scholarly journals Management of EGFR-mutated non-small-cell lung cancer: practical implications from a clinical and pathology perspective

2017 ◽  
Vol 24 (2) ◽  
pp. 111 ◽  
Author(s):  
M. Cabanero ◽  
R. Sangha ◽  
B.S. Sheffield ◽  
M. Sukhai ◽  
M. Pakkal ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Molecular Subtype ◽  
Small Cell ◽  
Driver Mutations ◽  
Small Cell Lung ◽  
Liquid Biopsies ◽  
Egfr Mutated

Starting in the early 2000s, non-small-cell lung cancer (nsclc) subtypes have evolved from being histologically described to molecularly defined. Management of lung adenocarcinomas now generally requires multiple molecular tests at baseline to define the optimal treatment strategy. More recently, second biopsies performed at progression in patients treated with tyrosine kinase inhibitors (tkis) have further defined the continued use of molecularly targeted therapy.In the present article, we focus on one molecular subtype: EGFR-mutated nsclc. For that patient population,multiple lines of tki therapy are now available either clinically or in clinical trials. Each line of treatment is guided by the specific mutations (for example, L858R, T790M, C797S) identified in EGFR. We first describe the various mechanisms of acquired resistance to EGFR tki treatment. We then focus on strategies that clinicians and pathologists can both use during tissue acquisition and handling to optimize patient results. We also discuss future directions for the molecular characterization of lung cancers with driver mutations, including liquid biopsies. Finally, we provide an algorithm to guide treating physicians managing patients with EGFR-mutated nsclc. The same framework can also be applied to other molecularly defined nsclc subgroups as resistance patterns are elucidated and additional lines of treatment are developed.

Response with pemrbolizumab in a patient with EGFR mutated non-small cell lung cancer harbouring insertion mutations in V834L and L858R

2021 ◽  
pp. 107815522110578
Author(s):  
Matthew J. Hadfield ◽  
Alla Turshudzhyan ◽  
Khalid Shalaby ◽  
Aswanth Reddy
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Durable Response ◽  
Egfr Mutated

Introduction Lung cancer is the leading cause of cancer-related deaths with non-small cell lung cancer (NSCLC) being the most common of them. About a third of NSCLC cases have an epidermal growth factor (EGFR) mutation, which is usually susceptible to tyrosine kinase inhibitors (TKIs). In rare cases where patients progress through TKI therapy, the use of immune checkpoint inhibitors (ICIs) remains controversial. Case report We describe a case of a patient with significant history of smoking and EGFR mutated programmed death ligand-1 (PD-L1) positive NSCLC who was initially treated with TKI therapy. Management/Outcome While patient progressed on TKI therapy, he was able to achieve a durable response with a single PD-L1 agent, pembrolizumab. Contrary to the available evidence, the presented EGFR mutant NSCLC responded to PD-L1 pathway inhibition. Discussion From our observation Pembrolizumab could be promising in patients with rare EGFR mutations who do not respond to EGFR directed therapy. Our report provides supporting data for the use of immunotherapies in patients with EGFR mutated NSCLC.

scholarly journals Concomitant driver mutations in advanced EGFR-mutated non-small-cell lung cancer and their impact on erlotinib treatment

Oncotarget ◽  
2018 ◽  
Vol 9 (40) ◽  
pp. 26195-26208 ◽  
Author(s):  
Jan Nyrop Jakobsen ◽  
Eric Santoni-Rugiu ◽  
Morten Grauslund ◽  
Linea Melchior ◽  
Jens Benn Sørensen
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Driver Mutations ◽  
Small Cell Lung ◽  
Egfr Mutated

Advances in the Treatment of Non-Small Cell Lung Cancer

2014 ◽  
Vol 12 (5S) ◽  
pp. 764-767 ◽  
Author(s):  
Leora Horn
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Small Cell ◽  
Driver Mutations ◽  
Annual Conference ◽  
Small Cell Lung ◽  
Nccn Guidelines

Clinical trial data continue to emerge on treatments in advanced non-small cell lung cancer (NSCLC), supporting the strategy that histology and molecular driver mutations should guide treatment selection. During her presentation at the NCCN 19th Annual Conference, Dr. Leora Horn highlighted 3 specific areas in which the 2014 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for NSCLC focus attention: updates on the assortment of chemotherapy options, targeted therapies and how acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors appears to have become the catalyst of the development of newer-generations of agents, and the revisited role of newer immunotherapeutic options.

scholarly journals CNS Response to Osimertinib Versus Standard Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients With Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer

