Treatment outcome of atypical EGFR mutations in the German National Network Genomic Medicine Lung Cancer (nNGM)
M Janning, J Süptitz, C Albers-Leischner, P Delpy, A Tufman, J-L Velthaus-Rusik, M Reck, A Jung, D Kauffmann-Guerrero, I Bonzheim, S Brändlein, H-D Hummel, M Wiesweg, H-U Schildhaus, J A Stratmann, M Sebastian, J Alt, J Buth, I Esposito, J Berger, L Tögel, F C Saalfeld, M Wermke, S Merkelbach-Bruse, A M Hillmer, F Klauschen, C Bokemeyer, R Buettner, J Wolf, S Loges, National Network Genomic Medicine Lung Cancer (nNGM), Ronald Simon, Guido Sauter, Alexander Volk, Jens Neumann, Frederick Klauschen, Wilko Weichert, Naser Kalhori, Reinhard Lüthen, Robert Stöhr, Chistoph Schubart, Heidemarie Wacker, Florian Fuchs, Nils Hartmann, Stefanie Graf, Christian Brandts, Peter Wild, Melanie Demes, Henning Reis, Gernot Rohde, M Janning, J Süptitz, C Albers-Leischner, P Delpy, A Tufman, J-L Velthaus-Rusik, M Reck, A Jung, D Kauffmann-Guerrero, I Bonzheim, S Brändlein, H-D Hummel, M Wiesweg, H-U Schildhaus, J A Stratmann, M Sebastian, J Alt, J Buth, I Esposito, J Berger, L Tögel, F C Saalfeld, M Wermke, S Merkelbach-Bruse, A M Hillmer, F Klauschen, C Bokemeyer, R Buettner, J Wolf, S Loges, National Network Genomic Medicine Lung Cancer (nNGM), Ronald Simon, Guido Sauter, Alexander Volk, Jens Neumann, Frederick Klauschen, Wilko Weichert, Naser Kalhori, Reinhard Lüthen, Robert Stöhr, Chistoph Schubart, Heidemarie Wacker, Florian Fuchs, Nils Hartmann, Stefanie Graf, Christian Brandts, Peter Wild, Melanie Demes, Henning Reis, Gernot Rohde
Abstract
Background: Atypical EGFR mutations occur in 10%-30% of non-small-cell lung cancer (NSCLC) patients with EGFR mutations and their sensitivity to classical epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) is highly heterogeneous. Patients harboring one group of uncommon, recurrent EGFR mutations (G719X, S768I, L861Q) respond to EGFR-TKI. Exon 20 insertions are mostly insensitive to EGFR-TKI but display sensitivity to exon 20 inhibitors. Clinical outcome data of patients with very rare point and compound mutations upon systemic treatments are still sparse to date.
Patients and methods: In this retrospective, multicenter study of the national Network Genomic Medicine (nNGM) in Germany, 856 NSCLC cases with atypical EGFR mutations including co-occurring mutations were reported from 12 centers. Clinical follow-up data after treatment with different EGFR-TKIs, chemotherapy and immune checkpoint inhibitors were available from 260 patients. Response to treatment was analyzed in three major groups: (i) uncommon mutations (G719X, S7681, L861Q and combinations), (ii) exon 20 insertions and (iii) very rare EGFR mutations (very rare single point mutations, compound mutations, exon 18 deletions, exon 19 insertions).
Results: Our study comprises the largest thus far reported real-world cohort of very rare EGFR single point and compound mutations treated with different systemic treatments. We validated higher efficacy of EGFR-TKI in comparison to chemotherapy in group 1 (uncommon), while most exon 20 insertions (group 2) were not EGFR-TKI responsive. In addition, we found TKI sensitivity of very rare point mutations (group 3) and of complex EGFR mutations containing exon 19 deletions or L858R mutations independent of the combination partner. Notably, treatment responses in group 3 (very rare) were highly heterogeneous. Co-occurring TP53 mutations exerted a non-significant trend for a detrimental effect on outcome in EGFR-TKI-treated patients in groups 2 and 3 but not in group 1.
Conclusions: Based on our findings, we propose a novel nNGM classification of atypical EGFR mutations.
Keywords: EGFR; atypical EGFR mutations; non-small-cell lung cancer.
Conflict of interest statement
Disclosure MJ: speaker’s honoraria and/or advisory board from Roche, Boehringer, Amgen, AstraZeneca, Novartis. AT: honoraria, consulting and/or travel support from Lilly, Pfizer, Boehringer, Celgene, MSD, BMS, Amgen, Roche, Takeda, GSK. JLVR: consulting and/or travel support from Roche, Lilly. MR: research funding from BMS. AJ: speaker honoraria, advisory board and/or travel support from Amgen, Archer, Astra Zeneca, Bayer, Biocartis, Boerhinger Ingelheim, BMS, Merck, MSD, Novartis, Pfizer, QuiP GmbH, Roche, Thermo Fisher. IB: honoraria, consulting and/or travel support from AstraZeneca, Novartis, BMS, Bayer. HDH: travel, accommodations or other expenses from Johnson & Johnson, Boehringer Ingelheim, Bristol-Myers Squibb and Amgen. JAS: honoraria, consulting and/or travel support from AstraZeneca, Novartis, Amgen, Roche; research funding from AstraZeneca. JA: consulting and/or travel support from AstraZeneca, Boehringer Ingelheim, BMS, Roche. JB: honoraria from Novartis. FCS: honoraria from Pfizer, Takeda; research funding from Roche; travel support from Lilly. MW: research funding from Roche; honoraria and/or advisory board fees from Roche, AstraZeneca, Boehringer, Kite, Novartis, Merk, BMS, Heidelberg Pharma; non-financial support from AstraZeneca, BMS, Glenmark. SMB: honoraria and/or advisory board from Amgen, AstraZeneca, Roche, Novartis, GSK, MSD, Targos Molecular Health, Merck, Onkowisse, QuIP GmbH and advisory board honoraria, speaker fees and non-financial support from Janssen and BMS. CB: honoraria and/or advisory board from AstraZeneca, Bayer, Berlin Chemie, BMS, Merck, Roche, Novartis, Sanofi, Lilly/ImClone and travel expenses from BMS, Merck, Pfizer and Sanofi. RB: employment with Targos Molecular Path Inc, Kassel, Germany, leadership role as Chief Scientific Officer at Targos Molecular Path Inc, stock from Targos Molecular Path Inc. JW: consulting and/or travel support from Amgen, AstraZeneca, Bayer, Blueprint, BMS, Boehringer-Ingelheim, Chugai, Daiichi Sankyo, Ignyta, Janssen, Lilly, Loxo, MSD, Novartis, Pfizer, Roche, Seattle Genetics, Takeda; research funding from BMS, Janssen Pharmaceutica, Novartis, Pfizer. SL: advisory board, speaker honoraria and travel support from Lilly, Sanofi, BerGenBio, Novartis, Boehringer Ingelheim, BMS, Roche, Astra Zeneca, MSD, Sanofi-Aventis, Janssen, Takeda, Daiichi-Sankyo and research funding from Roche, BMS and BerGenBio. All other authors have declared no conflicts of interest.
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Source: PubMed