LBA72 - Unraveling the mechanism of action and resistance to trastuzumab deruxtecan (T-DXd): Biomarker analyses from patients from DAISY trial

Background

T-DXd is an anti-HER2 antibody-drug conjugate that demonstrated high efficacy in patients with HER2-overexpressing and HER2-low metastatic breast cancer (mBC). We aimed to explore the mechanism of action and resistance to 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 reported previously (Dieras et al, SABCS 2021; Mosele et al, ESMO BREAST 2022). To further explore the mechanism of action of T-DXd, we assessed the spatial genomic response according to HER2 expression by GeoMx in biopsies at D2-4 after cycle 1 of T-DXd (n=8). In addition, biopsies at baseline with no detection of HER2 by IHC were assessed by RT-PCR (n=36). Finally, primary and secondary resistance were explored by whole-exome sequencing in biopsies at baseline (n=88) and at progression (n=20); and T-DXd distribution was assessed by IHC in biopsies at ≤6 weeks after last infusion at progression (n=6).

Results

Serotonin receptor pathways in HER2-overexpressing and interferon alpha pathways in HER2-negative area were activated after T-DXd administration. No association between ERBB2 expression and clinical response to T-DXd was observed. No recurrent driver alteration was associated with resistance. ERBB2 hemizygous deletion was detected in 5 out of 88 (6%) patients at baseline; four of them did not respond to T-DXd. SLX4 mutation was acquired in 2 biopsies out of 10 pairs (20%) at progression and was found in 2 samples unmatched with baseline (20%). In two BC cell lines, SLX4 silencing mediated resistance to DXd. T-DXd distribution was observed in 4 out of 6 patients at progression.

Conclusions

T-DXd could trigger anti-tumor immune response in HER2-negative mBC. No recurrent drivers were identified at resistance. ERBB2 hemizygous deletion seems to be associated with T-DXd upfront resistance. SLX4 could induce secondary resistance; however, it needs to be confirmed. T-DXd uptake is not suggested to be a mechanism of resistance.

Clinical trial identification

NCT04132960.

Editorial acknowledgement

Legal entity responsible for the study

Gustave Roussy and Unicancer.

Funding

Daiichi Sankyo.

Disclosure

M.F. Mosele: Personal and Institutional, Pegascy. V.C. Dieras: Financial Interests, Personal, Advisory Board, National advisory board: Pierre Fabre Oncologie; Financial Interests, Personal, Advisory Board, Steering comittee, 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 comitte: AbbVie; Financial Interests, Personal, Advisory Board: EISAI; Financial Interests, Personal, Other, IDMC: Sanofi; Financial Interests, Personal and Institutional, Other, IDMC: Sanofi; Financial Interests, Institutional, Invited Speaker: ROCHE Genentech, Astra Zeneca; Financial Interests, Institutional, Invited Speaker, Steering comittee: Lilly; Financial Interests, Institutional, Invited Speaker, IDMC: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker, PI: Seagen. 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, funding for conference travel: AstraZeneca, Daiichi, Roche, Amgen. B. Pistilli: Financial Interests, Institutional, Advisory Role: AstraZeneca, Myriad, Pierre Fabre, Pfizer; Financial Interests, Institutional, Speaker’s Bureau: Daiichi Sankyo, Novartis, Puma; Financial Interests, Personal, Training: 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. M. Kobayashi: Personal, Employee of Daiichi Sankyo RD Novare, which belongs to Daiichi Sankyo Group. Daiichi Sankyo Group is developing T-DXd: Daiichi Sankyo RD Novare. T. Kakewaga: Personal, 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 and Institutional, Invited Speaker: Daiichi Sankyo RD Novare; Financial Interests, Personal and Institutional, Training: AstraZeneca. F. André: Financial Interests, Institutional, Research Grant: AstraZeneca, Lilly, Novartis, Pfizer, Roche, Daiichi; Founder: Pegacsy. All other authors have declared no conflicts of interest.