2018 ◽  
Vol 36 (33) ◽  
pp. 3290-3297 ◽  
Author(s):  
Thanyanan Reungwetwattana ◽  
Kazuhiko Nakagawa ◽  
Byoung Chul Cho ◽  
Manuel Cobo ◽  
Eun Kyung Cho ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Progression Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
Egfr Mutated ◽  
Cns Lesions ◽  
Egfr Tkis

Purpose We report CNS efficacy of osimertinib versus standard epidermal growth factor receptor ( EGFR) tyrosine kinase inhibitors (TKIs) in patients with untreated EGFR-mutated advanced non–small-cell lung cancer from the phase III FLAURA study. Patients and Methods Patients (N = 556) were randomly assigned to osimertinib or standard EGFR-TKIs (gefitinib or erlotinib); brain scans were not mandated unless clinically indicated. Patients with asymptomatic or stable CNS metastases were included. In patients with symptomatic CNS metastases, neurologic status was required to be stable for ≥ 2 weeks after completion of definitive therapy and corticosteroids. A preplanned subgroup analysis with CNS progression-free survival as primary objective was conducted in patients with measurable and/or nonmeasurable CNS lesions on baseline brain scan by blinded independent central neuroradiologic review. The CNS evaluable-for-response set included patients with ≥ one measurable CNS lesion. Results Of 200 patients with available brain scans at baseline, 128 (osimertinib, n = 61; standard EGFR-TKIs, n = 67) had measurable and/or nonmeasurable CNS lesions, including 41 patients (osimertinib, n = 22; standard EGFR-TKIs, n = 19) with ≥ one measurable CNS lesion. Median CNS progression-free survival in patients with measurable and/or nonmeasurable CNS lesions was not reached with osimertinib (95% CI, 16.5 months to not calculable) and 13.9 months (95% CI, 8.3 months to not calculable) with standard EGFR-TKIs (hazard ratio, 0.48; 95% CI, 0.26 to 0.86; P = .014 [nominally statistically significant]). CNS objective response rates were 91% and 68% in patients with ≥ one measurable CNS lesion (odds ratio, 4.6; 95% CI, 0.9 to 34.9; P = .066) and 66% and 43% in patients with measurable and/or nonmeasurable CNS lesions (odds ratio, 2.5; 95% CI, 1.2 to 5.2; P = .011) treated with osimertinib and standard EGFR-TKIs, respectively. Probability of experiencing a CNS progression event was consistently lower with osimertinib versus standard EGFR-TKIs. Conclusion Osimertinib has CNS efficacy in patients with untreated EGFR-mutated non–small-cell lung cancer. These results suggest a reduced risk of CNS progression with osimertinib versus standard EGFR-TKIs.

scholarly journals New Targetable Oncogenes in Non–Small-Cell Lung Cancer

2013 ◽  
Vol 31 (8) ◽  
pp. 1097-1104 ◽  
Author(s):  
Geoffrey R. Oxnard ◽  
Adam Binder ◽  
Pasi A. Jänne
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Small Cell ◽  
Driver Mutations ◽  
Small Cell Lung ◽  
Braf Mutations ◽  
Pik3ca Mutations ◽  
Anaplastic Lymphoma

The identification of oncogenic driver mutations underlying sensitivity to epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors has led to a surge of interest in identifying additional targetable oncogenes in non–small-cell lung cancer. A number of new potentially oncogenic gene alterations have been characterized in recent years, including BRAF mutations, HER2 insertions, PIK3CA mutations, FGFR1 amplifications, DDR2 mutations, ROS1 rearrangements, and RET rearrangements. In this review, we will discuss the techniques used to discover each of these candidate oncogenes, the prevalence of each in non–small-cell lung cancer, the preclinical data supporting their role in lung cancer, and data on small molecular inhibitors in development.

scholarly journals Partial Response to Platinum Doublets in Refractory EGFR-Positive Non-Small Cell Lung Cancer Patients after RRx-001: Evidence of Episensitization

2016 ◽  
Vol 9 (1) ◽  
pp. 62-67 ◽  
Author(s):  
Corey A. Carter ◽  
Bryan T. Oronsky ◽  
Scott Z. Caroen ◽  
Jan J. Scicinski ◽  
Pedro Cabrales ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Partial Response ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Treatment Options ◽  
Small Cell ◽  
Small Cell Lung ◽  
Lung Cancer Patients ◽  
Egfr Mutated

