2019 ASCO Annual Meeting!
Session: Lung Cancer—Non-Small Cell Metastatic
Type: Poster Session
Time: Sunday June 2, 8:00 AM to 11:00 AM
Location: Hall A
Clonal evolution and osimertinib resistance mechanisms identified by whole exome and transcriptome sequencing in EGFR mutant NSCLC.
Metastatic Non-Small Cell Lung Cancer
Lung Cancer—Non-Small Cell Metastatic
2019 ASCO Annual Meeting
Poster Board Number:
Poster Session (Board #372)
J Clin Oncol 37, 2019 (suppl; abstr 9049)
Author(s): Nitin Roper, Anna-Leigh Brown, Sivasish Sindiri, Constance M. Cultraro, Shaojian Gao, Chul Kim, Chuong D. Hoang, Tapan K Maity, Elizabeth Akoth, Arun Rajan, Abhilash Karavattu Venugopalan, Christopher Trindade, Jun S. Wei, Anna Panchenko, Stephen M. Hewitt, Javed Khan, Udayan Guha; Thoracic and GI Malignancies Branch, CCR, NCI, NIH, Bethesda, MD; National Library of Medicine, Bethesda, MD; Genetics Branch, CCR, NCI, NIH, Bethesda, MD; Thoracic Surgery Branch, CCR, NCI, NIH, Bethesda, MD; Laboratory of Pathology, CCR, NCI, NIH, Bethesda, MD
Background: Osimertinib, a 3rd generation EGFR TKI, has been approved for treatment naïve patients (pts) with metastatic EGFR mutant NSCLC. Mechanisms of resistance to osimertinib are emerging from limited studies using targeted sequencing platforms. Methods: We performed whole exome (WES) and RNA-sequencing of osimertinib resistant tumors of EGFR-mutant NSCLC pts treated in a prospective clinical trial (NCT02759835). Treatment naïve EGFR mutant pts or pts with T790M-positive NSCLC after EGFR-TKI treatment receive osimertinib. Upon progression, pts with ≤5 progressing sites undergo local ablative therapy (LAT; surgery, radiation, RFA) and resume osimertinib. We analyzed paired pre-treatment and post-progression tumors in 10 patients and post-progression tumors in 3 additional patients and investigated intra- and inter-metastatic tumor heterogeneity using tumors procured from LAT surgeries and autopsies. Results: Acquired, focal copy number amplifications (CNA) of oncogenes occurred in the majority of patients (54%, n = 7/13) whereas acquired osimertinib resistance mutation EGFR C797S was less common (15%, n = 2/13). Early progression on osimertinib ( < 12 months PFS) in treatment naïve pts was associated with acquired, focal CNA. Despite pre-existing EGFR amplification, further amplification of the mutant allele of EGFR was the most common focal CNA (33%, n = 3/9). Other oncogenes amplified in resistant tumors include MET, KRAS, ERBB2 and YES1. CD274 (PD-L1) amplification occurred as the only putative mechanism of resistance in a pt without prior EGFR-TKI treatment. Using RNA-seq, we identified a pt who retained NSCLC histology, but upregulated genes associated with neuroendocrine differentiation upon osimertinib resistance. Clonal evolutionary analysis using WES of prospectively collected sensitive and resistant tumor tissue, including at autopsy is underway. Conclusions: Unbiased WES and transcriptome sequencing revealed heterogeneity, clonal evolution and novel osimertinib resistance mechanisms. Majority of pts had two or more resistance mechanisms suggesting the requirement of combination therapies to overcome resistance. Clinical trial information: NCT02759835