Combination Osimertinib and Gefitinib in C797S and T790M EGFR-Mutated Non–Small Cell Lung Cancer

Arulananda, Surein; Do, Hongdo; Musafer, Ashan; Mitchell, Paul; Dobrovic, Alexander; John, Thomas

doi:10.1016/j.jtho.2017.08.006

Cited by 151 publications

(133 citation statements)

References 16 publications

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“…Till now, limited studies reported the resistant mechanism of osimertinib and extreme complicated resistant profiles were identified based on current data [49][50][51]. Fortunately, several preclinical and small size studies have provided potential treatment modalities to overcome the resistance, but an umbrella trial should be designed to address the pending issues [48,[52][53][54][55][56][57][58][59][60][61][62][63]. On the other hand, considering the rapid development of checkpoint inhibitors (CPIs) in advanced NSCLC, whether CPIs could benefit in patients with pan-negative oncogenes after osimertinib or treatment failure of novel combination modality remained to be explored in prospective trials.…”

Section: Osimertinib (Azd9291)mentioning

confidence: 99%

Emerging therapies for non-small cell lung cancer

et al. 2019

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Recent advances in the field of novel anticancer agents prolong patients' survival and show a promising future. Tyrosine kinase inhibitors and immunotherapy for lung cancer are the two major areas undergoing rapid development. Although increasing novel anticancer agents were innovated, how to translate and optimize these novel agents into clinical practice remains to be explored. Besides, toxicities and availability of these drugs in specific regions should also be considered during clinical determination. Herein, we summarize emerging agents including tyrosine kinase inhibitors, checkpoint inhibitors, and other potential immunotherapy such as chimeric antigen receptor T cell for non-small cell lung cancer attempting to provide insights and perspectives of the future in anticancer treatment.

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Section: Osimertinib (Azd9291)mentioning

confidence: 99%

Emerging therapies for non-small cell lung cancer

et al. 2019

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“…4 Identification of NSCLC patients likely to profit from these novel therapies relies on the detection of specific biomarkers in tumor biopsies. 5 Further targets, including SSH and ERBB3 in NSCLC are under investigation, [11][12][13] and novel molecular resistance mechanisms, such as EGFR C797S in case of thirdgeneration EGFR TKI, 14 are continuously being discovered, requiring expeditious adaptability of testing approaches to supply clinically relevant genetic information to medical oncologists. In addition, patients with a pulmonary squamous cell carcinoma (SCC) and high clinical suspicion for actionable mutations, based for example on a never-or light-smoking history and/or young age, should be offered molecular testing as well.…”

Section: Introductionmentioning

confidence: 99%

“…Analysis of EGFR, ALK 9 and ROS1 10 is mandatory, and the inclusion of additional drug targets, such as BRAF, MET, RET, ERBB2 (HER2), as well as additonal markers, like KRAS, is recommended. 5 Further targets, including SSH and ERBB3 in NSCLC are under investigation, [11][12][13] and novel molecular resistance mechanisms, such as EGFR C797S in case of thirdgeneration EGFR TKI, 14 are continuously being discovered, requiring expeditious adaptability of testing approaches to supply clinically relevant genetic information to medical oncologists.…”

Section: Introductionmentioning

confidence: 99%

Combined targeted DNA and RNA sequencing of advanced NSCLC in routine molecular diagnostics: Analysis of the first 3,000 Heidelberg cases

Volckmar

Leichsenring

Kirchner

et al. 2019

Intl Journal of Cancer

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Tyrosine kinase inhibitors currently confer the greatest survival gain for nonsmall cell lung cancer (NSCLC) patients with actionable genetic alterations. Simultaneously, the increasing number of targets and compounds poses the challenge of reliable, broad and timely molecular assays for the identification of patients likely to benefit from novel treatments. Here, we demonstrate the feasibility and clinical utility of comprehensive, NGS‐based genetic profiling for routine workup of advanced NSCLC based on the first 3,000 patients analyzed in our department. Following automated extraction of DNA and RNA from formalin‐fixed, paraffin‐embedded tissue samples, parallel sequencing of DNA and RNA for detection of mutations and gene fusions, respectively, was performed using PCR‐based enrichment with an ion semiconductor sequencing platform. Overall, 807 patients (27%) were eligible for currently approved, EGFR‐/BRAF‐/ALK‐ and ROS1‐directed therapies, while 218 additional cases (7%) with MET, ERBB2 (HER2) and RET alterations could potentially benefit from experimental targeted compounds. In addition, routine capturing of comutations, e.g. TP53 (55%), KEAP1 (11%) and STK11 (11%), as well as the precise typing of fusion partners and involved exons in case of actionable translocations including ALK and ROS1, are prognostic and predictive tools currently gaining importance for further refinement of therapeutic and surveillance strategies. The reliability, low dropout rates (<5%), minimal tissue requirements, fast turnaround times (6 days on average) and lower costs of the diagnostic approach presented here compared to sequential single‐gene testing, highlight its practicability in order to support individualized decisions in routine patient care, enrollment in molecularly stratified clinical trials, as well as translational research.

