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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-Gastric05 trial overview

Tumor

Unresectable, locally advanced or metastatic HER2+ gastric/GEJ cancer

Trial Identifier

NCT06731478

Phase

III

Stage

Untreated, unresectable, locally advanced or metastatic gastric or GEJ adenocarcinoma

Regimen

T-DXd + chemotherapy ± pembrolizumab vs trastuzumab + chemotherapy ± pembrolizumab

Visit ct.gov

fam-trastuzumab deruxtecan-nxki in US only; trastuzumab deruxtecan in other regions of world. This study is sponsored by Daiichi Sankyo, Inc.

Study Design

Inclusion criteria

The key inclusion criteria are –

Adults, age ≥18 years.
Histologically confirmed, previously untreated, unresectable, locally advanced, or metastatic gastric or GEJ cancer.
Prior perioperative and/or adjuvant treatment is allowed if >6 months between the end of perioperative or neoadjuvant treatment and diagnosis of recurrent disease.
Prior use of IO therapy (e.g., anti-PD-1/PD-L1) in the (neo) adjuvant setting is allowed if >6 months between the end of IO therapy and the diagnosis of recurrent disease.
Centrally determined HER2+ (IHC 3+ or IHC 2+/ISH-positive) gastric or GEJ cancer by ASCO-CAP guidelines for GC, as detected by prospective central test on new (core, incisional, excisional biopsy) or existing tumor tissue taken at the time of diagnosis of locally advanced or metastatic disease.
All participants must provide a tumor sample for tissue-based IHC staining to centrally determine HER2 expression, PD-L1 CPS, and other correlatives.
Left ventricular ejection fraction (LVEF) ≥50% within 28 days prior to randomization.

Reference:

Study NCT06731478. ClinicalTrials.gov website.

Exclusion criteria

The key exclusion criteria are –

Prior exposure to other HER2-targeting therapies (including ADCs)
History of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli within 3 months of the trial randomization, severe asthma, severe COPD, restrictive lung disease, pleural effusion, etc)
Lack of physiological integrity of the upper GI tract or malabsorption syndrome that would preclude feasibility of oral chemotherapy
Known DPD enzyme deficiency
Myocardial infarction within 6 months before randomization or symptomatic CHF
Corrected QT interval (QTcF) prolongation to >470 ms (females) or >450 ms (males) based on the average of the screening triplicate 12-lead ECG

Abbreviations