LBA21 - Human epidermal growth factor receptor 2 (HER2)-low and HER2-ultralow status determination in tumors of patients (pts) with hormone receptor–positive (HR+) metastatic breast cancer (mBC) in DESTINY-Breast06 (DB-06)

Background

In DB-06, pts with a history of HER2-negative status by local test were screened; pts with HER2-low (immunohistochemistry [IHC] 1+, 2+/in situ hybridization [ISH]−) or HER2-ultralow (IHC 0 with membrane staining) mBC by central test were randomized to trastuzumab deruxtecan (T-DXd) or treatment of physician’s choice (TPC). T-DXd demonstrated a statistically significant and clinically meaningful improvement in median progression-free survival (PFS) vs TPC in pts with HR+, HER2-low mBC who received ≥1L of endocrine therapy and no chemotherapy for mBC; outcomes were consistent for HER2-ultralow. Clinical validation of local and central HER2 scoring was performed.

Methods

HER2 scores were centrally determined using the VENTANA anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody (Roche) assay, and an on-market HER2 ISH assay, as applicable, per manufacturer’s instructions. Samples from pts with metastatic disease were tested. Concordance between local and central HER2 scores was assessed by overall percent agreement (OPA), and subgroup analyses of PFS were performed by sample characteristics.

Results

Valid central and local HER2 test results were available for 1629 pts; central tests found 12% IHC 0 (absent membrane staining), 21% HER2-ultralow, and 67% HER2-low. OPA was 77.8% for HER2-low. Of 349 pts scored as HER2 IHC 0 locally, 85 (24%) were centrally determined as HER2-low and 140 (40%) as HER2-ultralow. A PFS benefit with T-DXd was consistently observed across subgroups, including by HER2 IHC score, sample type, and tumor location.

Conclusions

Pts with HR+ mBC determined as HER2-low or HER2-ultralow using the VENTANA HER2 (4B5) assay (and ISH when applicable) derived clinical benefit from T-DXd, irrespective of sample type used to determine HER2 status. Of note, 64% of pts with a local HER2 IHC 0 score were classed as HER2-low or HER2-ultralow by central test. It may be advisable for pts with HR+ HER2 IHC 0 mBC to be reassessed to determine T-DXd eligibility. As the HER2-ultralow cutoff is not part of standard clinical practice, increased awareness of low HER2 expression levels is desirable.

Clinical trial identification

NCT04494425.

Editorial acknowledgement

Under the guidance of the authors, medical writing support was provided by Frances Singer, PhD, of Helios Medical Communications, part of Helios Global Group, and was funded by AstraZeneca in accordance with Good Publication Practice (GPP) guidelines (http://www.ismpp.org/gpp-2022).

Legal entity responsible for the study

AstraZeneca and Daiichi Sankyo.

Funding

This study is sponsored by AstraZeneca in collaboration with Daiichi Sankyo. In March 2019, AstraZeneca entered into a global development and commercialization collaboration agreement with Daiichi Sankyo for trastuzumab deruxtecan (T-DXd; DS-8201).

