scholarly journals Real-world implementation of sequential targeted therapies for EGFR-mutated lung cancer

2021 ◽  
Vol 13 ◽  
pp. 175883592199650
Author(s):  
Nikolaus Magios ◽  
Farastuk Bozorgmehr ◽  
Anna-Lena Volckmar ◽  
Daniel Kazdal ◽  
Martina Kirchner ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Targeted Therapies ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Resistance Mechanisms ◽  
Subsequent Treatment ◽  
Clinical Deterioration ◽  
Published Data ◽  
Tki Treatment ◽  
Nsclc Patients

Background: Epidermal growth factor receptor-mutated (EGFR+) non-small-cell lung cancer (NSCLC) patients failing tyrosine kinase inhibitors (TKI) can benefit from next-line targeted therapies, but implementation is challenging. Methods: EGFR+ NSCLC patients treated with first/second-generation (1G/2G) TKI at our institution with a last follow-up after osimertinib approval (February 2016), were analyzed retrospectively, and the results compared with published data under osimertinib. Results: A total of 207 patients received erlotinib (37%), gefitinib (16%) or afatinib (47%). The median age was 66 years, with a predominance of female (70%), never/light-smokers (69%). T790M testing was performed in 174/202 progressive cases (86%), positive in 93/174 (53%), and followed by osimertinib in 87/93 (94%). Among the 135 deceased patients, 94 (70%) received subsequent systemic treatment (43% chemotherapy, 39% osimertinib), while 30% died without, either before (4%) or after progression, due to rapid clinical deterioration (22%), patient refusal of further therapy (2%), or severe competing illness (2%). Lack of subsequent treatment was significantly (4.5x, p < 0.001) associated with lack of T790M testing, whose most frequent cause (in approximately 50% of cases) was also rapid clinical decline. Among the 127 consecutive patients with failure of 1G/2G TKI started after November 2015, 47 (37%) received osimertinib, with a median overall survival of 36 months versus 24 and 21 months for patients with alternative and no subsequent therapies ( p = 0.003). Conclusion: Osimertinib after 1G/2G TKI failure prolongs survival, but approximately 15% and 30% of patients forego molecular retesting and subsequent treatment, respectively, mainly due to rapid clinical deterioration. This is an important remediable obstacle to sequential TKI treatment for EGFR+ NSCLC. It pertains also to other actionable resistance mechanisms emerging under 1G/2G inhibitors or osimertinib, whose rate for lack of next-line therapy is similar (approximately 35% in the FLAURA/AURA3 trials), and highlights the need for closer monitoring alongside broader profiling of TKI-treated EGFR+ NSCLC in the future.

scholarly journals MET Gene Dysregulation as a Promising Therapeutic Target in Lung Cancer—A Review

2021 ◽  
Vol 11 (12) ◽  
pp. 1370
Author(s):  
Paulina Terlecka ◽  
Paweł Krawczyk ◽  
Anna Grenda ◽  
Janusz Milanowski
Keyword(s):  
Lung Cancer ◽  
Clinical Trials ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Point Mutations ◽  
Growth Factor Receptor ◽  
Molecular Abnormalities ◽  
Promising Therapeutic Target ◽  
Tumorigenic Activity ◽  
Nsclc Patients

Several molecular abnormalities in the MET gene have been identified, including overexpression, amplification, point mutations, and “skipping mutation” in exon 14. Even though deregulated MET signaling occurs rarely in non-small cell lung cancer (NSCLC), it possesses tumorigenic activity. Since the discovery of the significant role played by MET dysregulations in resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI), many clinical trials have been focused on mechanisms underlying this acquired resistance. Therefore, new therapeutic strategies are being considered in the personalized therapy of NSCLC patients carrying MET abnormalities. First, MET kinase inhibitors (tepotinib and capmatinib) have been shown to be effective in the first and subsequent lines of treatment in NSCLC patients with “skipping mutations” in exon 14 of MET gene. In this article, the authors show the role of MET signaling pathway alterations and describe the results of clinical trials with MET inhibitors in NSCLC patients.

scholarly journals Tumour tissue sampling for lung cancer management in the era of personalised therapy: what is good enough for molecular testing?

