Abstract 432P
Background
Results of DESTINY-Breast04 (NCT03734029) showed improved progression-free survival (PFS) and overall survival for trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice (TPC) in patients (pts) with HER2-low (IHC 1+ or 2+/ISH-negative) metastatic breast cancer. We present an exploratory biomarker analysis from hormone receptor positive pts enrolled in DESTINY-Breast04.
Methods
Transcriptional analysis via RNA sequencing and multiplex IHC analysis to assess stromal tumor infiltrating lymphocytes (sTILs) were performed on tissue samples collected at baseline from 387 and 315 pts, respectively. Baseline ctDNA samples were analyzed using Guardant OMNI for HER2 (ERBB2)–activating mutations (414 pts) and BRCA1/2 mutations and/or homologous recombination repair (HRR) gene alterations (235 pts). Relationships between biomarker status and objective response rate (ORR) or PFS were investigated.
Results
A trend for improved ORR and PFS was observed with T-DXd in pts with higher versus lower than median HER2 gene expression (Table) and HER2-activating mutations versus no detectable mutation (data not shown). A trend for shorter PFS was observed in pts with BRCA1/2 (Table) or HRR gene alterations (data not shown) and those with higher expression of DNA damage repair (DDR)/cell proliferation gene signatures (data not shown) in both treatment arms. A trend toward longer PFS with high sTIL levels (cutoff based on median) was observed in both treatment arms (Table). A limitation is the small sample size in some subgroups.
Conclusions
Treatment with T-DXd demonstrated clinically meaningful improvement in PFS and ORR versus TPC across all biomarker subgroups analyzed, including HER2 gene expression level, BRCA1/2 or HRR gene alteration status, DDR/cell proliferation signature status, and immune status (sTILs). Table: 432P
| Subgroup (N TPC, T-DXd) | T-DXd ORR, (95% CI) | TPC ORR, % (95% CI) | T-DXd PFS, mo (95% CI) | TPC PFS, mo (95% CI) | PFS Hazard Ratio | Interaction P value |
| HER2 >median (63, 131) | 59 (50-67) | 16 (8-27) | 11.4 (9.5-15.1) | 6.2 (2.8-8.6) | 0.46 (0.31-0.67) | 0.15 |
HER2 Clinical trial identificationNCT03734029. Editorial acknowledgementUnder the guidance of authors, assistance in medical writing and editorial support was provided by Sara Duggan, PhD, and Lynda Wiseman, PhD, of ApotheCom, and was funded by Daiichi Sankyo, Inc. Legal entity responsible for the studyThis study was funded by Daiichi Sankyo, Inc., and AstraZeneca. FundingDaiichi Sankyo, Inc., and AstraZeneca. DisclosureN.T. Ueno: Financial Interests, Personal, Advisory Board: Daiichi Sankyo, Pfizer, Bayer, Bristol Myers Squibb, Carna BioScienec, Preferred Medicine, Eisai, Gilead Science, Lilly; Financial Interests, Personal, Invited Speaker: AstraZeneca, Kyowa Kirin, Chugai Roche, Medsir, Genomic Health, Medscape; Financial Interests, Personal, Stocks/Shares: Pear Bio; Financial Interests, Personal, Royalties: Sysmex; Financial Interests, Personal and Institutional, Coordinating PI: Daiichi Sankyo. N. Niikura: Financial Interests, Personal, Invited Speaker: AstraZeneca, Pfizer, Daiichi Sankyo; Financial Interests, Institutional, Funding: Chugai; Financial Interests, Institutional, Principal Investigator: Eisai, Chugai, Daiichi Sankyo, Novartis; Financial Interests, Institutional, Research Grant: Boehringer-Ingelheim. T. Yamashita: Financial Interests, Institutional, Research Grant: Chugai, Taiho, Nippon Kayaku, Eli Lilly, Daiichi Sankyo, Pfizer, Astrazeneca, Seagen, MSD, Kyowa kirin, Ono, Gilead Sciences, Eisai; Financial Interests, Personal, Invited Speaker: Chugai, Eisai, Daiichi Sankyo, Taiho, Nippon Kayaku, Astrazeneca, Kyowa kirin, Pfizer, Eli Lilly, Novartis Pharma, MSD. W. Jacot: Financial Interests, Personal, Advisory Board: AstraZeneca, Eisai, Novartis, Roche, Pfizer, Eli Lilly, MSD, BMS, Chugai, Seagen, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca, Pfizer, Seagen, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory Board: Gilead; Financial Interests, Institutional, Research Grant: AstraZeneca, Daiichi Sankyo; Financial Interests, Coordinating PI: Roche, Daiichi Sankyo; Financial Interests, Local PI: Roche, Novartis, Daiichi Sankyo. D.A. Cameron: Financial Interests, Institutional, Advisory