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Proffered Paper session 2

LBA1 - Unraveling the mechanism of action and resistance to Trastuzumab deruxtecan (T-DXd): biomarker analyses from patients from DAISY trial

Date

04 May 2022

Session

Proffered Paper session 2

Presenters

Maria Fernanda Mosele

Citation

Annals of Oncology (2022) 33 (suppl_3): S123-S147. 10.1016/annonc/annonc888

Authors

M.F. Mosele1, A. Lusque2, V. Dieras3, E. Deluche4, A. Ducoulombier5, B. Pistilli1, T. Bachelot6, F. Viret7, C. Levy8, N. Signolle1, D. TRAN9, I.J. Garberis10, L. Le-Bescond11, A. TRAN DIEN12, N. Droin12, M. Kobayashi13, T. Kakegawa13, M. Jimenez14, M. Lacroix-Triki15, F. André16

Author affiliations

  • 1 Gustave Roussy - Cancer Campus, Villejuif/FR
  • 2 Institut Claudius Regaud, Toulouse/FR
  • 3 Centre Eugene - Marquis, Rennes/FR
  • 4 CHU Limoges - Hopital Dupuytren, Limoges/FR
  • 5 Centre Anticancer Antoine Lacassagne, 06189 - Nice/FR
  • 6 Centre Léon Bérard, Lyon/FR
  • 7 IPC - Institut Paoli-Calmettes, Marseille/FR
  • 8 Centre Francois Baclesse, 14076 - Caen/FR
  • 9 Institut Gustave Roussy - INSERM UMR 981, Villejuif/FR
  • 10 Institut Gustave Roussy, Villejuif/FR
  • 11 CentraleSupélec - Paris-Saclay campus, Gif sur Yvette/FR
  • 12 Institut Gustave Roussy, Villejuif, Cedex/FR
  • 13 Daiichi Sankyo Co., Ltd., Tokyo/JP
  • 14 Unicancer, 75654 - Paris/FR
  • 15 Institut Gustave Roussy, 94805 - Villejuif/FR
  • 16 Breast Cancer Unit, Medical Oncology Department, Gustave Roussy - Cancer Campus, 94805 - Villejuif/FR
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Resources

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Abstract LBA1

Background

T-DXd is an anti-HER2 antibody-drug conjugate that has demonstrated high antitumor activity in HER2-positive and HER2-low metastatic breast cancer (mBC). We aimed to unravel the mechanism of action and resistance to T-DXd in patients from DAISY trial.

Methods

DAISY is a phase II clinical trial (NCT04132960) that assessed T-DXd efficacy in mBC according to HER2-expression (HER2-positive, HER2-low, and HER2-negative). Bystander effect and T-DXd uptake were analyzed by immunohistochemistry (IHC) (HER2, gH2AX, and T-DXd) on tumor biopsies at baseline and on-treatment (n=10 patients). T-DXd immune effects were explored by multiplex immunofluorescence (CD3, CD4, CD8, CD68, FoxP3, PD-1, PD-L1, CK/SOX10 antibodies) on tumor biopsies at baseline and on-treatment (Day 22 or 43, n=31 patients). Mechanisms of resistance were analyzed on tumor samples at baseline (n=118) and at progression by whole exome sequencing (n=24) and IHC (n=25). The predictive value of HER2 spatial distribution was investigated by artificial intelligence (AI) using weakly supervised and clustering algorithms on HER2-positive slides images at baseline (n=61).

Results

Molecular analyses showed that cancer cells expressing low levels of HER2, but not HER2-null cells, uptake T-DXd (p=0.053). In the whole population (n=31), a decrease of PDL1-positive cells was associated with a best objective response (BOR) (p=0.008). No modulation of T cells and macrophages was observed (p=0.6 and p=0.9 respectively). A decrease of PDL1 expression was detected in HER2-positive mBC (n=18; p=0.02). Clustering algorithms identified a cluster associated with a lower BOR (p=0.007), whose features identified by AI included a high percentage of HER2-negative cells currently under investigation. At progression, a decrease of HER2 expression was observed in 13/25 (52%) patients (p=0.07). DNA sequencing and final AI results will be available at the meeting.

Conclusions

A correlation between HER2 expression and T-DXd uptake in cancer cells was observed in on-treatment biopsies. T-DXd did not modulate intratumoral lymphocytes but decreased PDL1 expression. WES analyses at baseline and progression samples will be presented on-site.

Legal entity responsible for the study

The authors

Funding

Unicancer and Daiichi Sankyo

Disclosure

V. Dieras: Financial Interests, Personal, Advisory Board, Travel Expenses: Roche, Novartis, Lilly, Pfizer, AstraZeneca, MSD, Daiichi Sankyo, Seagen, Gilead; Financial Interests, Personal, Invited Speaker, Travel Expenses: Lilly, Pfizer, AstraZeneca, MSD, Daiichi Sankyo, Seagen, Gilead; Financial Interests, Personal, Principal Investigator, Travel Expenses: Pfizer, Daiichi Sankyo, Seagen; Financial Interests, Personal, Advisory Board: AbbVie; Financial Interests, Personal, Principal Investigator: AbbVie; Non-Financial Interests, Personal, Advisory Board: Eisai, Pierre Fabre Oncologie. E. Deluche: Financial Interests, Personal, Advisory Board: Novartis, Pfizer, Fresenius Kabi, Lilly; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Other, scientific events: Lilly, GSK; Financial Interests, Personal, Other, funding for conference travel: AstraZeneca-Daiichi, Roche, Amgen. B. Pistilli: Financial Interests, Institutional, Other, Consulting Fees: AstraZeneca, Pfizer; Financial Interests, Personal, Other, Consulting Fees: Myriad, Pierre Fabre; Financial Interests, Institutional, Speaker’s Bureau: Daiichi Sankyo, Novartis, Puma; Financial Interests, Institutional, Writing Engagements: Daiichi Sankyo, Novartis, Puma; Financial Interests, Personal, Other, Attending Meetings and/or Travel: AstraZeneca, Pierre Fabre, MSD; Financial Interests, Institutional, Advisory Board: Novartis, AstraZeneca, Daiichi Sankyo. T. Bachelot: Financial Interests, Personal, Advisory Board: Roche, Novartis, AstraZeneca, Pfizer, Seagen; Financial Interests, Institutional, Research Grant: Novartis, Roche, AstraZeneca, Seagen, Pfizer; Financial Interests, Personal, Invited Speaker: Roche. D. Tran: Non-Financial Interests, Institutional, Full or part-time Employment, Full-time: DIEP T. N. TRAN. N. Droin: Non-Financial Interests, Institutional, Full or part-time Employment, Part-time: Nathalie Droin. M. Kobayashi, T. Kakegawa: Other, Personal, Full or part-time Employment, Employee of Daiichi Sankyo RD Novare, which belongs to Daiichi Sankyo Group. Daiichi Sankyo Group is developing T-DXd: Daiichi Sankyo RD Novare. M. Lacroix-Triki: Financial Interests, Personal, Invited Speaker: AstraZeneca, Daiichi Sankyo; Financial Interests, Personal, Other, Consulting Fees: AstraZeneca, Daiichi Sankyo. F. André: Financial Interests, Institutional, Research Grant: AstraZeneca, Lilly, Novartis, Pfizer, Roche, Daiichi; Other, Founder: Pegacsy. All other authors have declared no conflicts of interest.

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