Treating Patients With EGFR-Sensitizing Mutations: First Line or Second Line—Is There a Difference?

2013 ◽  
Vol 31 (8) ◽  
pp. 1081-1088 ◽  
Author(s):  
Tony Mok ◽  
Jin-Ji Yang ◽  
Kwok-Chi Lam
Keyword(s):  
Drug Exposure ◽  
Tumor Response ◽  
Kinase Inhibitor ◽  
Performance Status ◽  
Egfr Mutations ◽  
Poor Performance Status ◽  
Second Line ◽  
First Line ◽  
The Impact ◽  
Egfr Tki

First-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) is a standard treatment for patients with activating EGFR mutations. Six randomized studies have demonstrated consistent improvement in tumor response rate and progression-free survival over platinum-based combination chemotherapy. The only reason to consider EGFR TKI as second-line therapy is that none of the six comparative studies has shown improvement in overall survival, which can be explained by the high proportion of patients from the chemotherapy arm crossing over to the EGFR TKI arm on progression. It is true that patients with EGFR mutations may benefit from second-line EGFR TKI therapy, but we cannot conclude that the benefit is either equal to or inferior to first-line EGFR TKI therapy. To date, there are no direct comparative data between first- and second-line EGFR TKI in patients with activating EGFR mutations. Tumor response rates to second-line EGFR TKI have been inconsistent, which could potentially be explained by the impact of first-line chemotherapy on the abundance of tumor cells with activating EGFR mutations. However, numerous arguments, including assurance on drug exposure, improvement in quality of life, better tolerance by patients with poor performance status, and deferral of whole-brain radiation therapy for patients with brain metastasis, support the general application of first-line EGFR TKI.

scholarly journals Molecular and Clinical Features of EGFR-TKI-Associated Lung Injury

2021 ◽  
Vol 22 (2) ◽  
pp. 792
Author(s):  
Tohru Ohmori ◽  
Toshimitsu Yamaoka ◽  
Koichi Ando ◽  
Sojiro Kusumoto ◽  
Yasunari Kishino ◽  
...  
Keyword(s):  
Lung Injury ◽  
Tyrosine Kinase ◽  
Performance Status ◽  
Cytotoxic Agents ◽  
Egfr Mutations ◽  
Poor Performance Status ◽  
Chronic Obstructive ◽  
Tki Treatment ◽  
Egfr Tki ◽  
Egfr Tkis

The tyrosine kinase activity of epidermal growth factor receptors (EGFRs) plays critical roles in cell proliferation, regeneration, tumorigenesis, and anticancer resistance. Non-small-cell lung cancer patients who responded to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) and obtained survival benefits had somatic EGFR mutations. EGFR-TKI-related adverse events (AEs) are usually tolerable and manageable, although serious AEs, including lung injury (specifically, interstitial lung disease (ILD), causing 58% of EGFR-TKI treatment-related deaths), occur infrequently. The etiopathogenesis of EGFR-TKI-induced ILD remains unknown. Risk factors, such as tobacco exposure, pre-existing lung fibrosis, chronic obstructive pulmonary disease, and poor performance status, indicate that lung inflammatory circumstances may worsen with EGFR-TKI treatment because of impaired epithelial healing of lung injuries. There is limited evidence from preclinical and clinical studies of the mechanisms underlying EGFR-TKI-induced ILD in the available literature. Herein, we evaluated the relationship between EGFR-TKIs and AEs, especially ILD. Recent reports on mechanisms inducing lung injury or resistance in cytokine-rich circumstances were reviewed. We discussed the relevance of cytotoxic agents or immunotherapeutic agents in combination with EGFR-TKIs as a potential mechanism of EGFR-TKI-related lung injury and reviewed recent developments in diagnostics and therapeutics that facilitate recovery from lung injury or overcoming resistance to anti-EGFR treatment.

