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Sebastian Michels
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Lunch & Poster Display session (ID 58)
- Event: ELCC 2019
- Type: Poster Display session
- Track:
- Presentations: 3
- 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): Sebastian Michels
- 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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147P - Impact on KRAS-subtypes and TP53 mutations on the prognostic value of KRAS/KEAP1 comutations in non-small cell lung cancer (NSCLC) (ID 493)
12:30 - 13:00 | Author(s): Sebastian Michels
- Abstract
Background
Recent studies suggest a devastating impact of KEAP1 mutations on survival in systemically treated advanced NSCLC for both KRAS-comutated and KRAS-wildtype patients. KRAS G12C mutations differ in their co-mutational properties from other KRAS mutations, and TP53 mutations affect the outcome in a subset of NSCLC like ALK-positive NSCLC. We set out this analysis to determine the impact of both KRAS G12C and co-occurring TP53 mutations on the prognostic value of KRAS/KEAP1 comutations.
a9ded1e5ce5d75814730bb4caaf49419 Methods
We pooled the data from three different analyses between 2013 and 2018 and looked for patients with stage IV NSCLC for whom survival data was available and who received systemic therapy. The patients had to be diagnosed by a comprehensive next-generation sequencing panel, comprising at least KRAS, KEAP1and TP53 mutations. Median overall survival (mOS) was assessed using Kaplan Meier statistics.
20c51b5f4e9aeb5334c90ff072e6f928 Results
We identified 35 patients with KRAS/KEAP1 comutation and available survival data. G12C was detected in 22 patients (62.9%). A co-occurring TP53 mutation could be found in 15 patients (42.9%), and 11 patients (31.4%) presented with both aberrations beside a KEAP1 mutation. 15 patients (42.9%) had neither comutation. The mOS for the whole cohort was 9.8 months (95% CI, 6.3-13.3 months). Neither the presence of a G12C mutation (mOS 9.8 months [5.7-13.4], log rank p = 0.724) nor the presence of a co-occurring TP53 mutation (mOS 9.0 months [5.8-12.2], log rank p = 0.407) had a significant influence on the outcome. For G12C/TP53 beside KEAP1 mutations, there was hardly any difference to the comparison cohort (mOS 9.8 months [5.4-14.2], log rank p = 0.998). Patients without G12C and TP53 had an mOS of 10.4 months (3.6-17.2 months, log rank p = 0.467).
fd69c5cf902969e6fb71d043085ddee6 Conclusions
The comutation status of TP53 mutations and/or the presence of the KRAS G12C subtype have no impact on the prognostic value of KRAS/KEAP1-mutated stage IV NSCLC. Further investigations are ongoing to reveal the influence of the mode of systemic therapy in larger cohorts to confirm these findings.
b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study
The authors.
213f68309caaa4ccc14d5f99789640ad Funding
Has not received any funding.
682889d0a1d3b50267a69346a750433d Disclosure
All authors have declared no conflicts of interest.
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184TiP - FIND: A phase II study to evaluate the efficacy of erdafitinib in FGFR-altered squamous NSCLC (ID 571)
12:30 - 13:00 | Author(s): Sebastian Michels
- Abstract
Background
Genomic FGFR alterations and their oncogenic driver potential are frequently observed in various cancers. Initial clinical trials with selective FGFR inhibitors showed moderate responses in FGFR amplified squamous NSCLC (sqNSCLC) patients. However, in FGFR mutated or translocated tumor types a response rate of above 30% was observed. Preclinical cell line and patient-derived sqNSCLC xenograft models with FGFR mutations or translocations indicate strong oncogenic activity and potential sensitivity to FGFR inhibitors. Approximately 3% of all sqNSCLC patients harbor somatic alterations within FGFR genes. However, only some of these mutations are shown to be oncogenic drivers in vitro and in vivo experiments or first in man trials.
a9ded1e5ce5d75814730bb4caaf49419 Trial design
Screening for FGFR mutations/translocations will be performed within the national Network of Genomic Medicine in 15 screening centers in Germany. SqNSCLC patients with activating FGFR genetic alterations will be treated in 11 clinical centers in Germany with the selective FGFR1-4 kinase inhibitor erdafitinib. Archival samples, fresh frozen tumor samples and blood for circulating tumor DNA will be collected before treatment and at time of progression. Patients will be treated until disease progression or unacceptable toxicity. The primary objective of the trial is to analyze the efficacy of erdafitinib in sqNSCLC patients with FGFR genetic driver alterations. Patients will be recruited into 3 cohorts: Cohort 1: high confidence activating FGFR translocations (max. 15 patients); Cohort 2: high confidence activating FGFR mutations (max. 15 patients); Cohort 3: low confidence activating FGFR alteration (ca. 20 patients). The study has been currently submitted by authorities and is currently targeted to start recruitment in Q1/2019.
d9b324a48b043b3d87bc9b3fe620f260 Clinical trial identification
EudraCT: 2018-000399-13.
7a6a3ffa2dadc03a6151ee2c4d6fa383 Legal entity responsible for the study
University of Cologne.
213f68309caaa4ccc14d5f99789640ad Funding
Janssen.
682889d0a1d3b50267a69346a750433d Disclosure
L. Nogova: Honoraria, advisory boards, travel fees: Boehringer Ingelheim, BMS, Celgene, Roche, Pfizer, Janssen, Novartis; Grants to institution: Pfizer, Novartis, BMS, Janssen. A. Hillmer: Honoraria, advisory board: MSD. S. Merkelbach-Bruse: Honoraria, advisory boards: Novartis, Roche. A. Pinto, C. Woempner: Grants to institution: BMS, Pfizer, Novartis, Janssen. R. Riedel: Honoraria, advisory boards: Boehringer Ingelheim, Novartis; Travel fee: Boehringer Ingelheim, Novartis, Lilly; Grants to institution: BMS, Pfizer, Novartis, Janssen. M. Scheffler: Honoraria, advisory boards: Boehringer Ingelheim; Grants to institution: Pfizer, BMS, Novartis, Janssen. S. Michels: Honoraria, Advisory boards: Novartis; Grants to institution: Pfizer, BMS, Novartis, Janssen. P. De Porre, A. Santiago-Walker: Employee: Janssen; Owning stock: J&J. R.N. Fischer: Honoraria: Bristol-Myers Squibb, MSD, Roche, Boehringer Ingelheim, Novartis, AstraZeneca; Grants to institution: Pfizer, BMS, Novartis, Janssen. D.S. Abdulla: Honoraria, advisory boards: Boehringer Ingelheim, Roche, AbbVie; Grants to institution: Pfizer, Novartis, BMS, Janssen. J. Wolf: Advisory boards, Honoraria, travel fees: AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Chugai, Ignyta, Lilly, MSD, Novartis, Pfizer, Roche; Grants to institution: MSD, BMS, Pfizer, Novartis, Janssen. All other authors have declared no conflicts of interest.
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