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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-Endometrial01 trial overview

Tumor

HER2-expressing (IHC 3+/2+), pMMR, primary advanced (Stage III/IV) or recurrent endometrial cancer

Trial Identifier

NCT06989112

Phase

III

Regimen

T-DXd + (rilvegostomig or pembrolizumab); chemotherapy + pembrolizumab

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 –

HER2 (IHC 3+/2+) and pMMR by central testing
Primary advanced (Stage III/IV) or first recurrent EC
Measurable disease per RECIST 1.1 criteria
Adequate FFPE tumor tissue sample of a tumor lesion that was not previously irradiated for central HER2, MMR, and PD-L1 IHC testing and valid central test results
Naïve to 1L systemic therapy. May have received prior radiation therapy for EC (washout period required)
Allowed 1 L of adjuvant/neoadjuvant chemo (+/- chemoradiation) if recurrence ≥6 months after last chemo; prior adjuvant/neoadjuvant trastuzumab allowed
No prior exposure to ADCs or immune checkpoint inhibitors including (but not limited to) anti-PD-1/PD-L1/PD-L2 and anti-CTLA-4 antibodies and therapeutic anticancer vaccines
ECOG Performance Status 0-1
Adequate organ/bone marrow function
LVEF ≥ 50% within 28 days before randomization

Reference:

Study NCT06989112. ClinicalTrials.gov website.

Exclusion criteria

The key exclusion criteria are –

History of organ transplant
Active or uncontrolled illness (infection, GI conditions)
Spinal cord compression or CNS metastases
History or current ILD/pneumonitis
Lung diseases (pulmonary emboli <3 months of enrollment, severe asthma, COPD, restrictive lung disease, pleural effusion, complete pneumonectomy)
Active or documented autoimmune or inflammatory disorders requiring immunosuppressive or steroids treatment
Active primary immunodeficiency/active infections (uncontrolled TB, HIV, or HBV/HCV)
Concurrent anticancer treatment without washout period
Cardiovascular diseases (history of MI <6 months before randomization, symptomatic CHF, arrhythmia or cardiomyopathy)

Abbreviations