2018
DOI: 10.1001/jamaoncol.2018.2969
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Assessment of Resistance Mechanisms and Clinical Implications in Patients WithEGFRT790M–Positive Lung Cancer and Acquired Resistance to Osimertinib

Abstract: Acquired resistance to osimertinib mediated by loss of the T790M mutation is associated with early resistance and a range of competing resistance mechanisms. These data provide clinical evidence of the heterogeneity of resistance in advanced NSCLC and a need for clinical trial strategies that can overcome multiple concomitant resistance mechanisms or strategies for preventing such resistance.

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Cited by 576 publications
(593 citation statements)
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“…NGS, the results for which are usually expressed as allele frequency, has the potential to become widely adopted for liquid biopsy analysis because it is able to simultaneously identify various genetic alterations including those responsible for resistance to targeted therapy. [24][25][26][27][28][29][30][31] Our findings suggest that the monitoring of allele frequency for EGFRactivating mutations in cfDNA by NGS may also be useful for the prediction of EGFR-TKI treatment efficacy.…”
Section: Discussionmentioning
confidence: 79%
See 1 more Smart Citation
“…NGS, the results for which are usually expressed as allele frequency, has the potential to become widely adopted for liquid biopsy analysis because it is able to simultaneously identify various genetic alterations including those responsible for resistance to targeted therapy. [24][25][26][27][28][29][30][31] Our findings suggest that the monitoring of allele frequency for EGFRactivating mutations in cfDNA by NGS may also be useful for the prediction of EGFR-TKI treatment efficacy.…”
Section: Discussionmentioning
confidence: 79%
“…Such a pattern was also evident for the allele frequency of EGFR ‐activating mutations (the ratio of the number of activating mutations to the total number of EGFR alleles) as determined by ddPCR (data not shown). NGS, the results for which are usually expressed as allele frequency, has the potential to become widely adopted for liquid biopsy analysis because it is able to simultaneously identify various genetic alterations including those responsible for resistance to targeted therapy . Our findings suggest that the monitoring of allele frequency for EGFR ‐activating mutations in cfDNA by NGS may also be useful for the prediction of EGFR‐TKI treatment efficacy.…”
Section: Discussionmentioning
confidence: 83%
“…Synthesizing this data however is problematic, as these studies are diverse with regards to line of therapy, use of tumor tissue or plasma circulating tumor DNA (ctDNA) and method and extent of genomic sequencing or alteration detection. Whilst there is some overlap with 1G/2G T790M negative mediated mechanisms of resistance, the presence of novel mechanisms such as kinase gene fusions (such as RET and FGFR fusions) and alternate drivers (such as BRAF and KRAS mutations) [24,25], suggest a different resistance landscape and altered tumor biology. Ultimately, comprehensive deep genomic and transcriptomic profiling of patients at baseline and resistance will be critical to wholly appreciate the importance and relevance of these novel findings.…”
Section: Should All Patients Receive Upfront 3 Rd Generation Egfr Tki?mentioning
confidence: 99%
“…While osimertinib can overcome T790M-mediated resistance to firstand second-generation EGFR-TKIs, 1 various alternate resistance mechanisms remain without effective therapies, including amplification of MET or HER2 genes, acquired mutations in oncogenes like BRAF, and small-cell transformation. 4 Emerging data indicate that resistance mechanisms that develop following treatment with osimertinib 5,6 include MET amplification and EGFR C797S mutation, as detected in plasma. 6 Another acquired resistance mechanism to EGFR-TKIs is up-regulation of the RAS/ RAF/MEK/ERK signaling pathway, key to cell survival and proliferation 7,8 ; this can occur downstream of various other signaling pathways.…”
Section: Introductionmentioning
confidence: 99%