Osimertinib and Cabozantinib Combinatorial Therapy in an EGFR -Mutant Lung Adenocarcinoma Patient with Multiple MET Secondary-Site Mutations after Resistance to Crizotinib

Kang, Jin Hyung; Chen, Hua-Jun; Wang, Zheng; Liu, Jing; Li, Bing; Zhang, Tengfei; Yang, Zhenfan; Wu, Yi‐Long; Yang, Jin‐Ji

doi:10.1016/j.jtho.2017.10.028

Cited by 48 publications

(44 citation statements)

References 7 publications

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“…The fact that resistance mechanisms against TKIs resulted in progressive disease, in combination with the disease control rates and the virtually mutual exclusivity of METex14del with other oncogenic driver mutations that we and others have demonstrated, support the valid claim that METex14del is an oncogenic driver mutation [5,10,12,[15][16][17][18][19][20][37][38][39].…”

Section: Discussionsupporting

confidence: 71%

“…Two patients, treated with crizotinib, showed MET resistance mutations after progression, concerning the MET c.3682 G > A; p.D1228N mutation for both patients. Patients with this mutation are described to be resistant to type I cMET inhibitors [37][38][39]. In silico modelling suggests that MET D1228N also mediates resistance against type II cMET inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…However, other resistance mechanisms to crizotinib, e.g. MET Y1230H, MET D1228H, and MET D1231Y, might still respond to type II inhibitors [38].…”

Section: Discussionmentioning

confidence: 99%

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Highly accurate DNA-based detection and treatment results of MET exon 14 skipping mutations in lung cancer

et al. 2020

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The oncogenic MET exon 14 skipping mutation (METex14del) is described to drive 1.3 %-5.7 % of non-small-cell lung cancer (NSCLC) and multiple studies with cMET inhibitors show promising clinical responses. RNA-based analysis seems most optimal for METex14del detection, however, acquiring sufficient RNA material is often problematic. An alternative is DNA-based analysis, but commercially available DNA-based panels only detect up to 63 % of known METex14del alterations. The goal of this study is to describe an optimized DNA-based diagnostic test for METex14del in NSCLC, including clinical features and follow-up of patients treated with cMET-targeted therapy and consequent resistance mechanisms. Material and methods: Routinely processed diagnostic pathology non-squamous NSCLC specimens were investigated by a custom-made DNA-based targeted amplicon-based next generation sequencing (NGS) panel, which includes 4 amplicons for METex14del detection. Retrospectively, histopathological characteristics and clinical follow up were investigated for advanced non-squamous NSCLC with METex14del. Results: In silico analysis showed that our NGS panel is able to detect 96 % of reported METex14 alterations. METex14del was found in 2 % of patients with non-squamous NSCLC tested for therapeutic purposes. In total, from May 2015-Sep 2018, METex14del was found in 46 patients. Thirty-six of these patients had advanced nonsquamous NSCLC, they were predominantly elderly (76.5 years [53-90]), male (25/36) and (ex)-smokers (23/ 36). Five patients received treatment with crizotinib (Pfizer Oncology), in a named patient based program, disease control was achieved for 4/5 patients (3 partial responses, 1 stable disease) and one patient had a mixed response. Two patients developed a MET D1228N mutation during crizotinib treatment, inducing a resistance mechanism to crizotinib. Conclusions: This study shows that METex14del can be reliably detected by routine DNA NGS analysis. Although a small cohort, patients responded well to targeted treatment, underlining the need for routine testing of METex14del in advanced non-squamous NSCLC to guarantee optimal personalized treatment.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

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Highly accurate DNA-based detection and treatment results of MET exon 14 skipping mutations in lung cancer

et al. 2020

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“…Targeting EGFR and MET simultaneously may be required to overcome resistance to EGFR-TKIs by MET alteration, making it necessary to assess MET status before osimertinib treatment. Thus, some studies have reported the successful administration of dual EGFR and MET therapies [28][29][30]. The combination of osimertinib and MET inhibitors can be safe and effective in NSCLC patients with MET amplification detected by ddPCR as an acquired resistance mechanism.…”

Section: Discussionmentioning

confidence: 99%

Detection of MET Alterations Using Cell Free DNA and Circulating Tumor Cells from Cancer Patients

Mondelo‐Macía

Rodríguez-López

Valiña

et al. 2020

Cells

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MET alterations may provide a potential biomarker to evaluate patients who will benefit from treatment with MET inhibitors. Therefore, the purpose of the present study is to investigate the utility of a liquid biopsy-based strategy to assess MET alterations in cancer patients. We analyzed MET amplification in circulating free DNA (cfDNA) from 174 patients with cancer and 49 healthy controls and demonstrated the accuracy of the analysis to detect its alteration in patients. Importantly, a significant correlation between cfDNA concentration and MET copy number (CN) in cancer patients (r = 0.57, p <10−10) was determined. Furthermore, we evaluated two approaches to detect the presence of MET on circulating tumor cells (CTCs), using the CellSearch® and Parsortix systems and monitored patients under anti-EGFR treatment (n = 30) combining both cfDNA and CTCs analyses. This follow-up provides evidence for the potential of MET CN assessment when patients develop resistance to anti-EGFR therapy and a significant association between the presence of CTCs MET+ and the Overall Survival (OS) in head and neck cancer patients (P = 0.05; HR = 6.66). In conclusion, we develop specific and noninvasive assays to monitor MET status in cfDNA/CTCs and demonstrate the utility of plasma MET CN determination as a biomarker for monitoring the appearance of resistance to anti-EGFR therapy.

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“…Treatment of patients with crizotinib eventually leads to resistant mutations ( Figure 1F). Two mutations in the A loop D1246H/N [141][142][143][144][145] and Y1248H/C/S [141,[144][145][146] stabilize the active conformation of the A loop and decreases the efficacy of the drug [147]. At least one study identified the G1181R in addition to the Y1248 and D1246 mutations when an exon 14 skipping patient was treated with crizotinib [145].…”

Section: Hepatocyte Growth Factor Receptor (Hfgr C-met)mentioning

confidence: 99%

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

Hamid

Petreaca

2020

Cancers

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Secondary resistant mutations in cancer cells arise in response to certain small molecule inhibitors. These mutations inevitably cause recurrence and often progression to a more aggressive form. Resistant mutations may manifest in various forms. For example, some mutations decrease or abrogate the affinity of the drug for the protein. Others restore the function of the enzyme even in the presence of the inhibitor. In some cases, resistance is acquired through activation of a parallel pathway which bypasses the function of the drug targeted pathway. The Catalogue of Somatic Mutations in Cancer (COSMIC) produced a compendium of resistant mutations to small molecule inhibitors reported in the literature. Here, we build on these data and provide a comprehensive review of resistant mutations in cancers. We also discuss mechanistic parallels of resistance.

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Osimertinib and Cabozantinib Combinatorial Therapy in an EGFR -Mutant Lung Adenocarcinoma Patient with Multiple MET Secondary-Site Mutations after Resistance to Crizotinib

Cited by 48 publications

References 7 publications

Highly accurate DNA-based detection and treatment results of MET exon 14 skipping mutations in lung cancer

Highly accurate DNA-based detection and treatment results of MET exon 14 skipping mutations in lung cancer

Detection of MET Alterations Using Cell Free DNA and Circulating Tumor Cells from Cancer Patients

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

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