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HER2 directed ADC

CompoundTrastuzumab deruxtecan (DS-8201a; in collaboration with Daiichi Sankyo)Fam-trastuzumab deruxtecan-nxki (DS-8201a; in collaboration with Daiichi Sankyo, Inc., Basking Ridge, NJ, US)

Area under investigation

Advanced solid tumors, Gastric/GEJ cancer, HER2-positive breast cancer, HER2-low breast cancer, NSCLC, BTCs, Metastatic urothelial carcinoma, Endometrial cancer, HER2 IHC 0 metastatic, Ovarian cancer, Cervical cancer

Scientific PillarAntibody-Drug Conjugates

Target Overview

The human epidermal growth factor receptor 2 (HER2) is a transmembrane tyrosine kinase receptor located on chromosome 17q21.1 It is a member of the epidermal growth factor receptor (EGFR) family.2

In normal cells, activation of HER2 via homo- or heterodimerization mediates cell-signaling pathways, including the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) pathways, which regulate cellular processes of proliferation, motility, and survival.2

HER2 acts as an oncogene in various cancers, its overexpression resulting in ligand-independent dimerization, which leads to constitutive activation of its cytoplasmic kinase domain. This further leads to activation of the PI3K/AKT and MAPK pathways, which promotes proliferation and progression of cancer.3,4

Compound Overview

Trastuzumab deruxtecana,b is composed of a humanized HER2-directed IgG1 monoclonal antibody with the same amino acid sequence as trastuzumab, covalently linked to a topoisomerase I inhibitor payload (an exatecan derivative) via a tetrapeptide-based cleavable linker. It was designed with the following key attributes – topoisomerase I inhibitor payload with a unique proposed mechanism of action, high potency of the payload, high drug-to-antibody ratio of ~8, payload with a short systemic half-life, stable linker-payload in plasma, tumor-selective cleavable linker, and bystander antitumor effect.5,6

Based on in vitro and in vivo models, the released payload DXd exerts bystander antitumor activity through cytotoxic activity in both the target cells and neighboring tumor cells owing to its high cell membrane permeability.5

afam-trastuzumab deruxtecan-nxki in US only; trastuzumab deruxtecan in other regions of world.

bIn collaboration with Daiichi Sankyo, Inc., Basking Ridge, NJ, US.

References

1. Leong AY and Zhuang Z. Pathobiology. 2011;78(2):99-114. 2. Marchiò C, Annaratone L, Marques A, et al. Semin Cancer Biol. 2021;72:123-135. 3. Raghav KPS and Moasser MM. Clin Cancer Res. 2023; 29(13): 2351–2361. 4. Wang J and Xu B. Signal Transduct Target Ther. 2019:4:34. 5. Nakada T, Sugihara K, Jikoh T, et al. Chem Pharm Bull (Tokyo). 2019;67(3):173-185. 6. Ogitani Y, Hagihara K, Oitate M, et al. Cancer Sci. 2016;107(7):1039-1046.