RRx-001, an experimental systemically non-toxic epi-immunotherapeutic agent, which potentiates the resensitization of resistant cancer cells to formerly effective therapies, is under active investigation in several clinical trials that are based on sequential or concomitant rechallenge to resistant first- or second-line regimens. One of these trials is designated TRIPLE THREAT (NCT02489903), because it explores the conditioning or priming effect of RRx-001 on three tumor types - non-small cell lung cancer (NSCLC), small cell lung cancer and high-grade neuroendocrine tumors - prior to re-administration of platinum doublets. In follow-up to a recent case study, which describes early monotherapeutic benefit with RRx-001 in a refractory EGFR-mutated NSCLC tumor, we present subsequent evidence of a radiological partial response to reintroduced platinum doublets after RRx-001. For the 50% of patients with EGFR-mutated NSCLC who progress on EGFR-tyrosine kinase inhibitors (without evidence of a T790M mutations) as well as platinum doublets and pemetrexed/taxane, no other clinically established treatment options exist. A retrial of these therapies in EGFR-positive NSCLC patients via priming with epigenetic agents such as RRx-001 constitutes a strategy to ‘episensitize' tumors (i.e. reverse resistance by epigenetic means) and to extend overall survival.

scholarly journals Plasma Predictive Features in Treating EGFR-Mutated Non-Small Cell Lung Cancer

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3179
Author(s):  
Christi M. J. Steendam ◽  
G. D. Marijn Veerman ◽  
Melinda A. Pruis ◽  
Peggy Atmodimedjo ◽  
Marthe S. Paats ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Egfr Mutation ◽  
Plasma Concentrations ◽  
Small Cell ◽  
Small Cell Lung ◽  
The Impact ◽  
Egfr Mutated

Although epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the preferred treatment for patients with EGFR-mutated non-small cell lung cancer (NSCLC), not all patients benefit. We therefore explored the impact of the presence of mutations found in cell-free DNA (cfDNA) and TKI plasma concentrations during treatment on progression-free survival (PFS). In the prospective START-TKI study blood samples from 41 patients with EGFR-mutated NSCLC treated with EGFR-TKIs were available. Next generation sequencing (NGS) on cfDNA was performed, and plasma TKI concentrations were measured. Patients without complete plasma conversion of EGFR mutation at week 6 had a significantly shorter PFS (5.5 vs. 17.0 months, p = 0.002) and OS (14.0 vs. 25.5 months, p = 0.003) compared to patients with plasma conversion. In thirteen (second line) osimertinib-treated patients with a (plasma or tissue) concomitant TP53 mutation at baseline, PFS was significantly shorter compared to six wild-type cases; 8.8 vs. 18.8 months, p = 0.017. Erlotinib Cmean decrease of ≥10% in the second tertile of treatment was also associated with a significantly shorter PFS; 8.9 vs. 23.6 months, p = 0.037. We obtained evidence that absence of plasma loss of the primary EGFR mutation, isolated plasma p.T790M loss after six weeks, baseline concomitant TP53 mutations, and erlotinib Cmean decrease during treatment are probably related to worse outcome.

scholarly journals Crizotinib inhibition of ROS1-positive tumours in advanced non-small-cell lung cancer: a Canadian perspective

2019 ◽  
Vol 26 (4) ◽  
Author(s):  
D. G. Bebb ◽  
J. Agulnik ◽  
R. Albadine ◽  
S. Banerji ◽  
G. Bigras ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Molecular Subtype ◽  
Treatment Options ◽  
Standard Of Care ◽  
Small Cell ◽  
Driver Mutations ◽  
Small Cell Lung ◽  
Ros1 Rearrangement

The ROS1 kinase is an oncogenic driver in non-small-cell lung cancer (NSCLC). Fusion events involving the ROS1 gene are found in 1%–2% of NSCLC patients and lead to deregulation of a tyrosine kinase–mediated multi-use intracellular signalling pathway, which then promotes the growth, proliferation, and progression of tumour cells. ROS1 fusion is a distinct molecular subtype of NSCLC, found independently of other recognized driver mutations, and it is predominantly identified in younger patients (<50 years of age), women, never-smokers, and patients with adenocarcinoma histology.    Targeted inhibition of the aberrant ros1 kinase with crizotinib is associated with increased progression-free survival (PFS) and improved quality-of-life measures. As the sole approved treatment for ROS1-rearranged NSCLC, crizotinib has been demonstrated, through a variety of clinical trials and retrospective analyses, to be a safe, effective, well-tolerated, and appropriate treatment for patients having the ROS1 rearrangement.    Canadian physicians endorse current guidelines which recommend that all patients with nonsquamous advanced NSCLC, regardless of clinical characteristics, be tested for ROS1 rearrangement. Future integration of multigene testing panels into the standard of care could allow for efficient and cost-effective comprehensive testing of all patients with advanced NSCL. If a ROS1 rearrangement is found, treatment with crizotinib, preferably in the first-line setting, constitutes the standard of care, with other treatment options being investigated, as appropriate, should resistance to crizotinib develop.

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