Biomarker analysis of plasma samples in YAMATO study: A randomized phase II trial comparing switching treatment of osimertinib following 8 months of afatinib (A) and osimertinib alone (B) in untreated advanced NSCLC patients with common EGFR mutation (TORG1939/WJOG12919L)

BackgroundWe previously reported the clinical outcomes of randomized phase II trial to assess the strategy of switching to osimertinib following 8 months of afatinib (A) compared with osimertinib alone (B). In this biomarker analysis, we report the results of comprehensive genetic analysis of plasma samples and measurement of soluble heregulin (sHRG) in plasma samples, and examine its association with the efficacy of the study treatment.MethodsPlasma samples were obtained at baseline and after disease progression (PD). ctDNA was extracted from the plasma and cancer personalized profiling by deep sequencing (CAPP-Seq) were performed. sHRG at baseline was measured using a quantitative sandwich immune assay kit (NRG1 beta 1 human ELISA Kit, Abcam, Cambridge, MA). The association between these biomarkers and efficacy outcomes (progression-free survival (PFS), time-to-treatment failure (TTF) and overall survival (OS)) of each group was evaluated.ResultsPlasma samples were obtained from 111 (A/B=54/57) and 50 (A/B=27/23) patients at baseline and after PD, respectively. The detection rate of common EGFR mutations (Ex19Del and L858R) were 61.1% and 73.7% at baseline and 65.4% and 52.2% after PD in A and B, respectively, which did not change significantly before and after. No secondary EGFR mutation such as T790M and C797S was detected in baseline samples. T790M was detected in one sample after PD during afatinib treatment in A. TP53 mutation was detected in 42.6% and 40.4% of samples at baseline in A and B, respectively. Mutations including BRAF, ERBB2, and MET were more common in samples after PD. The OS of A was better than that of B among patients with co-mutation in EGFR L858R/TP53 (log-rank p=0.026), and similar trend was observed for PFS and TTF. Among patients with positive sHRG at baseline (A/B=13/17), there was a trend toward better PFS and OS in A compared to B.ConclusionsConcomitant TP53 mutation and the level of sHRG in plasma might affect the efficacy of switching treatment of afatinib followed by osimertinib.Clinical trial identificationjRCTs031200021.Legal entity responsible for the studyThoracic Oncology Research Group (TORG) and West Japan Oncology Group (WJOG).FundingBoehringer Ingelheim.DisclosureH. Yoshioka: Financial Interests, Personal, Invited Speaker, Lecture fee: Eli Lilly Japan K.K., Takeda Pharmaceutical, Nippon Boehringer Ingelheim, Nippon Kayaku, Chugai Pharmaceutical, Taiho Pharmaceutical, Bristol Myers Squibb, MSD, AstraZeneca, Ono Pharmaceutical, Novartis Pharma, Kyowa Kirin, Otsuka Pharmaceutical, Amgen, Pfizer, Daiichi Sankyo, Nipro Pharma, Merck Biopharma; Financial Interests, Personal, Other, Consulting fee: Delta-Fly Pharma, Inc.; Financial Interests, Institutional, Local PI: Daiichi Sankyo, AstraZeneca, Janssen Pharmaceutical, MSD, Novartis Pharma; Financial Interests, Institutional, Coordinating PI: Delta-Fly Pharma, Boehringer Ingelheim. K. Sakai: Financial Interests, Personal, Invited Speaker: Qiagen, Inc., Takeda Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd. K. Nishio: Financial Interests, Personal, Invited Speaker: AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Novartis Pharma K.K., MSD K.K., Ono Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Daiichi Sankyo, Invitae Japan, Nichirei Biosciences Inc., Maruho Co., Ltd.; Financial Interests, Personal, Advisory Board: Otsuka Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Limited., Guardant Health Inc., Janssen Pharmaceutical; Financial Interests, Personal, Research Grant: West Japan Oncology Group, Nichirei Biosciences Inc., Hitachi, Ltd., Osakaminami Hospital, Sysmex Corporation, Otsuka Pharmaceutical, Thoracic Oncology Research Group, University Public Corporation Osaka. K. Yonesaka: Financial Interests, Personal, Invited Speaker: Amgen, MSD, Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., AstraZeneca, Eli Lilly Japan K.K, Takeda Pharmaceutical Co., Ltd.; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim Japan Inc.; Financial Interests, Personal, Royalties: Daiichi Sankyo Co., Ltd.; Financial Interests, Institutional, Research Grant: Daiichi Sankyo Co., Ltd., Boehringer Ingelheim Japan Inc. T. Misumi: Financial Interests, Personal, Invited Speaker: Miyarisan, Chugai. H. Itani: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K.; Financial Interests, Institutional, Funding: Chugai Pharmaceutical Co. Ltd. M. Tachihara: Financial Interests, Personal, Invited Speaker: Eli Lilly Japan K.K., Chugai Pharmaceutical Co.,Ltd., AstraZeneca K.K, MSD K.K., Ono Pharmaceutical Co., Ltd., Bristol Myers Squibb Co. Ltd., Nippon Boehringer Ingelheim Co., Ltd., Pfizer Japan Inc., Daiichi Sankyo, Janssen Pharmaceutical K.K., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Research Grant: AstraZeneca K.K., Eli Lilly Japan K.K., Chugai Pharmaceutical Co., Ltd. H. Kanemura: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd., AstraZeneca K.K., Daiichi Sankyo Co., Ltd.; Financial Interests, Institutional, Coordinating PI: Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd. H. Akamatsu: Financial Interests, Personal, Advisory Board: Amgen Inc., Janssen Pharmaceutical K.K., Sandoz; Financial Interests, Personal, Invited Speaker: AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Bristol Myers Squibb, Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., MSD K.K., Nippon Kayaku. Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co. Ltd., Pfizer Inc., Takeda Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co. Ltd.; Financial Interests, Institutional, Coordinating PI: Amgen Inc., Chugai Pharmaceutical Co. Ltd. A. Ono: Financial Interests, Institutional, Local PI: AstraZeneca, Janssen Research & Development, Chugai. N. Yamamoto: Financial Interests, Personal, Invited Speaker: MSD K.K, AstraZeneca, Ono Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Novartis, Pfizer Inc., Amgen Inc., Merck Biopharma; Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Novartis; Financial Interests, Institutional, Research Grant: MSD K.K; Financial Interests, Institutional, Local PI: AstraZeneca, Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Amgen Inc., Janssen Pharmaceutical K.K., Novartis, Eisai, Eli Lilly Japan; Financial Interests, Institutional, Funding: Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Sanofi. H. Okamoto: Financial Interests, Institutional, Research Grant: MSD, Taiho, Bristol Myers Squibb, AstraZeneca. T. Kurata: Financial Interests, Personal, Invited Speaker: MSD, AstraZeneca, Pfizer, Bristol Myers, Takeda, Eli Lilly, Chugai, Nipponkayaku, Ono; Financial Interests, Institutional, Local PI: MSD, Takeda, Janssen, AstraZeneca, Daiichi Sankyo, Chugai, Amgen, Novartis, Ono. All other authors have declared no conflicts of interest.