Disclosure

R.F. Salgado: Financial Interests, Personal, Advisory Board: Roche, BMS, Exact Sciences, Daichhi Sankyo, AstraZeneca; Financial Interests, Personal, Invited Speaker: Daichii Sankyo, AstraZeneca; Financial Interests, Personal, Funding, Roche funded personally the assessment of immune-markers in a research study. This was in 2019: Roche; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Funding: Puma Biotechnology. A. Bardia: Financial Interests, Personal, Advisory Board: Pfizer, Novartis, Genentech, Merck, Sanofi, Eisai, Lilly, Mersana, AstraZeneca/Daiichi, Menarini, Gilead; Financial Interests, Personal, Royalties: UpToDate; Financial Interests, Institutional, Coordinating PI: Genentech, Novartis, Pfizer, Merck, Sanofi, Gilead, Daiichi Pharma/AstraZeneca, Eli Lilly, Menarini; Non-Financial Interests, Principal Investigator: Gilead, Mersana, AstraZeneca/Daiichi, Novartis, Pfizer, Genentech, Lilly, Merck, Sanofi. G. Curigliano: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Daiichi Sankyo, Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Daiichi Sankyo, Lilly, Pfizer, Veracyte, BMS, Merck, Exact Sciences, Celcuity; Financial Interests, Personal, Writing Engagement: Pfizer; Financial Interests, Personal, Advisory Board, Advisory Board: Menarini, Gilead; Financial Interests, Personal, Other, Advisory Board: Ellipsis; Financial Interests, Institutional, Research Grant, Investigator Initiated Trial: Merck; Financial Interests, Institutional, Funding, Phase I studies: BMS, Novartis, AstraZeneca, Daiichi Sankyo, Roche, Blueprint Medicine, Kymab, Astellas, Sanofi, Philogen; Financial Interests, Institutional, Coordinating PI, Phase I clinical basket trial: Relay Therapeutics; Non-Financial Interests, Officer, Italian National Health Council as Advisor for Ministry of Health: Consiglio Superiore di Sanità; Non-Financial Interests, Advisory Role, Member of the Scientific Council. Patient advocacy association: Europa Donna; Non-Financial Interests, Advisory Role, Cancer Research Foundation: Fondazione Beretta; Non-Financial Interests, Officer, Editor of Chief of ESMO Open: ESMO; Non-Financial Interests, Leadership Role, Until the end of 2024: EUSOMA. X. Hu: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Institutional, Other, Funding our investigator-initiated trial: Merck Sharpe & Dohme; Financial Interests, Institutional, Local PI: AstraZeneca, Novartis. R.A. Dent: Financial Interests, Personal, Advisory Board: AstraZeneca, Roche, Pfizer, Merck, Lilly, Eisai; Financial Interests, Personal, Invited Speaker: AstraZeneca, Roche, Pfizer, Merck, Lilly; Financial Interests, Personal and Institutional, Trial Chair: Roche; Financial Interests, Personal, Steering Committee Member: AstraZeneca; Financial Interests, Personal and Institutional, Research Grant, Investigator Initiated Trial: AstraZeneca. J. Pierga: Financial Interests, Personal, Advisory Board: Pfizer, Lilly, Seagen, MSD, Novartis, ExactSciences, Gilead, AstraZeneca, Eisai; Financial Interests, Personal, Invited Speaker: Roche, Daiichi Sankyo, Menarini, Veracyte, Pfizer, Lilly, Seagen, MSD, Novartis, Daiichy Sankyo; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Daiichi Sankyo; Financial Interests, Institutional, Steering Committee Member: Novartis; Financial Interests, Institutional, Other, IDMC: Sanofi; Financial Interests, Institutional, Funding: Servier. 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. H. Wildiers: Financial Interests, Institutional, Other, Consultancy: Roche, Gilead, Pfizer, Immutep Limited, Novartis, Augustine Therapeutics, Stemline Therapeutics Switzerland, MediMix BV, NV Hict; Financial Interests, Institutional, Advisory Board, + Consultancy: Lilly, AstraZeneca, Daiichi Sankyo; Financial Interests, Institutional, Advisory Board: AstraZeneca, E Squared Communications LLC, PSI CRO AG; Financial Interests, Institutional, Invited Speaker: Seagen; Financial Interests, Institutional, Research Grant, Grant to the Leuven Breast Center to support the research database: Roche; Financial Interests, Institutional, Research Grant, Grant to institute to perform a multicentric national academic trial: Novartis; Financial Interests, Institutional, Local PI: Syneos Health; Other, Travel & accommodations: Pfizer; Other, Subscription fee: Gilead; Other, Travel support: Daiichi Sankyo. G.R.R. Ricciardi: Financial Interests, Personal, Other, Advisory board, Invited Speaker: Daichii Sankyo, Novartis, Eisai, Eli Lilly, Gilead, Pfizer; Financial Interests, Personal, Advisory Board: AstraZeneca, GSK; Financial Interests, Personal, Invited Speaker: Gentili. C. Marchiò: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Bayer, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Veracyte; Non-Financial