2014 ◽  
Vol 44 (4) ◽  
pp. 1011-1022 ◽  
Author(s):  
Lucia Kim ◽  
Ming Sound Tsao
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Tumour Progression ◽  
Growth Factor Receptor ◽  
Nonsmall Cell Lung Cancer ◽  
Tumour Tissue ◽  
Molecular Testing ◽  
Anaplastic Lymphoma ◽  
Cancer Management ◽  
Nsclc Patients

In the era of personalised cancer therapy, the demand for molecular profiling of the patient’s tumour is steadily increasing. In advanced nonsmall cell lung cancer (NSCLC) patients, testing for epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements has become an essential component of clinical practice to select patients who are most likely to benefit from EGFR and ALK tyrosine kinase inhibitors, respectively. Furthermore, obtaining tissue specimens from recurrent or metastatic tumours or from patients who develop resistance to initial effective therapies are essential for our understanding of the molecular basis of tumour progression and development of drug resistance. Therefore, the sampling of tumour tissue that is representative and is adequate in quantity and quality for pathological diagnosis and genomic profiling is crucial. In this review, we will discuss factors that should be considered in obtaining and processing biopsy specimens to enable routine molecular analysis in NSCLC patients.

scholarly journals Genetic Alteration Profiling of Chinese Lung Adenocarcinoma and Its Effect on Targeted Therapy Efficacy

2021 ◽  
Vol 11 ◽  
Author(s):  
Jie Liu ◽  
Wang-yang Xu ◽  
Maosong Ye ◽  
Zilong Liu ◽  
Chun Li
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Lung Adenocarcinoma ◽  
Receptor Tyrosine Kinase ◽  
Targeted Therapies ◽  
Kinase Inhibitors ◽  
Eastern China ◽  
Growth Factor Receptor ◽  
Treatment Decision ◽  
Tyrosine Kinase 2

BackgroundNon-small cell lung cancer (NSCLC) is the most common type of lung cancer and a highly heterogeneous disease with a diversity of phenotypes and genotypes in different populations. The purpose of this study is to investigate oncogenic alterations of lung adenocarcinoma (LUAD) in eastern China and their significance in targeted therapies.MethodsThis study enrolled 101 LUAD patients and used a customized DNA panel to detect molecular alterations. Comprehensive analysis of mutations and clinical application of genomic profiling was carried out.ResultsThe most commonly mutated genes were epidermal growth factor receptor (EGFR) (53%) and tumor protein p53 (TP53) (32%). The less frequently mutated genes were erb-b2 receptor tyrosine kinase 2 (ERBB2) (25%), ATR serine/threonine kinase (ATR) (20%), CCAAT enhancer binding protein alpha (CEBPA) (16%), RB transcriptional corepressor 1 (RB1) (16%), transcription factor 7 like 2 (TCF7L2) (14%), ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) (12%) and spectrin alpha, erythrocytic 1 (SPTA1) (12%). Among them, the frequency of ERBB2, ATR, CEBPA, RB1 and TCF7L2 mutations was much higher than that in the databases. Seventy percent of the patients harbored at least one actionable alteration according to the OncoKB evidence. CEBPA mutations affected the efficacy of EGFR-tyrosine kinase inhibitors. ERBB2, CEBPA and TCF7L2 mutated tumors tend to have higher tumor mutation burden (TMB).ConclusionsLUAD patients from eastern China have a unique profile of mutations. The targeted DNA panel is helpful for personalized treatment decision of LUAD patients, and specific mutations may affect the efficacy of targeted therapies.

scholarly journals Detection of TP53 Mutations in Tissue or Liquid Rebiopsies at Progression Identifies ALK+ Lung Cancer Patients with Poor Survival

Cancers ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 124 ◽  
Author(s):  
Petros Christopoulos ◽  
Steffen Dietz ◽  
Martina Kirchner ◽  
Anna-Lena Volckmar ◽  
Volker Endris ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Resistance Mechanisms ◽  
Wild Type ◽  
Tp53 Mutations ◽  
Lung Cancer Patients ◽  
Anaplastic Lymphoma ◽  
Nsclc Patients

Anaplastic lymphoma kinase (ALK) sequencing can identify resistance mechanisms and guide next-line therapy in ALK+ non-small-cell lung cancer (NSCLC), but the clinical significance of other rebiopsy findings remains unclear. We analysed all stage-IV ALK+ NSCLC patients with longitudinally assessable TP53 status treated in our institutions (n = 62). Patients with TP53 mutations at baseline (TP53mutbas, n = 23) had worse overall survival (OS) than patients with initially wild-type tumours (TP53wtbas, n = 39, 44 vs. 62 months in median, p = 0.018). Within the generally favourable TP53wtbas group, detection of TP53 mutations at progression defined a “converted” subgroup (TP53mutconv, n = 9) with inferior OS, similar to that of TP53mutbas and shorter than that of patients remaining TP53 wild-type (TP53wtprogr, 45 vs. 94 months, p = 0.043). Progression-free survival (PFS) under treatment with tyrosine kinase inhibitors (TKI) for TP53mutconv was comparable to that of TP53mutbas and also shorter than that of TP53wtprogr cases (5 and 8 vs. 13 months, p = 0.0039). Fewer TP53wtprogr than TP53mutbas or TP53mutconv cases presented with metastatic disease at diagnosis (67% vs. 91% or 100%, p < 0.05). Thus, acquisition of TP53 mutations at progression is associated with more aggressive disease, shorter TKI responses and inferior OS in ALK+ NSCLC, comparable to primary TP53 mutated cases.

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