American Society of Clinical Oncology Provisional Clinical Opinion: Epidermal Growth Factor Receptor (EGFR) Mutation Testing for Patients With Advanced Non–Small-Cell Lung Cancer Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy

2011 ◽  
Vol 29 (15) ◽  
pp. 2121-2127 ◽  
Author(s):  
Vicki Leigh Keedy ◽  
Sarah Temin ◽  
Mark R. Somerfield ◽  
Mary Beth Beasley ◽  
David H. Johnson ◽  
...  
Keyword(s):  
Egfr Mutation ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Mutation Testing ◽  
Phase Iii ◽  
Egfr Mutations ◽  
First Line ◽  
First Line Therapy ◽  
Egfr Tki ◽  
Egfr Mutation Testing

Purpose An American Society of Clinical Oncology (ASCO) provisional clinical opinion (PCO) offers timely clinical direction to ASCO's membership following publication or presentation of potentially practice-changing data from major studies. This PCO addresses the clinical utility of using epidermal growth factor receptor (EGFR) mutation testing for patients with advanced non–small-cell lung cancer (NSCLC) to predict the benefit of taking a first-line EGFR tyrosine kinase inhibitor (TKI). Clinical Context Patients with EGFR-mutated NSCLC have a significantly higher rate of partial responses to the EGFR TKIs gefitinib and erlotinib. In the United States, approximately 15% of patients with adenocarcinoma of the lung harbor activating EGFR mutations. EGFR mutation testing is widespread at academic medical centers and in some locales in community practice. As of yet, there is no evidence of an overall survival (OS) benefit from selecting treatment based on performing this testing. Recent Data One large phase III trial (the Iressa Pan-Asia Study [IPASS] trial), three smaller phase III randomized controlled trials using progression-free survival as the primary end point, and one small phase III trial with OS as the primary end point, all involving first-line EGFR TKIs and chemotherapy doublets, form the basis of this PCO. Provisional Clinical Opinion On the basis of the results of five phase III randomized controlled trials, patients with NSCLC who are being considered for first-line therapy with an EGFR TKI (patients who have not previously received chemotherapy or an EGFR TKI) should have their tumor tested for EGFR mutations to determine whether an EGFR TKI or chemotherapy is the appropriate first-line therapy. NOTE. ASCO's provisional clinical opinions (PCOs) reflect expert consensus based on clinical evidence and literature available at the time they are written and are intended to assist physicians in clinical decision making and identify questions and settings for further research. Because of the rapid flow of scientific information in oncology, new evidence may have emerged since the time a PCO was submitted for publication. PCOs are not continually updated and may not reflect the most recent evidence. PCOs cannot account for individual variation among patients and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It is the responsibility of the treating physician or other health care provider, relying on independent experience and knowledge of the patient, to determine the best course of treatment for the patient. Accordingly, adherence to any PCO is voluntary, with the ultimate determination regarding its application to be made by the physician in light of each patient's individual circumstances. ASCO PCOs describe the use of procedures and therapies in clinical practice and cannot be assumed to apply to the use of these interventions in the context of clinical trials. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of ASCO's PCOs, or for any errors or omissions.

scholarly journals Clinical Outcomes After First-Line Egfr-Tki for Patients with Nsclc, Egfr Mutation, and Poor Performance Status

2014 ◽  
Vol 25 ◽  
pp. v95
Author(s):  
Makoto Nagamata ◽  
Yusuke Okuma ◽  
Kuniko Sunami ◽  
Yukio Hosomi ◽  
Tatsuru Okamura
Keyword(s):  
Clinical Outcomes ◽  
Egfr Mutation ◽  
Performance Status ◽  
Poor Performance ◽  
Poor Performance Status ◽  
First Line ◽  
Egfr Tki

scholarly journals A Real-World, Observational, Prospective Study to Assess the Molecular Epidemiology of Epidermal Growth Factor Receptor (EGFR) Mutations upon Progression on or after First-Line Therapy with a First- or Second-Generation EGFR Tyrosine Kinase Inhibitor in EGFR Mutation-Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer: The ‘LUNGFUL’ Study

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3172
Author(s):  
Giannis Mountzios ◽  
Anna Koumarianou ◽  
Alexandros Bokas ◽  
Dimitrios Mavroudis ◽  
Epaminondas Samantas ◽  
...  
Keyword(s):  
Molecular Epidemiology ◽  
Disease Progression ◽  
Real World ◽  
Second Generation ◽  
Egfr Mutation ◽  
Kinase Inhibitor ◽  
Performance Status ◽  
Locally Advanced ◽  
Egfr Mutations ◽  
Egfr Tki