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“…To investigate the current reporting practices for NGS‐based ctDNA analysis and to assess the reporting consistency between different laboratories, a set of simulated ctDNA samples and a corresponding case scenario were distributed to genetic testing laboratories for ctDNA analysis. The sample design and corresponding clinical information originated from recently published case reports . Four commonly detected and clinically relevant variants in the EGFR and TP53 genes, with variant allelic frequencies (VAF) ranging from 0.1% to 10%, were incorporated into our panel.…”

Section: Methodsmentioning

confidence: 99%

From Somatic Variants Toward Precision Oncology: An Investigation of Reporting Practice for Next-Generation Sequencing-Based Circulating Tumor DNA Analysis

et al. 2019

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Background With the accelerated development of next‐generation sequencing (NGS), identified variants, and targeted therapies, clinicians who confront the complicated and multifarious genetic information may not effectively incorporate NGS‐based circulating tumor DNA (ctDNA) analysis into routine patient care. Consequently, standardized ctDNA testing reports are of vital importance. In an effort to guarantee high‐quality reporting performance, we conducted an investigation of the current detection and reporting practices for NGS‐based ctDNA analysis. Materials and Methods A set of simulated ctDNA samples with known variants at known allelic frequencies and a corresponding case scenario were distributed to 66 genetic testing laboratories for ctDNA analysis. Written reports were collected to evaluate the detection accuracy, reporting integrity, and information sufficiency using 21 predefined criteria. Results Current reporting practices for NGS‐based ctDNA analysis were found to be far from satisfactory, especially regarding testing interpretation and methodological details. Only 42.4% of laboratories reported the results in complete concordance with the expected results. Moreover, 74.2% of reports only listed aberrations with direct and well‐known treatment consequences for the tumor type in question. Genetic aberrations for which experimental agents and/or drug access programs are available may thus be overlooked. Furthermore, methodological details for the interpretation of results were missing from the majority of reports (87.9%). Conclusion This proof‐of‐principle study suggests that the capacity for accurate identification of variants, rational interpretation of genotypes, comprehensive recommendation of potential medications, and detailed description of methodologies need to be further improved before ctDNA analysis can be formally implemented in the clinic. Implications for Practice Accurate, comprehensive, and standardized clinical sequencing reports can help to translate complex genetic information into patient‐centered clinical decisions, thereby shepherding precision oncology into daily practice. However, standards, guidelines, and quality requirements for clinical reports of next‐generation sequencing (NGS)‐based circulating tumor DNA (ctDNA) analysis are currently absent. By using a set of simulated clinical ctDNA samples and a corresponding case scenario, current practices were evaluated to identify deficiencies in clinical sequencing reports of ctDNA analysis. The recommendations provided here may serve as a roadmap for the improved implementation of NGS‐based ctDNA analysis in the clinic.

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Combination Osimertinib and Gefitinib in C797S and T790M EGFR-Mutated Non–Small Cell Lung Cancer

Abstract: This is, to the best of our knowledge, the first reported case of combination EGFR tyrosine kinase inhibitor therapy tailored to the allelic conformation of T790M and C797S mutation that resulted in brief clinical improvement without toxicity.

Cited by 151 publications

References 16 publications

Emerging therapies for non-small cell lung cancer

Emerging therapies for non-small cell lung cancer

Combined targeted DNA and RNA sequencing of advanced NSCLC in routine molecular diagnostics: Analysis of the first 3,000 Heidelberg cases

From Somatic Variants Toward Precision Oncology: An Investigation of Reporting Practice for Next-Generation Sequencing-Based Circulating Tumor DNA Analysis

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