Management and Future Directions in Non-Small Cell Lung Cancer with Known Activating Mutations

2014 ◽  
pp. e353-e365 ◽  
Author(s):  
David E. Gerber ◽  
Leena Gandhi ◽  
Daniel B. Costa
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Advanced Nsclc ◽  
Small Cell ◽  
Egfr Mutations ◽  
Symptom Improvement ◽  
Small Cell Lung ◽  
T790m Mutation ◽  
Egfr Tkis

Lung cancer accounts for a quarter of all cancer deaths. Non-small cell lung cancer (NSCLC) is currently segregated by the presence of actionable driver oncogenes. This review will provide an overview of molecular subsets of lung cancer, including descriptions of the defining oncogenes ( EGFR, ALK, KRAS, ROS1, RET, BRAF, ERBB2, NTRK1, FGFR, among others) and how these predict for response to small molecule tyrosine kinase inhibitors (TKIs) that are either clinically available or in clinical trial development for advanced NSCLC. Particular focus will be placed on subsets with EGFR mutated and ALK rearranged NSCLC. Somatic TKI-sensitizing EGFR mutations (such as exon 19 deletions and L858R substitutions) are the most robust predictive biomarker for symptom improvement, radiographic response, and increment in progression-free survival (PFS) when EGFR TKIs (gefitinib, erlotinib, and afatinib) are used for patients with advanced NSCLC. However, the palliative benefits that EGFR TKIs afford are limited by multiple biologic mechanisms of tumor adaptation/resistance (such as the EGFR-T790M mutation and oncogene bypass tracks), and future efforts toward delaying, preventing, and treating resistance are underway. Similar to EGFR mutations, ALK rearrangements exemplify an oncogene-driven NSCLC that can be effectively palliated with a precision TKI therapy (the multitargeted ALK/MET/ROS1 TKI crizotinib). When resistance to first-line crizotinib therapy occurs, multiple second generation ALK TKIs have demonstrated impressive rates of disease control in clinical trials, and these may modify long-term outcomes for patients with ALK-positive NSCLC. The development of TKIs for other oncogene-driven NSCLCs may expand the portfolio of precision therapies for this recalcitrant cancer.

Genomic landscape differences in patients with advanced non-small cell lung cancer by sex and age.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9108-9108
Author(s):  
ErinMarie Kimbrough ◽  
Hiba I. Dada ◽  
Leylah Drusbosky ◽  
Yujie Zhao ◽  
Rami Manochakian ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Advanced Nsclc ◽  
Age Groups ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Genomic Alterations ◽  
Genomic Landscape

9108 Background: Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related death in the U.S. The median age at diagnosis is 70 years, and NSCLC is uncommon among younger individuals ( < 50 years).Overall, outcomes in NSCLC have improved significantly with targeted therapy. A prior study demonstrated patients < 50 are more likely to have targetable alterations including EGFR, ALK, ERBB2, and ROS1. Another study reported an increased prevalence of EGFR mutations in females and KRAS mutations in males with NSCLC. The comprehensive genomic landscape of NSCLC patients in different age groups and genders remains largely unknown. In our study, we aim to investigate the genomic alterations in patients with advanced NSCLC according to age and sex. Efforts that are focused on identifying targetable alterations in NSCLC will likely help personalize treatment and improve outcomes. Methods: We performed a retrospective review of de-identified data from the Guardant Health database from March 2018 through October 2020. We reviewed 34,237 profiles from patients with NSCLC who underwent molecular profiling using the plasma-based circulating-tumor DNA (ctDNA) Next-Generation Sequencing (NGS) assay Guardant360. Single nucleotide variants (SNV), fusions, indels and copy number variations (CNV) of up to 83 genes were analyzed. We assessed for genomic differences among patients with advanced NSCLC by both sex and age (≥70 and < 70). We conducted two-tailed tests of equality of proportions comparing males to females and ≥70 to < 70. Results: Of the 34,237 profiles reviewed, somatic alterations were seen in 81.7% (n = 27,972) of the patients. The median age was 70 (range 16-102) and 55% were female. Our study demonstrated that the most common genomic alterations in both age groups and genders were TP53, EGFR, KRAS, ATM, and MET. Patients ≥70 were more likely to have ATM (21% versus 14%, p < 0.0001) and MET (12% versus 10 %, p < 0.0001) mutations than those < 70. Patients < 70 were more likely to have EGFR (30% versus 27%, p < 0.0001), STK11 (14% versus 11%, p = 0.0056), and KRAS (26% versus 24%, p < 0.0001) alterations. EGFR was seen more frequently in females (33% versus 26%, p < 0.0001). ATM (11% versus 6%, p < 0.0001) and MET (8% versus 5%, p = 0.0050) were seen more frequently in males. Conclusions: Significant differences in the distribution of targetable genomic alterations were identified among different age groups and genders in patients with advanced NSCLC. These findings highlight the importance of taking personalized approaches to diagnostic testing and treatment of advanced NSCLC.