Background: Real-world data on the molecular epidemiology of EGFR resistance mutations at or after progression with first- or second-generation EGFR-TKIs in patients with advanced NSCLC are lacking. Methods: This ongoing observational study was carried out by 23 hospital-based physicians in Greece. The decision to perform cobas®EGFR Mutation Test v2 in tissue and/or plasma at disease progression was made before enrollment. For patients with negative/inconclusive T790M plasma-based results, tissue re-biopsy could be performed. Results: Ninety-six (96) eligible patients were consecutively enrolled (median age: 67.8 years) between July-2017 and September-2019. Of the patients, 98% were tested upon progression using plasma and 2% using tissue/cytology biopsy. The T790M mutation was detected in 16.0% of liquid biopsies. Tissue re-biopsy was performed in 22.8% of patients with a T790M-negative plasma result. In total, the T790M positivity rate was 21.9%, not differing between patients on first- or second-generation EGFR-TKI. Higher (≥2) ECOG performance status and longer (≥10 months) time to disease progression following EGFR-TKI treatment initiation were associated with T790M positivity. Conclusions: Results from plasma/tissue-cytology samples in a real-world setting, yielded a T790M positivity rate lower than previous reports. Fewer than one in four patients with negative plasma-based testing underwent tissue re-biopsy, indicating the challenges in routine care settings.

scholarly journals A Real-World, Observational, Prospective Study to Assess the Molecular Epidemiology of Epidermal Growth Factor Receptor (EGFR) Mutations upon Progression on or after First-Line Therapy with a First or Second Generation EGFR Tyrosine Kinase Inhibitor in EGFR Mutation-Positive Locally Advanced or Metastatic Non-small Cell Lung Cancer: The ‘LUNGFUL’ Study

2021 ◽  
Author(s):  
Giannis Mountzios ◽  
Anna Koumarianou ◽  
Alexandros Bokas ◽  
Dimitrios Mavroudis ◽  
Epaminondas Samantas ◽  
...  
Keyword(s):  
Molecular Epidemiology ◽  
Disease Progression ◽  
Real World ◽  
Second Generation ◽  
Egfr Mutation ◽  
Kinase Inhibitor ◽  
Performance Status ◽  
Locally Advanced ◽  
Egfr Mutations ◽  
Egfr Tki

Background: Real-world data on the molecular epidemiology of EGFR resistance mutations at or after progression with first- or second-generation EGFR-TKIs in patients with advanced NSCLC are lacking. Methods: This ongoing observational study was carried out by 23 hospital-based physicians in Greece. The decision to perform Cobas® EGFR Mutation Test v2 in tissue and/or plasma at disease progression was made before enrollment. For patients with negative/inconclusive T790M plasma-based results, tissue re-biopsy could be performed. Results: Ninety-six (96) eligible patients were consecutively enrolled (median age: 67.8 years) between July-2017 and September-2019. Of the patients, 98% were tested upon progression using plasma and 2% using tissue/cytology biopsy. The T790M mutation was detected in 16.0% of liquid biopsies. Tissue re-biopsy was performed in 22.8% of patients with a T790M-negative plasma result. In total, the T790M positivity rate was 21.9%, not differing between patients on first- or second-generation EGFR-TKI. Higher (≥2) ECOG performance status and longer (≥10 months) time to disease progression following EGFR-TKI treatment initiation were associated with T790M positivity. Conclusions: Results from plasma/tissue-cytology samples in a real-world setting, yielded a T790M positivity rate lower than previous reports. Fewer than one in four patients with negative plasma-based testing underwent tissue re-biopsy, indicating the challenges in routine care settings.

scholarly journals Case report: Management of Progressive Lung Cancer Patients after First-Line EGFR Tyrosine Kinase Inhibitor Therapy

2019 ◽  
Vol 55 (3) ◽  
pp. 239
Author(s):  
Sahrun Sahrun ◽  
Laksmi Wulandari
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Kinase Inhibitor ◽  
Egfr Mutations ◽  
First Line ◽  
T790m Mutation ◽  
Lung Cancer Patients ◽  
First Line Therapy ◽  
Egfr Tki

