343MO - Unraveling the mechanisms of action and resistance to trastuzumab deruxtecan (T-DXd): Supplementary biomarker analyses from DAISY trial

Background

T-DXd is an anti-HER2 antibody-drug conjugate that demonstrated clinically meaningful efficacy in patients with HER2-positive and HER2-low metastatic breast cancer (mBC). Additionally, antitumor activity was observed in patients with HER2 score 0 mBC by immunohistochemistry (IHC). We aimed to explore the mechanisms of action and resistance of T-DXd in patients from DAISY trial.

Methods

DAISY is a phase II, multicenter, open-label trial (NCT04132960) that assessed T-DXd efficacy in three cohorts of patients with mBC according to HER2 expression and performed biomarker analyses. Efficacy and biomarker results have been previously reported (Mosele et al, Nature Medicine 2023). To further explore the mechanisms of action and resistance of T-DXd, we assessed the activation of CD8+ T lymphocytes by granzyme B (GrB+) staining using multiplex IHC on baseline and on-treatment biopsies with different levels of HER2 expression (n=24). In addition, biopsies at baseline HER2 IHC score 0 were assessed using RNAscope® (n=20). Finally, resistance was explored by whole-exome sequencing in biopsies at baseline (n=92) and progression (n=30).

Results

There was no significant increase in the density of GrB+/CD8+ T lymphocytes during treatment with T-DXd in tissue biopsies performed on C2D1 or C3D1 (p=0.76). No significant association was found between the spatial distribution of ERBB2 RNA expression and response to T-DXd (p=0.39). Moreover, in the analyzable samples at baseline and progression we did not find any recurrent driver alteration associated with resistance, nor any additional SLX4 mutations.

Conclusions

T-DXd does not seem to activate CD8+ T lymphocytes within the immune tumor microenvironment. Furthermore, spatial ERBB2 expression does not emerge as a significant determinant of T-DXd efficacy in patients with HER2 non-expressing mBC. Recurrent driver alterations were not identified as contributing factors to resistance.

Clinical trial identification

NCT04132960.

Editorial acknowledgement

Legal entity responsible for the study

UNICANCER in collboration with GUSTAVE ROUSSY and DAIICHI SANKYO.

Funding

DAIICHI SANKYO.

Disclosure

M.F. Mosele: Financial Interests, Personal, Full or part-time Employment: pegascy; Financial Interests, Institutional, Advisory Board: Novartis. V.C. Dieras: Financial Interests, Personal, Advisory Board, National advisory board: Pierre Fabre Oncologie; Financial Interests, Personal, Advisory Board, Steering Committee, consultant, Symposium, travel expenses: Roche Genentech; Financial Interests, Personal, Advisory Board, + Symposia and travel expenses: Novartis; Financial Interests, Personal, Advisory Board, Advisory boards, symposia, travel expenses: Pfizer; Financial Interests, Personal, Advisory Board, Symposia, travel expenses: Lilly, AstraZeneca, MSD; Financial Interests, Personal, Advisory Board, Symposia,travel expenses: Daiichi Sankyo; Financial Interests, Personal, Advisory Board, symposia,travel expenses: Seagen, Gilead; Financial Interests, Personal, Advisory Board, Steering Committee: AbbVie; Financial Interests, Personal, Advisory Board: Eisai, Medac GmbH; Financial Interests, Personal, Other, IDMC: Sanofi; Financial Interests, Personal, Advisory Board, national board: MENARINI; Financial Interests, Personal and Institutional, Other, IDMC: Sanofi; Financial Interests, Institutional, Steering Committee Member: Roche Genentech; Financial Interests, Institutional, Coordinating PI, Steering Committee: Lilly; Financial Interests, Institutional, Coordinating PI: AstraZeneca; Financial Interests, Institutional, Coordinating PI, + IDMC: Daiichi Sankyo; Financial Interests, Institutional, Steering Committee Member, PI: Seagen. E. Deluche: Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Board: pfizer, astrazeneca, GSK, Daiichi Sankyo, MSD, Lilly; Non-Financial Interests, Personal, Advisory Board: Novartis, pfizer, astrazeneca, Daiichi Sankyo, GSK, Lilly, MSD. B. Pistilli: Financial Interests, Institutional, Advisory Board: ASTRAZENECA, SEAGEN, LILLY, DAIICHI SANKYO, MSD; Financial Interests, Institutional, Invited Speaker: GILEAD, NOVARTIS; Financial Interests, Personal, Advisory Board: PIERRE FABRE, DAIICHI SANKYO; Financial Interests, Personal, Other, travel support: ASTRAZENECA, PIERRE FABRE, MSD, DAIICHI SANKYO; Financial Interests, Personal, Other, Travel support: PFIZER; Financial Interests, Institutional, Steering Committee Member: ASTRAZENECA, NOVARTIS; Financial Interests, Institutional, Research Grant: ASTRAZENECA; Financial Interests, Institutional, Local PI: ASTRAZENECA, GILEAD, SEAGEN, MSD, NOVARTIS; Financial Interests, Institutional, Funding: DAIICHI SANKYO; Non-Financial Interests, Project Lead: UNICANCER. T. Bachelot: Financial Interests, Personal, Advisory Board: Novartis, AstraZeneca, Pfizer, Seagen, Daiichi Sankyo; Financial Interests, Institutional, Advisory Board: Lilly; Financial Interests, Institutional, Research Grant: Novartis, Roche, AstraZeneca, Seagen, Pfizer; Financial Interests, Personal, Steering Committee Member: Roche; Financial Interests, Institutional, Steering Committee Member: AstraZeneca; Non-Financial Interests, Principal Investigator: Roche, AstraZeneca. M. Kobayashi: Financial Interests, Personal, Full or part-time Employment: daiichi sankyo. T. Kakewaga: Financial Interests, Personal, Full or part-time Employment: daiichi sankyo. M. Lacroix-Triki: Financial Interests, Personal and Institutional, Advisory Role: astrazeneca, daiichi sankyo. F. André: Financial Interests, Personal, Advisory Board: Lilly France; Financial Interests, Institutional, Advisory Board: AstraZeneca, Daiichi Sankyo, Roche, Lilly, Pfizer, Owkin, Novartis, Guardant Health, N-Power Medicine, Servier, Gilead, Boston Pharmaceuticals; Financial Interests, Institutional, Research Grant: AstraZeneca, Lilly, Novartis, Pfizer, Roche, Daiichi Sankyo, Guardant Health, Owkin. All other authors have declared no conflicts of interest.