561P - Mechanisms of osimertinib resistance using circulating tumor DNA analyses for EGFR-mutated non-small cell lung cancer, results from ELUCIDATOR: A prospective observational multicenter study

Background

Introduction: Osimertinib (Osi) is the key standard therapy for patients (pts) with chemo-naive advanced non-small cell lung cancer (NSCLC) harboring sensitizing epidermal growth factor receptor (EGFR) mutations. However, many of cases treated with Osi experience the progressive disease (PD). Therefore, understanding first-line osimertinib resistance mechanisms is essential for future therapeutic strategies. Therefore, to clarify Osi resistance mechanisms, we proposed to analyze circulating tumor (ct) deoxyribonucleic acid (DNA) by the ultra-sensitive next-generation sequencing (NGS) method.

Methods

This trial is the multicenter prospective research, named ELUCIDATOR trial, and we prospectively collected ct-DNA samples before starting Osi as baseline and immediately after PD point. Then using these ct-DNA, we analyzed the Osi resistance by ultra-sensitive NGS. Acquired mechanisms of resistance were identified by comparing paired plasma samples at baseline and at PD in patients with and without detectable plasma EGFR mutation.

Results

188 pts were enrolled, 178 pts were included in the analyses, and 111 experienced PD and, among these,85 could analyze ct-DNA using NGS. Among 188 patients, 125 (66%) patients were female, 96 (51%) were EGFR exon 19 deletion mutation, and 109 (58%) were never smoker. New adaptive mutations or amplification (amp) at PD were MET amplification (amp) 4, cases, TP53 4, PIK3CA in 3, BRIMP3 2, BRAF 2, and APC 1 case. Furthermore, additional EGFR resistance mutations, such as C797S, were 1 case.

Conclusions

MET amp and PIK3CA mutation are the common resistance mechanisms of osimertinib PD, and the rate of additional EGFR resistance mutations is lower compared with prior studies.

Clinical trial identification

jRCTs031180051.

Editorial acknowledgement

Legal entity responsible for the study

National Hospital Organization, Japan.

Funding

National Hospital Organization, Japan. and AstraZeneca.

Disclosure

D. Harada: Financial Interests, Personal, Invited Speaker: Takeda, Eli Lilly, Chugai Pharmaceutical, AstraZeneca, Taiho Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb, Towa Pharmaceutical, Boehringer Ingelheim; Financial Interests, Personal, Funding: MSD, AstraZeneca, Pfizer, Ono Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Bristol Myers Squibb, Takeda; Financial Interests, Personal, Advisory Role: Eli Lilly. A. Tamiya: Financial Interests, Personal, Invited Speaker: AstraZeneca, Ono Pharmaceutical, MSD, Chugai Pharmaceutical, Novartis, Taiho Pharmaceutical, Boehringer Ingelheim, Kyowa Kirin, Eli Lilly, Daiichi Sankyo, Nihon-Kayaku, Pfizer, Amgen, Takeda, Merk BioPharma, Thermo Fischer, Bristol Myers Squibb; Financial Interests, Personal, Funding: Daiichi Sankyo, BeiGene, AstraZeneca. Y. Taniguchi: Financial Interests, Personal, Invited Speaker: AstraZeneca, Ono Pharmaceutical, MSD, Chugai Pharmaceutical. M. Oki: Financial Interests, Personal, Funding: AbbVie Inc., AstraZeneca, Chugai Pharmaceutical, Fujifilm Toyama Chemical Co Ltd., GSK K.K, Janssen Pharmaceutical, MSD, Ono Pharmaceutical, Parxel International Corporation, Pfizer, Sanofi; Financial Interests, Personal, Invited Speaker: AMCO, AstraZeneca, Canon Medical System Corporation, Chugai Pharmaceutical, Fujifilm Toyama Chemical Co Ltd., Kaneka Medix Corp., Merit Medical Japan K.K, Novartis, Olympus, Sanofi. M. Mori: Financial Interests, Personal, Invited Speaker: AstraZeneca, Boehringer Ingelheim, MSD, Eli Lilly, Novartis, Chugai Pharmaceutical, Taiho Pharmaceutical, Kyowa Kirin, Ono Pharmaceutical, Otsuka, Nihon-Kayaku, Pfizer, Daiichi Sankyo, Takeda, Shionogi; Financial Interests, Personal, Funding: Ono Pharmaceutical, Chugai Pharmaceutical, MSD, Delta-fly. Y. Koh: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical, Guardant Health, Amgen, Takeda, Tosoh Corporation; Financial Interests, Personal, Advisory Board: Tosoh Corporation; Financial Interests, Personal, Funding: Boehringer Ingelheim, AstraZeneca, Chugai Pharmaceutical, Tosoh Corporation, Daiichi Sankyo, Zeon Corporation, Amgen, Takeda. All other authors have declared no conflicts of interest.