Various tyrosine kinase inhibitor (TKI) drugs have been widely used as therapy for cancer that has EGFR mutations, or abnormal EGFR activation. However, patients who have a mutation in the gene that activates EGFR only benefit from EGFR-TKI therapy for less than one year, because after that resistance occurs. In the management of patients according to NCCN 2017, patients who experience progress after receiving TKI as the first-line therapy must undergo an examination to identify the presence of T790M mutation. If the T790M mutation is positive, the choice of therapy that needs to be provided is the third generation (Osimertinib). Many recent studies have proved the significance of the effectiveness and response of Osimertinib therapy in lung cancer with EGFR T790M mutation. We reported the management of a pulmonary adenocarcinoma patient with positive EGFR mutation who had received first-line EGFR TKI who had progressive disease and T790M mutation in Dr. Seotomo Hospital. The patient finally received Osimertinib through an Early Access Program with a therapeutic response that improved significantly.

Impact of concomitant use of anti-acid agents on efficacy of gefitinib in EGFR-mutant non-small-cell lung cancer (NSCLC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19008-e19008
Author(s):  
Kenichi Chikamori ◽  
Keisuke Aoe ◽  
Tadashi Maeda ◽  
Daizo Kishino ◽  
Keiji Oishi ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Performance Status ◽  
Univariate Analysis ◽  
Area Under The Curve ◽  
Progression Free Survival ◽  
Egfr Mutations ◽  
Clinical Practices ◽  
Acid Agent ◽  
Egfr Mutant ◽  
The Impact

e19008 Background: Gefitinib, an EGFR-tyrosine kinase inhibitor, is an essential agent for EGFR-mutant NSCLC. The preclinical studies revealed its reduced area under the curve (AUC) by elevation of pH in GI tract, potentially leading to alteration in the absorption of gefitinib. It, however, has been controversial as to whether and how simultaneous use of anti-acid agents, commonly used in clinical practices, could alter the sensitivity of gefitinib, especially in EGFR-mutant NSCLC. Thus, we conducted a retrospective cohort study to clarify this issue. Methods: We evaluated progression-free survival (PFS) and overall survival (OS) from the medical charts of chemotherapy-naïve patients with EGFR-mutant NSCLC treated with gefitinib monotherapy in our institution. We also identified history of concomitant use of anti-acid agents (proton pomp inhibitors and histamine type 2 receptor blockers) at the time of initiation of gefitinib therapy and assessed its impact on the efficacy of gefitinib using Cox’s proportional hazard model. Results: Between 2006 and 2012, consecutive 83 patients received gefitinib therapy, of whom 29 (34.9%) used anti-acid agents simultaneously. Baseline clinical characteristics between the two groups (use and non-use of anti-acid agents) were well balanced except performance status (PS) of 0: 17.2% vs. 37.0% respectively. Neither PFS nor OS were influenced by concomitant use of anti-acid agents in univariate analysis (hazard ratio: 1.12; 95% confidence interval: 0.66-1.92 and 1.67; 0.86-3.44, respectively). Multivariate analysis also showed no significant effect of anti-acid agent use on PFS and OS (1.18; 0.67-2.06 and 1.66; 0.81-3.38, respectively), whilst poor PS affected OS (2.03; 1.27-3.26). Additionally, no difference in the impact of use of anti-acid agents on the gefitinib sensitivity was observed when stratified by the type of EGFR mutations. Conclusions: Concomitant use of anti-acid agents does not seem to affect efficacy of gefitinib in EGFR-mutant NSCLC. It is unlikely that physicians need to keep in mind the drug interaction of gefitinib and anti-acid agents in daily clinical practices, although further extensive cohort studies are warranted.

scholarly journals SHP2 inhibition enhances the anticancer effect of Osimertinib in EGFR T790M mutant lung adenocarcinoma by blocking CXCL8 loop mediated stemness

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Leiming Xia ◽  
Fan Yang ◽  
Xiao Wu ◽  
Suzhi Li ◽  
Chen Kan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Drug Resistance ◽  
Lung Adenocarcinoma ◽  
Feedback Loop ◽  
Kinase Inhibitor ◽  
Therapeutic Option ◽  
Egfr Mutations ◽  
The Impact ◽  
Egfr Tki ◽  
Egfr T790m

