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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 mBC, Ovarian cancer, Cervical cancer

Scientific PillarAntibody-Drug Conjugates

Overview
Clinical Trials
Abbreviations

Target Overview

The human epidermal growth factor receptor 2 (HER2) is a transmembrane tyrosine kinase receptor; its encoding gene is 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 may act 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 deruxtecan^a,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 AS-Y 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.

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DESTINY-Breast15 trial overview

Tumor

HER2-low or HER2 IHC 0 unresectable or metastatic breast cancer

Trial Identifier

NCT05950945

Phase

III

Regimen

T-DXd

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

Study Design

Inclusion criteria

The key inclusion criteria are^1,2–

Age ≥18 years
Newly obtained tumor biopsy or archival biopsy obtained within 6 weeks before enrollment screening
Pathologically documented HR− or HR+, HER2-low (IHC 1+ or IHC 2+/ISH−) or HER2 IHC 0 unresectable and/or mBC that was never previously HER2+ (IHC 3+ or IHC 2+/ISH+) and was never previously treated with anti-HER2 therapy in the metastatic setting
Between 1 to 2 prior lines of therapy in the metastatic setting
Patients with HR+ HER2-low mBC (Cohort 3) must have either had recurrent disease within 2 years of initiation of adjuvant ET, disease progression on CDK4/6i-based regimen within 12 months of completion of CDK4/6i therapy, or disease progression within 12 months of CDK4/6i therapy in the metastatic setting
Presence of at least one measurable lesion based on computed tomography or MRI per RECIST v1.1
ECOG PS of 0 or 1
Patients with brain metastases are allowed in the study. The brain lesion(s) should be small (<2 cm), untreated, asymptomatic, not requiring urgent medical intervention, and are asymptomatic and clinically stable
Minimum life expectancy of 12 weeks at screening
Left ventricular ejection fraction ≥50% within 28 days before enrollment
Adequate organ and bone marrow function as defined by the protocol

Reference:

1. Study NCT05950945. ClinicalTrials.gov website.

2. Modi S, et al. Presented at: San Antonio Breast Cancer Symposium (SABCS) 2023 Meeting. December 5-9. Poster PO2-19-06.

Exclusion criteria

The key exclusion criteria are^1,2 –

Prior treatment with an antibody drug conjugate (ADC)
Uncontrolled or significant cardiovascular disease including myocardial infarction within 6 months before randomization, symptomatic congestive heart failure, or clinically significant arrhythmias
Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
Has spinal cord compression or clinically active central nervous system metastases
Subjects with clinically inactive brain metastases may be included in the study. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study
Has unresolved toxicities from previous anticancer therapy
Lung-specific intercurrent clinically significant illnesses
Any autoimmune, connective tissue, or inflammatory disorders

Abbreviations