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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-BTC01 trial overview

Tumor

Advanced HER2-expressing BTCs, 1L

Trial Identifier

NCT06467357

Phase

III

Regimen

T-DXd + rilvegostomig; T-DXd; gemcitabine + cisplatin + durvalumab

Visit ct.gov

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

Study Design

Inclusion criteria

The key inclusion criteria are-

Adults ≥ 18 years
Unresectable, previously untreated, locally advanced or metastatic BTC.
Prior treatment in the perioperative and/or adjuvant setting is permissible provided there is > 6 months between the end of adjuvant treatment and the diagnosis of locally advanced or metastatic disease.

Histologically confirmed HER2-expressing (IHC 3+/2+) BTC
Provision of FFPE tumor sample that is no older than 3 years
At least one target lesion assessed by the Investigator based on RECIST v1.1 (randomized portion only)
WHO/ECOG performance status of 0 or 1
Adequate organ and bone marrow function within 14 days before randomization

Reference:

Study NCT06467357. ClinicalTrials.gov website.

Exclusion criteria

The key exclusion criteria are-

Prior exposure to other HER2 targeting therapies, ADCs, immune checkpoint inhibitors and therapeutic anticancer vaccines
Histologically confirmed ampullary carcinoma
Spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms
History of myocardial infarction within 6 months before randomization/enrollment, symptomatic CHF (NYHA Class II to IV), unstable angina pectoris, clinically important cardiac arrhythmias, or a recent (<6 months) cardiovascular event including stroke
Serious chronic gastrointestinal conditions associated with diarrhea (eg, active inflammatory bowel disease); active non-infectious skin disease (including any grade rash, urticaria, dermatitis, ulceration, or psoriasis) requiring systemic treatment
Corrected QT interval (QTcF) prolongation to > 470 msec (females) or > 450 msec (males) based on average of the screening triplicate 12-lead ECG
History of (non-infectious) ILD/pneumonitis, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
Active primary immunodeficiency, known uncontrolled active HIV infection or HCV

Abbreviations