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Grainne O'Kane
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P35 - Pathology - Genomics (ID 105)
- Event: WCLC 2020
- Type: Posters
- Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P35.03 - Methylation Signatures Associated with T790M Status in Progressive NSCLC (ID 2337)
00:00 - 00:00 | Presenting Author(s): Grainne O'Kane
- Abstract
Introduction
Emergence of the EGFR T790M mutation accounts for acquired first generation EGFR tyrosine kinase inhibitor (TKI) resistance in over half of patients with EGFR mutant NSCLC. In patients without emergent T790M, resistance mechanisms are less well understood. We explored the impact of DNA methylation status and TKI treatment failure in these patients.
Methods
Using a prospective cohort of patients with acquired TKI resistance, tumour tissue samples pre/post TKI exposure were identified. DNA was extracted from FFPE tissue using the Qiagen AllPrep DNA/RNA FFPE Extraction Protocol, and subsequently analyzed using the Illumina Infinium EPIC array. Raw microarray data files were processed using the software package minfi for data normalization (Illumina method) and extraction of methylation levels (M-values). Samples were split into two groups according to the T790M status of each sample (T790M + or T790M-). The set of most informative probes, those whose M-value profiles align most closely with the T790M status of the study samples, was generated by selecting the 1,000 probes with lowest ANOVA’s p-value. The stability of the resulting sample clustering was assessed by hierarchical clustering (Euclidean distance), classification with internal cross-validation (SVM leave-one-out), and non-parametric dimensional reduction (t-SNE).
Results
40 samples from 36 EGFR mutant NSCLC patients were successfully profiled. Pre TKI samples were available in 10 patients with an EGFR mutation of which 4 had matched post TKI tissue (3 T790M+, 1 T790M-). The remaining 26 samples in post TKI patients included 17 T790M + and 9 T790M- cases. A DNA methylation-based signature was developed by selecting the array probes that best discriminated T790M+ from T790M- cases. Group membership was stable, as shown by cross-validation by three different methods (hierarchical clustering, SVM leave-one-out and t-SNE). The 1,000 probe cut-off was arbitrarily selected; however, identical sample clusters were obtained using 500 or 2,000 methylation array probes. When analyzing the genomic location of the set of probes that form the signature, we found broad distribution across all chromosomes, thus, ruling out the possibility of selection bias due to focal or chromosome-level aberrations. Several genes contained a higher number of the selected probes, including EGFR, whose expression levels are known to be regulated at the methylation level in certain cancer types. Cluster analysis using the 1,000-probe signature revealed a high degree of concordance between EGFR T790M and DNA methylation status. All post-TKI (n=20) T790M+ samples concentrated within epi-group 2, whereas 8/10 T790M- samples were found within epi-group 1. Of the 4 patients with matched samples, 2 had baseline samples within epi-group 2 and went on to develop EGFR T790M post TKI. Of the 2 with baseline samples within epi-group 1, one went on to develop T790M (post-TKI epigroup 2) and one did not (post-TKI epigroup 1).
Conclusion
We observed a concordance between T790M status and epi-group suggesting that the development of resistance to EGFR-TKIs may be associated with distinct DNA methylation signatures. This signature may be present at baseline and predict for subsequent emergence of T790M.
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P86 - Targeted Therapy - Clinically Focused - New Target (ID 263)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P86.08 - Phase 2 Study of Zenocutuzumab (MCLA-128), a Bispecific HER2/HER3 Antibody in NRG1 Fusion-Positive Advanced Solid Tumors (ID 3619)
00:00 - 00:00 | Author(s): Grainne O'Kane
- Abstract
Introduction
Neuregulin 1 (NRG1) gene fusions are oncogenic drivers in multiple cancer types. NRG1 fusion proteins bind to HER3 and signal through HER2/HER3 heterodimers, leading to increased downstream signaling and tumor growth. Clinical responses to agents that target this pathway have been reported. Zenocutuzumab (Zeno, MCLA-128) is a HER2/HER3 bispecific antibody that binds to or ‘docks’ onto the more abundant cell surface HER2 protein, potently blocking NRG1 fusion protein binding and preventing HER2/HER3 dimerization. As an initial proof-of-concept, three patients with chemotherapy-resistant NRG1-positive KRAS-wild-type pancreatic adenocarcinoma or non-small cell lung cancer (NSCLC) who received Zeno through FDA-approved single-patient protocols showed significant tumor shrinkage. These data supported the further evaluation of Zeno in NRG1 fusion-positive cancers. A version of this Clinical Trials in Progress abstract was presented previously at ESMO Congress 2019 (685TiP, Schram et al. Reused with permission) and ASCO Virtual Congress 2020 (#302671; © 2020 American Society of Clinical Oncology, Inc. Reused with permission. All rights reserved).
Methods
The eNRGy trial is a global, open-label, multicenter phase 2 trial of Zeno in patients with solid tumors harboring NRG1 gene fusions. Main eligibility criteria include previously treated, locally advanced unresectable or metastatic NRG1 fusion-positive cancer. Genomic screening of tumor tissue is performed by local (with post-hoc central confirmation) or central (RNA sequencing) laboratories. Three cohorts of patients with NRG1 fusion-positive cancers are being enrolled: NSCLC, pancreatic cancer, and other solid tumors. The primary endpoint in all cohorts is investigator-assessed objective response rate (RECIST v1.1), and the key secondary endpoint is duration of response. Other secondary endpoints include progression-free and overall survival. Eligible patients receive a dosing regimen of 750 mg of Zeno (2-hour infusion), every 2 weeks, in 4-week cycles. The study is actively accruing patients in more than 30 sites across North America, Europe, and Asia.
