Assessment of Resistance Mechanisms and Clinical Implications in Patients With<i>EGFR</i>T790M–Positive Lung Cancer and Acquired Resistance to Osimertinib

Oxnard, Geoffrey R.; Hu, Yuebi; Mileham, Kathryn F.; Husain, Hatim; Costa, Daniel B.; Tracy, Philip; Feeney, Nora; Sholl, Lynette M.; Dahlberg, Suzanne E.; Redig, Amanda J.; Kwiatkowski, David J.; Rabin, Michael S.; Paweletz, Cloud P.; Thress, Kenneth S.; Jänne, Pasi A.

doi:10.1001/jamaoncol.2018.2969

Cited by 543 publications

(559 citation statements)

References 40 publications

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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%

“…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%

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Longitudinal monitoring of somatic genetic alterations in circulating cell‐free DNA during treatment with epidermal growth factor receptor–tyrosine kinase inhibitors

Iwama

Sakai

Hidaka

et al. 2019

Cancer

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Background The aim of this study was to evaluate the potential of liquid biopsy for prediction of the efficacy of epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) treatment and for assessment of the changes in genetic alterations during such treatment. Methods Plasma samples were prospectively collected from non–small cell lung cancer patients with EGFR‐activating mutations during EGFR‐TKI treatment until disease progression and were analyzed for such mutations with droplet digital polymerase chain reaction and for other somatic alterations with next‐generation sequencing. Results One hundred patients, including 87 who were EGFR‐TKI naïve, were enrolled. Median progression‐free survival was significantly shorter for EGFR‐TKI–naïve patients with EGFR‐activating mutations detected in plasma at baseline than for those without them (7.9 vs 19.0 months; P < .001), with the values being significantly longer for initially positive patients who became negative for these mutations at 12 or 24 weeks than for those who remained positive. An increase in the number of alleles positive for EGFR‐activating mutations in plasma during treatment was associated with disease progression, with a hazard ratio of 4.72 (95% CI, 2.07‐10.79; P < .001) for EGFR‐TKI–naïve patients showing an increase within 36 weeks. For 55 patients with available samples, the total number of somatic alterations (other than activating mutations or T790M of EGFR) in plasma was higher at disease progression than at baseline (33 vs 19; P = 0.04). Conclusion Liquid biopsy shows potential for prediction of EGFR‐TKI efficacy and elucidation of clonal tumor evolution during targeted therapy.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 83%

Longitudinal monitoring of somatic genetic alterations in circulating cell‐free DNA during treatment with epidermal growth factor receptor–tyrosine kinase inhibitors

Iwama

Sakai

Hidaka

et al. 2019

Cancer

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“…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%

Third generation EGFR TKI landscape for metastatic EGFR mutant non-small cell lung cancer (NSCLC)

Tan

Teh

Lai

et al. 2019

Expert Review of Anticancer Therapy

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“…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%

TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer

et al. 2020

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Background: Osimertinib is a potent, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). The multi-arm phase Ib TATTON study (NCT02143466) was designed to assess the safety and tolerability of osimertinib in combination with other targeted therapies: selumetinib (MEK1/2 inhibitor), savolitinib (MET-TKI), or durvalumab [anti-programmed cell death ligand 1 (anti-PD-L1) monoclonal antibody]. Patients and methods: Patients with advanced EGFR-mutant non-small-cell lung cancer and disease progression on a prior EGFR-TKI were enrolled and allocated to dose-escalating cohorts combining osimertinib 80 mg orally (p.o.) once a day with selumetinib (25e75 mg p.o. twice a day; continuous or intermittent), savolitinib (600e800 mg p.o. once a day), or durvalumab (3e10 mg/kg intravenous every 2 weeks). Results: At data cut-off (28 February 2018), 77 patients were enrolled and received osimertinib plus selumetinib (n ¼ 36), savolitinib (n ¼ 18), or durvalumab (n ¼ 23). Most common adverse events (any grade), occurring in 20% of patients across dose groups, were: selumetinib armddiarrhea (75%), rash (58%), nausea (47%); savolitinib armdnausea (67%), rash (56%), vomiting (50%); durvalumab armdrash (48%), vomiting (43%), diarrhea (39%). Dose-limiting toxicities were reported in the selumetinib 25 mg (n ¼ 1), 50 mg (n ¼ 1), and 75 mg (n ¼ 4) continuous-dose groups, savolitinib 600 mg (n ¼ 1) and 800 mg dose groups (n ¼ 2), and durvalumab 10 mg/kg (n ¼ 1) dose group. The objective response rate was 42% (95% confidence interval 26% to 59%), 44% (22% to 69%), and 43% (23% to 66%) in the selumetinib, savolitinib, and durvalumab arms, respectively. Conclusion: Our results demonstrate the feasibility of combining osimertinib 80 mg with selumetinib or savolitinib at identified tolerable, active doses. A combination of osimertinib with durvalumab was not feasible due to increased reporting of interstitial lung disease. Osimertinib-based combination therapies represent a compelling approach now being further investigated. Clinical trials number: NCT02143466.

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Assessment of Resistance Mechanisms and Clinical Implications in Patients WithEGFRT790M–Positive Lung Cancer and Acquired Resistance to Osimertinib

Cited by 543 publications

References 40 publications

Longitudinal monitoring of somatic genetic alterations in circulating cell‐free DNA during treatment with epidermal growth factor receptor–tyrosine kinase inhibitors

Longitudinal monitoring of somatic genetic alterations in circulating cell‐free DNA during treatment with epidermal growth factor receptor–tyrosine kinase inhibitors

Third generation EGFR TKI landscape for metastatic EGFR mutant non-small cell lung cancer (NSCLC)

TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer

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