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MA15 - Colliding Approaches - EGFR and Immunotherapy (ID 916)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Targeted Therapy
- Presentations: 1
- Coordinates: 9/25/2018, 13:30 - 15:00, Room 107
MA15.06 - Circulating Tumor DNA Portrays the Resistance Landscape to a Novel Third Generation EGFR Inhibitor, AC0010 (ID 13641)
14:05 - 14:10 | Author(s): Han Zhang-Han
In a Phase I/II dose-escalation and expansion study conducted at Guangdong Lung Cancer Institute, AC0010 demonstrated promising efficacy and good tolerability in advanced NSCLC patients with EGFR T790M-mediated resistance to previous EGFR TKIs, (NCT02330367). As disease progression (PD) with EGFR T790M-directed therapy also emerges over time, we investigated the resistance mechanisms to AC0010 in this study.a9ded1e5ce5d75814730bb4caaf49419 Method
Serial ctDNA samples obtained from patients who developed PD with AC0010 were analyzed using ultra-deep sequencing capturing 295 cancer-related genes. Alterations that were absent before treatment and acquired at PD or that increased in abundance during treatment were identified as putative resistance mechanisms.4c3880bb027f159e801041b1021e88e8 Result
Longitudinal plasma samples were obtained from 23 patients who progressed on AC0010 (data cut-off October 14, 2016; figure1). Putative resistance mechanisms to AC0010 were identified in 19/23 patients (>1 putative resistance mechanism was detected in some patients). EGFR amplification was the predominant resistance mechanism (21.1% [4/19 patients]), followed by TP53 loss of heterozygosity (15.8% [3/19]). EGFR C797S mutation, Met amplification and mutations in the PI3KCA pathway each occurred in 10.5% of patients (2/19). SCLC transformation, ERBB2 amplification, CD79A_A32G mutation, CDKN2A_R80 mutation, CRLF2 amplification, MLH1 amplification, Rb1 loss, and concurrent rise in the allelic fraction of tumor suppressor gene TP53 and Rb1 were each detected in 5.3% of patients (1/19). In a patient with PD following single-agent AC0010 and EGFR amplification as the putative resistance mechanism to AC0010, subsequent treatment with AC0010 plus nimotuzumab (EGFR monoclonal antibody) successfully overcame resistance, resulting in a response that lasted for 7.7 months.
The resistance landscape to AC0010 appears to differ from that described previously with osimertinib. In this cohort of patients in China, EGFR amplification was the predominant resistance mechanism to AC0010 and could be potentially overcome by EGFR dual inhibition.6f8b794f3246b0c1e1780bb4d4d5dc53
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