, suggesting this is a potential predictive marker for EGFRi treatment. Furthermore, we coincidentally found that levels of IGFBP3 are predictive for overall survival, indicating this might be a prognostic factor in advanced NSCLC patients. [Table: see text]

72: Audit of outcomes of NSCLC patients treated with first line EGFR inhibitors in North East England

Lung Cancer ◽  
2015 ◽  
Vol 87 ◽  
pp. S28
Author(s):  
J. Margetts ◽  
E. Smith ◽  
E. Aynsley ◽  
J. Gardiner ◽  
A. Hughes ◽  
...  
Keyword(s):  
Egfr Inhibitors ◽  
First Line ◽  
North East ◽  
Nsclc Patients
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