Interests, Member, Participation to the ESMO precision Medicine and Translational Research Working Group: ESMO. F. Penault-Llorca: Financial Interests, Personal, Invited Speaker, HRD, BRCA, HER2 low: AstraZeneca; Financial Interests, Personal, Advisory Board, HRD, BRCA, HER2low: AstraZeneca; Financial Interests, Personal, Invited Speaker, NTRK symposium: Bayer; Financial Interests, Personal, Advisory Board, NTRK: Bayer; Financial Interests, Personal, Advisory Board, DLL3 PARPi: AbbVie; Financial Interests, Personal, Invited Speaker, Training prof breast cancer: Eisai, Janssen; Financial Interests, Personal, Invited Speaker, Symposium IO and AI France and European: BMS; Financial Interests, Personal, Advisory Board, Immunotherapy pan t: BMS; Financial Interests, Personal, Invited Speaker, Immunotherapy BRCA: MSD; Financial Interests, Personal, Advisory Board, Symposium preparation: MSD; Financial Interests, Personal, Invited Speaker, RET & breast cancer prognosis and biomarker: Lilly; Financial Interests, Personal, Advisory Board, Ret & breast cancer: Lilly; Financial Interests, Personal, Advisory Board, ER+ breast cancer: Pfizer; Financial Interests, Personal, Invited Speaker, BRCA breast cancer, ER+ BC, biomarkers in lung cancer: Pfizer; Financial Interests, Personal, Advisory Board, PIK3CA and biomarkers in general: Novartis; Financial Interests, Personal, Invited Speaker, PIK3CA: Novartis; Financial Interests, Personal, Advisory Board, Ventana NTRK PD-L1: Roche; Financial Interests, Institutional, Other, Clin trial pathology form review: Roche; Financial Interests, Personal, Invited Speaker, FMI test, biomarkers in lung cancer: Roche; Financial Interests, Institutional, Advisory Board, Endometrial cancer: GSK; Financial Interests, Institutional, Advisory Board, Strategy: Lilly, AstraZeneca; Financial Interests, Personal, Invited Speaker, HER2 breast cancer: Pierre Fabre; Financial Interests, Personal, Advisory Board, Neratinib: Pierre Fabre; Financial Interests, Personal, Advisory Board, NGS: Illumina; Financial Interests, Personal, Invited Speaker, ESMO symposium: Illumina; Financial Interests, Personal, Invited Speaker, HER2 low: Daiichi Sankyo; Financial Interests, Personal, Advisory Board, HER2 low: Daiichi Sankyo; Financial Interests, Personal, Advisory Board, biomarkers in CRC: Sanofi; Financial Interests, Personal, Invited Speaker, webminar on TailorX: exact science; Financial Interests, Personal, Invited Speaker, Mammaprint and Blue Print: Agendia; Financial Interests, Institutional, Invited Speaker, hospitalization at home: Janssen; Financial Interests, Personal, Advisory Board, biomarkers in lung cancer: Amgen; Financial Interests, Personal, Invited Speaker, educational session biomarkers in lung cancer: Amgen; Financial Interests, Personal, Advisory Board, biomarkers in gastric cancer: astellas; Financial Interests, Personal, Advisory Board, biomarkers in cholangiocarcinoma: Servier; Financial Interests, Personal, Advisory Board, HER2 breast cancer: Seagen; Financial Interests, Personal, Invited Speaker, her2 breast cancer: Seagen; Financial Interests, Personal, Advisory Board, biomarkers in TNBC: Gilead; Financial Interests, Personal, Invited Speaker, training of Gilead employees on biomarkers in BC and symposia on Biomarkers in TNBC: Gilead; Financial Interests, Personal, Advisory Board, adboard and consulting on ESR1 strategy in France: Stemline Menarini; Financial Interests, Personal, Advisory Board, european Adboard precision medicine: Janssen; Financial Interests, Personal, Advisory Board, eosophaghal cancer biomarkers: BeiGene; Financial Interests, Institutional, Research Grant, NTRK testing: Bayer; Financial Interests, Institutional, Research Grant, GEOMX breast TNBC: Nanostring; Financial Interests, Institutional, Local PI, RetroBC HER2 low study: Daiichi Sankyo. A. Andrzejuk-Cwik: Financial Interests, Personal, Full or part-time Employment, Global Development Scientist Director: AstraZeneca. A. Darilay: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. T. Matsuo: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks or ownership: AstraZeneca. R. Shami: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks or ownership: AstraZeneca. F. Jones: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. G. Viale: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Daiichi Sankyo, MSD Oncology, Pfizer; Financial Interests, Personal, Other, Consulting fees: Agilent; Financial Interests, Personal, Invited Speaker: Gilead; Financial Interests, Personal, Other, Educational webinar: Medscape; Financial Interests, Institutional, Coordinating PI: AstraZeneca; Financial Interests, Institutional, Research Grant: Roche. All other authors have declared no conflicts of interest.