scholarly journals Clinical Characteristics of Osimertinib Responder in Non-Small Cell Lung Cancer Patients with EGFR-T790M Mutation

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 365 ◽  
Author(s):  
Akihiro Yoshimura ◽  
Tadaaki Yamada ◽  
Naoko Okura ◽  
Takayuki Takeda ◽  
Kazuki Hirose ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
T790m Mutation ◽  
Nsclc Patients ◽  
Egfr T790m ◽  
Egfr Tkis

Osimertinib is a mutant-selective EGFR inhibitor that is effective against non-small cell lung cancer (NSCLC) in patients with the EGFR-T790M mutation, who are resistant to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, the factors affecting response to osimertinib treatment are unknown. In this retrospective study, 27 NSCLC patients with the EGFR-T790M mutation were enrolled at five institutions in Japan. Among several parameters tested, the progression-free survival (PFS) associated with the initial EGFR-TKIs was positively correlated with the PFS after osimertinib treatment (p = 0.021). The median PFS following osimertinib treatment and the overall survival (OS) were longer in patients who responded to osimertinib than in those who did not (17.7 months versus 3.5 months, p = 0.009 and 24.2 months versus 13.5 months, p = 0.021, respectively). A multivariate analysis demonstrated that the PFS with initial EGFR-TKIs was significantly related to the PFS with osimertinib treatment (p = 0.035), whereas osimertinib response was significantly related to the PFS and OS with osimertinib treatment (p = 0.016 and p = 0.006, respectively). Our retrospective observations indicate that PFS following the initial EGFR-TKI treatment and the response rate to osimertinib might be promising predictors for effective osimertinib treatment in NSCLC patients with the EGFR-T790M mutation.

Secondary T790M mutation and novel G796A mutation in exon20 of EGFR gene in patients with non-small cell lung cancer who show resistance to gefitinib

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7703-7703
Author(s):  
H. Uramoto ◽  
K. Sugio ◽  
T. Oyama ◽  
T. Iwata ◽  
T. Onizuka ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Missense Mutation ◽  
Cell Lung Cancer ◽  
Acquired Resistance ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
T790m Mutation ◽  
Egfr Gene

7703 Background: Somatically acquired mutations in the EGFR gene in non-small cell lung cancer are associated with a significant clinical response to a tyrosine kinase inhibitor (TKI). EGFR mutations occur predominantly in exon19 and/or exon21, namely, an in-frame deletion in exon19 or a missense mutation in exon21 (L858R), which have been found to be related to the sensitivity to TKI. However, most patients with such sensitive mutations in their tumor show progression during the TKI treatment. In such resistant tumors, a secondary threonine- to-methionine mutation at codon 790 (T790M) in exon20 has been reported to be related the resistance to either gefitinib or erlotinib. Methods: EGFR mutations in exons19–21 were examined by sequencing in 37 pretreatment tumors obtained from patients with NSCLC, who were treated by gefitinib. Of the 22 cases having sensitive EGFR mutations (19del or L858R), 15 showed CR/PR and 7 showed SD/PD. Of the 15 patients with CR/PR, 4 tumor samples (2 lung, 1 liver, and 1 pleural effusion) that became refractory to gefitinib, were obtained. In pretreatment tumor samples from 4 patients, an in-frame deletion of exon19 was observed in 3 tumors and a L858R mutation of exon21 was in 1 tumor. We next examined whether a secondary mutation occurred in a tumor with acquired resistance to gefitinib in 4 patients by the sequencing of exons 19–21, with informed consent. Results: Three of 4 tumor samples had a secondary T790M mutation, which was not detected in the pretreatment tumor samples. These 3 samples also had an in-frame deletion in exon19. There were no other novel secondary mutations in exons 19,20,21. In 7 cases showing resistance to gefitinib (SD/PD) in spite of the existence of sensitive mutations, 1 tumor demonstrated the co-existence of a missense mutation (G796A) in exon20. In vitro, a stable clone of cells bearing the G796A mutation was approximately 50,000-fold less sensitive to gefitinib in comparison to the cells carrying exon19 deletion. Conclusions: The T790M mutation is common in patients with acquired resistance to gefitinb. Our results suggest that screening tumor samples for a range of EGFR mutations may therefore improve our ability to identify the patients most likely to benefit from treatment with TKI. No significant financial relationships to disclose.

