scholarly journals Cytoreductive Stereotactic Body Radiotherapy with Tyrosine Kinase Inhibitors for Intrathoracic Oligoprogressive EGFR-mutated Lung Cancer

2021 ◽  
Author(s):  
Anupam Rishi ◽  
Steven Sun ◽  
Ahmad M Karimi ◽  
Austin J Sim ◽  
Michael Shafique ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Stereotactic Body Radiotherapy ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Patient Reported ◽  
Edmonton Symptom Assessment Scale ◽  
Egfr Mutated ◽  
Egfr Tki

Abstract Background: Epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) shows an impressive initial response to EGFR tyrosine kinase inhibitors (EGFR-TKI). However, resistance invariably develops, commonly involving the site of initial gross disease. Cytoreductive stereotactic body radiotherapy (SBRT) for thoracic oligoprogressive disease (OPD) may effectively delay progression through EGFR-TKI therapy.Methods: From a prospectively maintained IRB-approved institutional registry, we identified 23 patients consecutively treated between 2011-2019 with thoracic SBRT and received EGFR-TKI within 6-months of SBRT. Radiographic progression-free (PFS) and overall survival (OS) were estimated using Kaplan-Meier analysis. Toxicity and patient-reported Edmonton Symptom Assessment Scale (ESAS) scores were reviewed.Results: Median follow-up after SBRT was 20-months (range, 4-100), and the median age was 68-years (range, 33-89). Most patients were females (n=21;91.3%). RT dose was 50-60 Gy in 5-10 fractions. EGFR-TKI administered were erlotinib, osimertinib and gefitinib in 15, 5, and 3 patients, respectively. Median PFS and OS following SBRT were 8-months and 31-months, respectively. 1-year PFS and OS were 34.8% and 78.3%. The median duration of EGFR-TKI therapy was 26-months (1-91). Most patients progressed in new distant sites, most commonly bones (n=5;21.7%) and distant lung (n=4;17.4%), with only 2/23 patients having initial progression within the SBRT field. Grade-2 pneumonitis (n=2) and rib fracture (n=1) were noted radiation-related toxicities. Dominant ESAS symptoms were fatigue (21.7%), pain (8.7%), and loss of appetite (8.7%).Conclusions: For EGFR-mutated NSCLC patients with thoracic OPD on EGFR-TKI, SBRT was well tolerated, resulted in changes in subsequent patterns of failure, lengthened PFS, and prolongs the duration of initial TKI therapy.

scholarly journals Efficacy and safety of tyrosine kinase inhibitors in advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutation: a network meta-analysis

2021 ◽  
Vol 10 (1) ◽  
pp. LMT43
Author(s):  
Abdullah Alanazi ◽  
Ismaeel Yunusa ◽  
Khaled Elenizi ◽  
Abdulaziz I Alzarea
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Small Cell ◽  
Efficacy And Safety ◽  
Small Cell Lung ◽  
Epidermal Growth ◽  
Egfr Tki

Aim: To compare the efficacy and safety of tyrosine kinase inhibitors (TKIs) as first-line treatment in patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) with positive EGFR mutation. Materials & methods: Following a systematic literature review until December 2019, we conducted a random-effects pairwise and network meta-analyses (NMA). We ranked treatments for efficacy and safety based on the surface under the cumulative ranking curve (SUCRA). Results: Tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR-TKI) improved survival outcomes with fewer grade 3 or higher adverse events compared to chemotherapy. Overall survival results suggest that osimertinib has the highest probability of being the most efficacious (SUCRA, 79.9%), followed by dacomitinib (SUCRA, 75.8%). Adverse events results suggest that osimertinib (SUCRA, 84.3%) and gefitinib (SUCRA, 78.9%) has the highest probability of being the safest. Conclusion: In this NMA, we found that osimertinib is the most efficacious and safest EGFR-TKI. These results may guide clinicians in choosing the most appropriate treatment option among EGFR-TKIs for their patient’s individual clinical characteristics.

scholarly journals Drug Tolerance to EGFR Tyrosine Kinase Inhibitors in Lung Cancers with EGFR Mutations

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1590
Author(s):  
Kenichi Suda ◽  
Tetsuya Mitsudomi
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Drug Tolerance ◽  
Lung Cancers ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Egfr Mutated