Board: Roche, Novartis, Pfizer, Lilly; Financial Interests, Institutional, Other: Synthon; Financial Interests, Institutional, Principal Investigator: GSK; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Personal, Other: Novartis; Financial Interests, Personal, Advisory Board: AstraZeneca; Non-Financial Interests, Personal, Principal Investigator: Daiichi Sankyo; Non-Financial Interests, Institutional, Principal Investigator: Daiichi Sankyo; Non-Financial Interests, Institutional, Advisory Board: Daiichi Sankyo. J. Tsurutani: Financial Interests, Personal, Advisory Board: Daiichi Sankyo, AstraZeneca, Eisai Inc., Daiichi Sankyo, Taiho Inc.; Financial Interests, Personal, Member of Board of Directors: West Japan Oncology Group; Financial Interests, Institutional, Research Grant: Eisai, Eli Lilly, Ono; Financial Interests, Institutional, Funding: Daiichi Sankyo, West Japan Oncology Group; Financial Interests, Institutional, Coordinating PI: FSJD. J. Sohn: Financial Interests, Institutional, Research Grant: MSD, Roche, Novartis, AstraZeneca, Lilly, Pfizer, GSK, Sanofi, Boehringer Ingelheim, Seagen; Financial Interests, Personal and Institutional, Other, Research Grant and Stock Option: Daiichi Sankyo. E. Tokunaga: Financial Interests, Personal, Invited Speaker: AstraZeneca, Eli Lilly, Daiichi Sankyo, Chugai. M.J. Vidal Losada: Financial Interests, Personal, Advisory Board: Novartis/Pfizer, Roche, Pfizer, Astrazeneca/Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Novartis/Pfizer, Roche/Genentech, Astrazeneca/Daiichi Sankyo, Gilead Sciences, Veracyte, Guardanthealth; Financial Interests, Personal, Other, Travel, Accommodations, expenses: Pfizer; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Gilead Sciences. Y.H. Park: Financial Interests, Personal, Advisory Board: AstraZeneca, Pfizer, Roche, Novartis, MSD, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca, Pfizer, Roche, Novartis, MSD, Daiichi Sankyo; Financial Interests, Institutional, Other, Research Grant: AstraZeneca, Pfizer, Roche, MSD; Financial Interests, Institutional, Writing Engagement: Pfizer; Non-Financial Interests, Principal Investigator: AstraZeneca, Pfizer, Novartis, MSD, Lilly, Roche, Daiichi Sankyo. K.S. Lee: Financial Interests, Personal, Advisory Board: Pfizer, Novartis, MSD, Eisai, Lili, Roche, Bixink, Everest Medicine, Daiichi Sankyo; Other, Institutional, Research Grant, Drug Supply: Dong-A ST. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pfizer, Peptomyc; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Institutional, Other, Contracted research: Boehringer, Medica Scientia inno. Research; Financial Interests, Personal, Advisory Board: AstraZeneca, Reveal Genomics, 1TRIALSP, S.L.; Financial Interests, Personal, Member of Board of Directors, Leadership role: Reveal Genomics, SL.; Financial Interests, Personal, Stocks/Shares: Reveal Genomics; Financial Interests, Personal, Royalties: Reveal Genomics, INTERNATIONAL ONCOLOGY BUREAU, S.L.,; Financial Interests, Institutional, Local PI: Roche, AstraZeneca; Financial Interests, Personal and Institutional, Steering Committee Member: Daiichi Sankyo; Financial Interests, Institutional, Coordinating PI: Novartis; Financial Interests, Institutional, Funding: Reveal Genomics; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: Actitud Frente al Cáncer Foundation; Non-Financial Interests, Personal, Other, Asociación Española de Investigación sobre el Cáncer: ASEICA; Non-Financial Interests, Personal, Other, Research Foundation that gives grants to researchers: FERO. Y. Kuwahara: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. A.D. Boran: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo; Financial Interests, Personal, Stocks/Shares: Daiichi Sankyo, Daiichi Sankyo. M. Kobayashi: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo co., Ltd. S. Modi: Financial Interests, Personal, Advisory Board, and invited speaker: Genentech, Daiichi Sankyo, AstraZeneca, Seagen, Gilead; Financial Interests, Institutional, Sponsor/Funding: Genentech, Daiichi Sankyo, AstraZeneca, Seagen, DualityBio, Nuvation; Financial Interests, Personal, Advisory Board: DualityBio. All other authors have declared no conflicts of interest. 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