Prospective correlative study of FDG-PET SUV and proteomic profile (VeriStrat) of non-small cell lung cancer patients treated with erlotinib.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18096-e18096
Author(s):  
Chiara Lazzari ◽  
Marcello Tiseo ◽  
Vanesa Gregorc ◽  
Fiorenza Latteri ◽  
Massimo Ippolito ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Fdg Pet ◽  
Advanced Nsclc ◽  
Standardized Uptake Value ◽  
Small Cell ◽  
Wilcoxon Test ◽  
Small Cell Lung ◽  
Egfr Tkis

e18096 Background: Matrix Assisted Laser Desorption Ionization Time of Flight Mass Spectrometry (MALDI TOF MS) was used to create and validate a plasma proteomic algorithm VeriStrat (VS), based on 8 m/z peaks, and able to select advanced NSCLC pts who may benefit from EGFR TKIs. The algorithm was associated with PFS and OS of patients treated with EGFR TKIs and not with chemotherapy. Standardized Uptake Value (SUV) is of prognostic value for survival in non-small cell lung cancer. Aim of the current study was to analyze the OS and TTP in advanced NSCLC pts treated with erlotinib (E) according to baseline VeriStrat classification and baseline SUVs of FDG-PET. Methods: Plasma samples were collected before the beginning of E from metastatic NSCLC patients. Acquired spectra were classified according to the VeriStrat algorithm. The FDG-PET was performed the day before the beginning of E. Results: Thirty eight NSCLC pts on E therapy with the following characteristics were analyzed: median age 62 years old, 63% were males, 53% had adenocarcinoma histology, response rate was 26%, median OS 10 mos and (TTP) 3.4 mos. Twenty-six (68%) were classified as VS Good, 12 (32%) as Poor. TTP and OS for VS Good and Poor were 4.1 vs 2.1 mos (HR 0.86, log-rank p=0.6) and 11.1 vs 4.1 mos (HR 0.45,log-rank p=0.02), respectively. Baseline SUV levels were associated with TTP (Wilcoxon test p=0.001) but not with OS (all pts progressed, 5 still alive). All Poor classified pts had SUV ≥ 7 and had the worst TTP and OS; VS Good classified patients had worse TTP and OS if their baseline SUV level was > 7 than those who were VS Good and had SUV<7(see Table: 3-curves comparison log-rank test p value for a trend). Conclusions: We confirmed that pts with VS Poor classification have significantly shorter OS than those classified as VS Good. Pts with VS Good profile and with low baseline SUV levels may benefit more from EGFR TKI than VS Good pts with high SUV.

scholarly journals EGFR Mutations Status For Non-Small-Cell Lung Cancer Patients

2016 ◽  
Vol 26 (5) ◽  
pp. 36-39
Author(s):  
Ieva Mirskytė ◽  
Jūratė Kasnauskienė ◽  
Alvydas Česas ◽  
Loreta Radvinskienė
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Liquid Biopsy ◽  
Small Cell ◽  
Small Cells ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
T790m Mutation ◽  
Tk Inhibitors

With the advent of the molecular-targeted therapy, rapid progress has been made in the treatment of advanced or recurrent non-small-cell lung cancer (NSCLC). EGFR mutations detection in tumor is important to determine an appropriate treatment of EGFR TK inhibitors. We investigated EGFR mutation status for patients with non-small cells lung carcinoma (NSCLC) patients’ tumorous cells from FFPE material in Klaipeda University Hospital, Lithuania (mutation test for the qualitative detection and identification of mutations in exons 18, 19, 20 and 21 of the EGFR gene) and T790M mutation in cfDNA (Liquid biopsy). Mutations of EGFR from FFPE were detected in 24 of the 119 patients (20%). EGFR mutations were more frequently found in women (13 of 36, 36%). cfDNA (Liquid biopsy) testing results show one of the patients had EGFR 20 exon T790M mutation detected which is resistance determining factor for the first and second generation EGFR TK Inhibitors treatment and a predicting marker for the third generation EGFR TK Inhibitors treatment.

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