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) serve as the standard of care for the first-line treatment of patients with lung cancers with EGFR-activating mutations. However, the acquisition of resistance to EGFR TKIs is almost inevitable, with extremely rare exceptions, and drug-tolerant cells (DTCs) that demonstrate reversible drug insensitivity and that survive the early phase of TKI exposure are hypothesized to be an important source of cancer cells that eventually acquire irreversible resistance. Numerous studies on the molecular mechanisms of drug tolerance of EGFR-mutated lung cancers employ lung cancer cell lines as models. Here, we reviewed these studies to generally describe the features, potential origins, and candidate molecular mechanisms of DTCs. The rapid development of an optimal treatment for EGFR-mutated lung cancer will require a better understanding of the underlying molecular mechanisms of the drug insensitivity of DTCs.

EGFR tyrosine kinase inhibitors in non-small cell lung cancer: treatment paradigm, current evidence, and challenges

2020 ◽  
pp. 030089162096813
Author(s):  
Arafat Tfayli ◽  
Razan Mohty
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Small Cell Lung Cancer ◽  
Tyrosine Kinase Inhibitors ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Egfr Tki

Therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for patients with EGFR-mutated non-small cell lung cancer (NSCLC) has been shown to have superior outcomes when compared to chemotherapy. First-generation EGFR TKI, including gefitinib and erlotinib, and second-generation EGFR TKI, including afatinib and dacomitinib, proved to be effective in patients with NSCLC harboring EGFR-sensitizing mutation. Later, resistance mutations were identified. Consequently, osimertinib, a third-generation EGFR TKI, was studied and demonstrated activity against EGFR-sensitizing and resistant mutations. Osimertinib moved recently to the first-line setting with the positive results of the FLAURA (AZD9291 Versus Gefitinib or Erlotinib in Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer) trial. The use of these drugs is limited by their cost and availability mainly in middle- to low-income countries.

Identification of RET fusion as mechanisms of resistance to EGFR tyrosine-kinase inhibitors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21074-e21074
Author(s):  
Zhongxing Bing ◽  
Weiran Wang ◽  
Danhua Wang ◽  
Tonghui Ma
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Next Generation Sequencing Data ◽  
Egfr Mutations ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Egfr Tki ◽  
Egfr Tkis

e21074 Background: Responses to EGFR-targeted therapy are generally temporary, due to inevitable drug resistance. Although RET fusions have been identified in resistant EGFR-mutant non–small cell lung cancer (NSCLC), their characteristics acquired resistance to EGFR tyrosine-kinase inhibitors (TKIs) are rarely investigated. Methods: We retrospectively reviewed next-generation sequencing data of EGFR+ lung cancer patients, and 8 patients were identified coexisting of EGFR mutations and RET fusion. Their treatment history was collected. Results: The co-occurrence of RET fusion with EGFR oncogenic variations was observed in eight patients, and all of the 8 patients have received previous EGFR-TKI treatment. EGFR mutations were including 4 L858R mutations, 4 exon 19 deletions, and 6 T790M mutations. And the partner genes of RET identified by NGS were including TRIM33 (2/8), GPRC6A (1/8), TLN1 (1/8), KIAA1598 (1/8), SPECC1 (1/8), TRIM24 (1/8) and CCDC6 (1/8). The allelic fractions (AFs) of first-generation EGFR-TKI sensitizing mutations were higher than AFs of EGFR T790M mutations as well as AFs of RET fusion. These RET fusions are fused with rare partner genes, rather than the most common KIF5B in lung cancer. Conclusions: This study extended the knowledge of RET fusion as resistance mechanism to EGFR TKIs in lung cancer. The detection of RET fusions may uncover potential resistance mechanisms of EGFR TKIs, which might inform therapeutic strategies, such as combination-therapy approaches.[Table: see text]

scholarly journals Minocycline prevents and repairs the skin disorder associated with afatinib, one of the epidermal growth factor receptor-tyrosine kinase inhibitors for non-small cell lung cancer

2020 ◽  
Author(s):  
Kazumi Sano ◽  
Kazuhiko Nakadate ◽  
Kazuhiko Hanada
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Skin Disorder ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Epidermal Growth ◽  
Egfr Tki

