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Reinhard Buettner



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    Lunch & Poster Display session (ID 58)

    • Event: ELCC 2019
    • Type: Poster Display session
    • Track:
    • Presentations: 2
    • Moderators:
    • Coordinates: 4/11/2019, 12:30 - 13:00, Hall 1
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      132P - New insights into acquired resistance mechanisms to third-generation EGFR tyrosine kinase inhibitor therapy in lung cancer (ID 307)

      12:30 - 13:00  |  Author(s): Reinhard Buettner

      • Abstract

      Background

      The emergence of acquired resistance (AR) against third-generation epidermal growth factor receptor tyrosine kinase inhibitors (TKI) remain a major clinical challenge in lung adenocarcinoma patients. Here we characterized the role of acquired resistance mechanism with a focus on inter-individual heterogeneity and co-occurring genetic aberrations. We could analyze pre- and post-treatment samples of patients treated with third-generation EGFR TKIs.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We characterized 128 patients, which are EGFR p.T790M positive to early generation EGFR TKIs within thedatabases of the Network Genomic Medicine (NGM), the NOWEL network, the Department of Thoracic Oncology of the Netherlands Cancer Institute and the Vall d’Hebron University Hospital. In 60 patients, corresponding analyses of third generation EGFR TKI treatment outcomes and molecular analyses were practicable.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Co-occurring aberrations were found in 75% of the samples with acquired resistance to early-generation TKI. TP53mutations were the most frequent aberrations detected. In MET, copy number variants were found (n = 6). In a subgroup, we identified 4 patients with the new EGFRresistance mutation p.G724S after third-generation TKI treatment. Still, loss of the EGFRp.T790M mutation and METamplification are the most common aberrations after third-generation TKI treatment.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      EGFR inhibitors represent a powerful tool for precision cancer medicine in genetically selected patients. We could show in this study that additional genetic aberrations are frequent in the setting of AR to EGFR TKIs and may mediate innate and acquired resistance to third-generation EGFR TKIs. Amplification of METwas strongly associated with primary treatment failure and thus the strongest factor in innate resistance. AR to third-generation EGFR TKI (p.G724S) can possibly be overcome with second-generation EGFR TKI.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Deutsche Forschungsgemeinschaft, Cluster of Excellence RESOLV, the Bundesministerium für Bildung und Forschung, Else Kröner-Fresenius Stiftung, Deutsche Krebshilfe, European Union, (NRW) as part of the EFRE initiative (EMODI, grant no. EFRE-0800397 to R.B. and M.L.S.) and by the German Ministry of Science and Education (BMBF) as part of the e:Med program (grant no. 01ZX1303A to R.B. and J.W). E.F. received funding by the Instituto de Salud Carlos III (PI17/00938), NEGECA, ITMC of TU Dortmund.

      682889d0a1d3b50267a69346a750433d Disclosure

      J. Fassunke: Honoraria: AstraZeneca. C. Heydt, S. Merkelbach-Bruse: Speaking honoraria: AstraZeneca. J. Wolf: Consulting, lecture fees: AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Chugai, Ignyta, Lilly, MSD, Novartis, Pfizer, Roche; Funding for scientific research: BMS, Johnson&Johnson, MSD, Novartis, Pfizer. R. Buettner: Employee: Targos Molecular Pathology. M.L. Sos: Commercial research grant: Novartis. D. Rauh: Consultant, lecture fees: AstraZeneca, Merck-Serono, Takeda, Pfizer, Novartis, Boehringer Ingelheim, Sanofi-Aventis. All other authors have declared no conflicts of interest.

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      134P - Mutational spectrum of acquired resistance to reversible versus irreversible EGFR tyrosine kinase inhibitors (ID 297)

      12:30 - 13:00  |  Author(s): Reinhard Buettner

      • Abstract

      Background

      Mutational spectrum of acquired resistance to reversible versus irreversible EGFR tyrosine kinase inhibitors Over the past years, EGFR tyrosine kinase inhibitors (TKI) revolutionized treatment response. 1st-generation (reversible) EGFR TKI later the 2nd –generation irreversible EGFR TKI Afatinib was aimed to improve treatment response. Nevertheless, diverse resistance mechanisms develop within the first year of therapy. Here, we evaluate the prevalence of acquired resistance mechanisms towards reversible and irreversible EGFR TKI.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Rebiopsies of patients after progression to EGFR TKI therapy (>6months) were targeted to histological and molecular analysis. Multiplexed targeted sequencing (NGS) was conducted to identify acquired resistance mutations (e.g. EGFR p.T790M). Further, Fluorescence in situ hybridisation (FISH) was applied to investigate the amplification status of bypass mechanisms like, MET or HER2.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      123 rebiopsy samples of patients that underwent firts-line EGFR TKI therapy ( PFS >6months) were histologically and molecularly profiled upon clinical progression. The EGFR p.T790M mutation ist the major mechanism of acquired resistance in patients treated with reversible as well as irreversible EGFR TKI. Nevertheless a statistically significant difference for the acquisition of T790M mutation has been idientified: 45% of afatinib- vs 65% of reversible EGFR TKI treated patients developed a T790M mutation (p-value 0.02). Progression free survival (PFS) was comparable in patients treated with irreversible EGFR irrespective of the sensitising primary mutation or the acquisition of p.T790M.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      The EGFR p.T790M gatekeeper mutation ist he most prominent mechanism of resistance to reversible and irreversible EGFR TKI therapy. Nevertheless there is a statistically significant prevalence of p.T790M acquisition between the two types of TKI, which might be of importance for clinical therapy decision.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Boehringer Ingelheim.

      682889d0a1d3b50267a69346a750433d Disclosure

      S. Wagener-Ryczek: Honoraria: Boehringer Ingelheim. C. Heydt: Honoraria: AstraZeneca, BMS, Illumina. S. Michels: Honoraria: Novartis, Pfizer, AstraZeneca, Boehringer Ingelheim; Advisory roles: Boehringer Ingelheim, Pfizer; Research funding: Pfizer, Novartis, BMS; Travel support/accommodations: Novartis. J. Fassunke: Honoraria, advisory role: AstraZeneca. M. Tiemann: Honoraria: Pfizer, Novartis, Roche. L. Heukamp: Co-founder: Neo New Oncology. J. Wolf: Honoraria: AstraZeneca, BMS, Clovis Oncology, Lilly, MSD, Novartis, Pfizer, Roche; Advisory roles: AstraZeneca, BMS, Clovis Oncology, Lilly, MSD, Novartis, Pfizer, Roche, Amgen. R. Buettner: Co-founder, Chief Scientific Officer: Targos Molecular Pathology; Honoraria: Roche, Pfizer, Novartis, AstraZeneca, Qiagen, MSD, BMS, Lilly. S. Merkelbach-Bruse: Honoraria: AstraZeneca; Advisory roles: AstraZeneca, Roche. All other authors have declared no conflicts of interest.

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