Efficacy of antibody drug conjugate (ADC) by mRNA expression of targeted genes in advanced solid tumors: SCRUM-Japan MONSTAR-SCREEN-2

BackgroundApproved ADCs have been developed for a diverse array of targets. However, a predictive biomarker for ADCs remains elusive, except for HER2. Herein, we evaluated the efficacy of ADC by mRNA expression level of targeted genes in advanced solid tumors from the SCRUM-Japan MONSTAR-SCREEN-2, a nationwide molecular profiling project (UMIN000043899).MethodsPatients (pts) with advanced solid tumors were enrolled; whole exome/transcriptome sequencing by Caris Life Sciences (Phoenix, AZ, USA) and immunohistochemistry (IHC) of HER2 were performed.ResultsAmong 2,037 pts enrolled as of July 2023, mRNA expression data of baseline tissue samples were available in 1,418 pts across 30 cancer subtypes: most common subtypes were colorectal (n=332), gastric (n=181), pancreatic (n=113) and breast cancers (n=107). ERBB2 mRNA and HER2 IHC expression were highly concordant (AUC, 0.92). Since HER2 overexpression in IHC corresponded to the top 9.3 percentile of mRNA level across all solid tumors, we defined the cutoff for high mRNA expression as the top 9.3 percentile. Seventy-one percent of the high mRNA expression of target genes for FDA-approved ADCs, such as HER2, Nectin-4, TROP-2, Tissue factor and Folate receptor, was found in off-label cancer types. In 52 patients treated with ADC monotherapy, the high mRNA expression group tended to have a better objective response rate (ORR) and significantly better progression-free survival (PFS) than the non-high mRNA expression group (ORR: 51.7% vs 30.4%, P = 0.16, PFS: 6.9 vs 3.0 months, hazard ratio [HR]: 0.40, 95% CI: 0.20-0.81). The significant difference in PFS was independent of ADC targets and cancer types.ConclusionsHigh mRNA levels were associated with better therapeutic efficacy of ADCs, highlighting the potential of mRNA level as a predictive biomarker of ADCs.Legal entity responsible for the studyNational Cancer Center Hospital East.FundingScrum-Japan.DisclosureT. Fujisawa: Financial Interests, Personal, Invited Speaker: Amelieff Co Ltd.. Y. Nakamura: Financial Interests, Personal, Invited Speaker: Chugai, Merck Biopharma, Guardant Health Pte Ltd, MSD K.K, Eisai, Zeria Pharmaceutical, Miyarisan pharmaceutical, CareNet, Inc., Hisamitsu Pharmaceutical, Taiho Pharmaceutical, Daiichi Sankyo Co., Ltd., Becton Dickinson, Guardant Health Japan Corp.; Financial Interests, Personal, Advisory Board: Natera, Inc., Roche Ltd., Seagen, Inc., Premo Partners, Inc., Daiichi Sankyo Co., Ltd., Takeda, Exact Sciences, Gilead Sciences, Guardant Health Pte Ltd; Financial Interests, Institutional, Funding: Taiho, Chugai, Guardant Health, Genomedia, Daiichi Sankyo, Roche Diagnostics, Guardant Health AMEA, Inc., Tempus; Financial Interests, Institutional, Coordinating PI: Seagen. M. Nagamine: Financial Interests, Personal, Advisory Role: GxD, Inc.; Financial Interests, Personal, Advisory Board: SRL, Inc.; Financial Interests, Personal, Speaker’s Bureau: Chugai Pharmaceutical Co., Ltd.. T. Kuwata: Financial Interests, Personal, Writing Engagement: Astellas; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, FALCO Biosystems, MSD, Roche Diagnostics; Financial Interests, Institutional, Research Grant: Takeda. G. Ishii: Financial Interests, Institutional, Research Grant: Daiichi Sankyo, INC., Ono Pharmaceutical Co., Ltd., Noile-Immune Biotech, Takeda Pharmaceutical Company Limited, Sumitomo Dainippon Pharma Co., Ltd., Nihon Medi-Physics Co., Ltd., Indivumed GmbH, H.U. Group Research Institute; Financial Interests, Personal, Advisory Role: Takeda Pharmaceutical Company Limited; Financial Interests, Personal, Speaker’s Bureau: Roche Diagnostics K.K., Chugai Pharmaceutical Co., Ltd., Novartis International AG, Eli Lilly Japan K.K., Takeda Pharmaceutical Company Limited, AstraZeneca, Riken Genesis Co., Ltd., Merck Biopharma Japan. C. Morizane: Financial Interests, Personal, Advisory Board: Yakult, MSD, Servier, Boehringer Ingelheim, AstraZeneca, Taiho Pharmaceutical, Merck biopharma; Financial Interests, Personal, Invited Speaker: Novartis, Teijin Pharma; Financial Interests, Institutional, Coordinating PI: Yakult Honsha, Ono Pharmaceutical, Taiho Pharmaceutical, Eisai, MSD K.K., J-Pharma, AstraZeneca, Merck biopharma; Financial Interests, Institutional, Funding: Daiichi Sankyo RD Novare, Hitachi. H. Iwata: Financial Interests, Personal, Advisory Board: Chugai, Daiichi Sankyo, AstraZeneca, Lilly, Sanofi; Financial Interests, Personal, Invited Speaker: Chugai, Daiichi Sankyo, AstraZeneca, Lilly, Pfizer, Sanofi, Taiho; Financial Interests, Personal and Institutional, Steering Committee Member: Chugai, Daiichi Sankyo, AstraZeneca, MSD, Amgen, Sanofi, Novartis, Pfizer, Kyowa Hakko Kirin; Financial Interests, Personal and Institutional, Local PI: Lilly, Bayer, Behringer, Nihon Kayaku. S. Okano: Financial Interests, Personal, Invited Speaker: MSD, Merck Biophama Co., Ltd., Ono Pharmaceutical Co., Ltd., Bristol Myers Squibb. K. Namikawa: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical, Novartis Pharma, MSD, Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Novartis Pharma, MSD. M. Imai-Sumida: Financial Interests, Personal, Advisory Role: Sumitomo Corporation Ltd.; Financial Interests, Personal, Advisory Board: Exact Science Inc., Caris Life Sciences; Financial Interests, Personal, Speaker’s Bureau: Chugai Pharmaceutical Co.. H. Bando: Financial Interests, Institutional, Research Grant: Ono pharmaceutical; Other, Lecture fee: Ono pharmaceutical, Taiho pharmaceutical, Eli Lilly Japan. M. Radovich, G. Sledge: Financial Interests, Personal, Full or part-time Employment: Caris Life Sciences; Financial Interests, Personal, Stocks/Shares: Caris Life Sciences. T. Yoshino: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Bayer Yakuhin, Ltd., Ono Pharmaceutical Co., Ltd., MSD K.K., Takeda Pharmaceutical Co., Ltd.; Financial Interests, Personal, Other, Consultancy: Sumitomo Corp.; Financial Interests, Institutional, Research Grant: Ono Pharmaceutical Co., Ltd, Sanofi K.K., MSD K.K., Taiho Pharmaceutical Co., Ltd., Molecular Health GmbH, Amgen K.K., Pfizer Japan Inc., Genomedia Inc., Sysmex Corp., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Eisai Co., Ltd., Roche Diagnostics K.K., FALCO Biosystems Ltd., Merus N.V., Bristol Myers Squibb K.K., Medical & Biological Laboratories Co., LTD., Takeda Pharmaceutical Co., Ltd.. All other authors have declared no conflicts of interest.