Abstract Background While epidermal growth factor receptor(EGFR) tyrosine kinase inhibitors(TKIs) exert a breakthrough effect, the incidence of skin disorders as a side effect has significantly reduced patients' quality of life. Objective This study aimed to develop a treatment for inflammatory ulcers as one of the side effects of afatinib (Geotrif®), a second-generation EGFR-TKI, and established a skin disorder mouse model to investigate the protective effect of minocycline. Methods First, under inhalation anesthesia with isoflurane, the back of a male ddy mouse was shaved, and afatinib petrolatum was applied alone or in combination with minocycline to observe the state of the skin and measure transepidermal water transpiration (TEWL). Next, afatinib was administered orally to mice, and minocycline petrolatum was applied to observe whether the skin disorder was prevented and its effect on repair of the skin disorder. Results Skin injury occurred on the back of the mouse following afatinib (1 mg/g in petrolatum) application, and scab formation was observed. Application of minocycline prevented and improved the skin disorder caused by afatinib. When the minocycline-petrolatum mixture was applied to the mouse that developed the skin disorder, a significant improvement in TEWL was observed, and skin repair was observed macroscopically. Discussion These results suggest that minocycline applied both locally and orally prevents and repairs afatinib-induced skin disorders. Histological examination of skin elucidated the mechanism of the occurrence of the EGFR-TKI-related skin disorder and suggested the efficacy of minocycline topical application in clinical practice.

scholarly journals Longitudinal health utilities, symptoms and toxicities in patients with ALK-rearranged lung cancer treated with tyrosine kinase inhibitors: a prospective real-world assessment

2020 ◽  
Vol 27 (6) ◽  
Author(s):  
B.C. Tse ◽  
B.I. Said ◽  
Z.J. Fan ◽  
K. Hueniken ◽  
D. Patel ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Real World ◽  
Kinase Inhibitors ◽  
Group Performance ◽  
Health Utility ◽  
Third Generation ◽  
Patient Reported ◽  
Utility Scores

Background Tyrosine kinase inhibitors (tkis) have dramatically improved the survival of patients with ALK-rearranged (ALK+) non-small-cell lung cancer (nsclc). Clinical trial data can generally compare drugs in a pair-wise fashion. Real-world collection of health utility data, symptoms, and toxicities allows for the direct comparison between multiple tki therapies in the population with ALK+ nsclc. Methods In a prospective cohort study, outpatients with ALK+ recruited between 2014 and 2018, treated with a variety of tkis, were assessed every 3 months for clinico-demographic, patient-reported symptom and toxicity data and EQ-5D-derived health utility scores (hus). Results In 499 longitudinal encounters of 76 patients with ALK+ nsclc, each tki had stable longitudinal hus when disease was controlled, even after months to years: the mean overall hus for each tki ranged from 0.805 to 0.858, and longitudinally from 0.774 to 0.912, with higher values associated with second- or third-generation tkis of alectinib, brigatinib, and lorlatinib. Disease progression was associated with a mean hus decrease of 0.065 (95% confidence interval: 0.02 to 0.11). Health utility scores were inversely correlated to multiple symptoms or toxicities: rho values ranged from –0.094 to –0.557. Fewer symptoms and toxicities were associated with the second- and third-generation tkis compared with crizotinib. In multivariable analysis, only stable disease state and baseline Eastern Cooperative Oncology Group performance status were associated with improved hus. Conclusions There was no significant decrease in hus when patients with ALK+ disease were treated longitudi­nally with each tki, as long as patients were clinically stable. Alectinib, brigatinib, and lorlatinib had the best toxicity profiles and exhibited high mean hus longitudinally in the real-world setting.

Are EGFR tyrosine kinase inhibitors effective in elderly patients with EGFR-mutated non-small cell lung cancer?

2017 ◽  
Vol 18 (1) ◽  
pp. 15-20 ◽  
Author(s):  
Giandomenico Roviello ◽  
Laura Zanotti ◽  
Maria Rosa Cappelletti ◽  
Angela Gobbi ◽  
Martina Dester ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Elderly Patients ◽  
Tyrosine Kinase ◽  
Small Cell Lung Cancer ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Egfr Mutated
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