Abstract Background Additional epidermal growth factor receptor (EGFR) mutations confer the drug resistance to generations of EGFR targeted tyrosine kinase inhibitor (EGFR-TKI), posing a major challenge to developing effective treatment of lung adenocarcinoma (LUAD). The strategy of combining EGFR-TKI with other synergistic or sensitizing therapeutic agents are considered a promising approach in the era of precision medicine. Moreover, the role and mechanism of SHP2, which is involved in cell proliferation, cytokine production, stemness maintenance and drug resistance, has not been carefully explored in lung adenocarcinoma (LUAD). Methods To evaluate the impact of SHP2 on the efficacy of EGFR T790M mutant LUAD cells to Osimertinib, SHP2 inhibition was tested in Osimertinib treated LUAD cells. Cell proliferation and stemness were tested in SHP2 modified LUAD cells. RNA sequencing was performed to explore the mechanism of SHP2 promoted stemness. Results This study demonstrated that high SHP2 expression level correlates with poor outcome of LUAD patients, and SHP2 expression is enriched in Osimertinib resistant LUAD cells. SHP2 inhibition suppressed the cell proliferation and damaged the stemness of EGFR T790M mutant LUAD. SHP2 facilitates the secretion of CXCL8 cytokine from the EGFR T790M mutant LUAD cells, through a CXCL8-CXCR1/2 positive feedback loop that promotes stemness and tumorigenesis. Our results further show that SHP2 mediates CXCL8-CXCR1/2 feedback loop through ERK-AKT-NFκB and GSK3β-β-Catenin signaling in EGFR T790M mutant LUAD cells. Conclusions Our data revealed that SHP2 inhibition enhances the anti-cancer effect of Osimertinib in EGFR T790M mutant LUAD by blocking CXCL8-CXCR1/2 loop mediated stemness, which may help provide an alternative therapeutic option to enhance the clinical efficacy of osimertinib in EGFR T790M mutant LUAD patients.

scholarly journals SHP2 inhibition enhances the anticancer effect of Osimertinib in EGFR T790M mutant lung adenocarcinoma by blocking CXCL8 loop mediated stemness

2021 ◽  
Author(s):  
Leiming Xia ◽  
Fan Yang ◽  
Suzhi Li ◽  
Chen Kan ◽  
Hong Zheng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Drug Resistance ◽  
Lung Adenocarcinoma ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Cxcl8 Secretion ◽  
The Impact ◽  
Egfr Tki ◽  
Egfr T790m

Abstract Background: Additional epidermal growth factor receptor (EGFR) mutations confer the drug resistance to generations of EGFR targeted tyrosine kinase inhibitor (EGFR-TKI), which is the thorny challenge to propel the treatment of lung adenocarcinoma (LUAD) forward. In the tailored targeting era, the strategy of EGFR-TKI combined regimen was considered the promising approach to conquer the big aforesaid question. The mechanism of SHP2 involved in the cell proliferation, cytokine production, stemness maintenance and drug resistance of LUAD was not yet fully explored.Methods: To determine the impact of SHP2 on the efficacy of EGFR T790M mutant LUAD cells to Osimertinib, SHP2 was tested in Osimertinib treated LUAD cells. Cell proliferation and stemness were tested in SHP2 modified LUAD cells. RNA sequencing were performed to explore the mechanism of SHP2 promoted stemness.Results: This study demonstrated that high SHP2 indicates poor outcome of LUAD patients, and enriched in Osimertinib resistant LUAD cells. Moreover, SHP2 inhibition suppressed the cell proliferation and damaged the stemness of EGFR T790M mutant LUAD. Furthermore, SHP2 facilitates the CXCL8 secretion of EGFR T790M mutant LUAD which derived from a CXCL8-CXCR1/2 positive feedback loop that promoted the stemness and tumorigenesis. Finally, we found SHP2 inhibited ERK-AKT-NFκB and GSK3β-β Catenin pathways in EGFR T790M mutant LUAD cells, inactivation of NF-κB confers to a blockage of CXCL8-CXCR1/2 loop, and stemness limited by restricting GSK3β/β-Catenin signaling.Conclusions: Our data revealed that inhibition of SHP2 enhances the anti-cancer effect of Osimertinib in EGFR T790M mutant LUAD by blocking CXCL8-CXCR1/2 loop mediated stemness, which may provide an alternative option to promote the efficacy of osimertinib in clinic of EGFR T790M mutant LUAD.

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