Clinical trial information


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Abbreviations

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  • 1L

    first line

  • 5-FU

    5-fluorouracil

  • ADC

    antibody drug conjugate

  • ADCC

    antibody-dependent cellular cytotoxicity

  • AESI

    adverse event of special interest

  • AJCC

    American Joint Committee on Cancer

  • AKT

    protein kinase B/also known as PKB

  • ASCO/CAP

    American Society of Clinical Oncology / College of American Pathologists

  • BC

    breast cancer

  • BICR

    blinded independent central review

  • BM

    brain metastases

  • BMFI

    brain metastases-free interval

  • CAPOX

    capecitabine plus oxaliplatin

  • CDK4/6

    cyclin-dependent kinase 4/6

  • CHF

    congestive heart failure

  • CNS

    central nervous system

  • COPD

    chronic obstructive pulmonary disease

  • CPS

    combined positive score

  • CTCAE

    Common Terminology Criteria for Adverse Events

  • ctDNA

    circulating tumor DNA

  • CTLA-4

    cytotoxic T–lymphocyte-associated antigen 4

  • DAR

    drug-to-antibody ratio

  • DCIS

    ductal carcinoma in situ

  • DCR

    disease control rate

  • DFS

    disease-free survival

  • DoR

    duration of response

  • DPD

    dihydropyrimidine dehydrogenase

  • DRFI

    distant recurrence-free interval

  • DXd

    deruxtecan

  • eBC

    early breast cancer

  • EC

    endometrial cancer

  • ECG

    electrocardiogram

  • ECOG PS

    Eastern Cooperative Oncology Group Performance Score

  • EGFR

    epidermal growth factor receptor

  • FFPE

    formalin-fixed paraffin-embedded

  • FLOT

    docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil

  • FP

    5-fluorouracil/capecitabine

  • GC

    gastric cancer

  • GEJ

    gastroesophageal junction

  • GI

    gastrointestinal

  • HBV

    hepatitis B virus

  • HCV

    hepatitis C virus

  • HER2

    human epidermal growth factor receptor 2

  • HIV

    human immunodeficiency virus

  • HR

    hormone receptor

  • HRQoL

    health-related quality of life

  • iDFS (IDFS)

    invasive disease-free survival

  • IgG1

    immunoglobulin G1

  • IHC

    immunohistochemistry

  • ILD

    interstitial lung disease

  • IO

    immuno-oncology

  • ISH

    in-situ hybridization

  • ITT

    intention to treat

  • IV

    intravenous

  • LVEF

    left ventricular ejection fraction

  • MAPK

    mitogen-activated protein kinase

  • mBC

    metastatic breast cancer

  • MI

    myocardial infarction

  • MMR

    mismatch repair

  • MRI

    magnetic resonance imaging

  • ms

    milliseconds

  • mTOR

    mechanistic or mammalian target of rapamycin

  • NSCLC

    non-small cell lung cancer

  • ORR

    overall or objective response rate

  • OS

    overall survival

  • OS-24

    overall survival at 24 months

  • pCR

    pathological complete response

  • PD-1

    programmed cell death-1

  • PD-L1

    programmed cell death ligand-1

  • PD-L2

    programmed cell death ligand-2

  • PFS

    progression-free survival

  • PFS-12

    progression-free survival at 12 months

  • PFS2

    time to second progression or death

  • PI3K

    phosphoinositide 3-kinase

  • PIK3CA

    phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha

  • PK

    pharmacokinetics

  • pLOT

    prior line of therapy

  • pMMR

    mismatch repair proficient

  • PRO

    patient-reported outcomes

  • Q3W

    every 3 weeks

  • QoL

    quality of life

  • R

    randomization

  • RECIST

    Response Evaluation Criteria in Solid Tumors

  • RECIST v1.1

    Response Evaluation Criteria in Solid Tumors version 1.1

  • rwPFS

    real-world progression-free survival

  • SAE

    serious adverse event

  • T-DM1

    ado-trastuzumab emtansine

  • T-DXd

    fam-trastuzumab deruxtecan-nxki in US only; trastuzumab deruxtecan in other regions of world

  • TB

    tuberculosis

  • TEAE

    treatment emergent adverse event

  • TFST

    time to first subsequent therapy

  • TNBC

    triple-negative breast cancer

  • TOP1i

    topoisomerase 1 inhibitor

  • TSST

    time to start of second subsequent therapy

  • TTD

    time to treatment discontinuation

  • TTNT

    time to next treatment

  • WHO

    World Health Organization

Some compounds herein refer to selected AstraZeneca pipeline products still under development. AstraZeneca pipeline products are investigational products and, as such, are not approved by the US Food & Drug Administration (FDA), the European Medicines Agency (EMA) or any other regulatory agency for the uses under investigation. Information regarding these investigational products should, under no circumstances, be regarded as a recommendation for their use or of their safety or efficacy.

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Veeva ID: Z4-80919 US-109129 DE-92568 Last Updated April 20263/26
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