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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

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 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 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.

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 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 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.

Clinical trial information


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Area under investigation=true,Advanced solid tumors,BTCs,Cervical cancer,Endometrial cancerGastric/GEJ cancer,HER2 IHC 0 mBC,HER2-positive breast cancer,HER2-low breast cancer,Metastatic urothelial carcinoma,NSCLC,Ovarian cancer

ARTEMIDE-Gastric01 trial overview

Tumor

HER2+ locally advanced or metastatic gastric or GEJ cancer whose tumors express PD-L1 CPS ≥1

Trial Identifier

NCT06764875

Phase

III

Stage

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

Regimen

T-DXd + rilvegostomig + fluoropyrimidine vs. trastuzumab + chemotherapy + pembrolizumab vs. trastuzumab + chemotherapy + rilvegostomig

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

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DESTINY-Breast09 trial overview

Tumor

HER2+ Advanced or metastatic breast cancer

Trial Identifier

NCT04784715

Phase

III

Regimen

T-DXd  ± pertuzumab; trastuzumab + pertuzumab + a taxane (investigator's choice of docetaxel or paclitaxel)

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

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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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DESTINY-BTC01 trial overview

Tumor

Advanced HER2-expressing BTCs, 1L

Trial Identifier

NCT06467357

Phase

III

Regimen

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

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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

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DESTINY-Endometrial02 trial overview

Tumor

HER2-expressing (IHC 3+/2+) endometrial cancer

Trial Identifier

NCT07022483

Phase

III

Regimen

T-DXd; chemotherapy

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

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DESTINY-Gastric03 trial overview

Tumor

HER2-expressing advanced/metastatic gastric/GEJ and esophageal adenocarcinoma

Trial Identifier

NCT04379596

Phase

Ib/II

Stage

Advanced

Regimen

T-DXd ± (chemotherapy or durvalumab or pembrolizumab); T-DXd + chemotherapy + (durvalumab or pembrolizumab); T-DXd + volrustomig + chemotherapy; T-DXd + rilvegostomig + chemotherapy

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DESTINY-Gastric04 trial overview

Tumor

HER2+ unresectable and/or metastatic gastric or GEJ adenocarcinoma

Trial Identifier

NCT04704934

Phase

III

Stage

Advanced

Regimen

T-DXd; ramucirumab + paclitaxel

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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

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DESTINY-Lung03 trial overview

Tumor

Unresectable locally advanced/metastatic non-squamous HER2 overexpressing NSCLC

Trial Identifier

NCT04686305

Phase

Ib

Stage

Metastatic, ≥1L

Regimen

T-DXd + durvalumab + (cisplatin/carboplatin/pemetrexed); T-DXd; T-DXd + volrustomig ± carboplatin; T-DXd + rilvegostomig ± carboplatin

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DESTINY-Lung04 trial overview

Tumor

Unresectable, locally advanced, or metastatic NSCLC with HER2 Exon 19 or 20 mutations

Trial Identifier

NCT05048797

Phase

III

Stage

Metastatic, 1L

Regimen

T-DXd; SoC (cisplatin or carboplatin + pemetrexed + pembrolizumab)

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

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DESTINY-Lung06 trial overview

Tumor

Locally advanced unresectable, or metastatic HER2 overexpressing and PD-L1 TPS <50% nonsquamous NSCLC

Trial Identifier

NCT06899126

Phase

III

Regimen

T-DXd + pembrolizumab; pembrolizumab + pemetrexed + platinum-based chemotherapy (cisplatin or carboplatin)

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DESTINY-Ovarian01 trial overview

Tumor

HER2-expressing (IHC 3+/2+/1+) advanced high-grade ovarian cancer

Trial Identifier

NCT06819007

Phase

III

Regimen

T-DXd + bevacizumab vs bevacizumab

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DESTINY-PanTumor02 trial overview

Tumor

Early-stage NSCLC adenocarcinoma following complete surgical resection (R0) that is ctDNA-positive or has high-risk pathological features

Trial Identifier

NCT06564844

Phase

III

Stage

Treatment-naïve Stage I

Regimen

Dato-DXd + rilvegostomig; rilvegostomig; SoC; abc

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DS8201-A-U106 trial overview

Tumor

Locally advanced/metastatic HER2-positive breast cancer (as per ASCO-CAP guidelines), HER2-low breast cancer (IHC 1+ or IHC 2+/ISH-), HER2-expressing NSCLC (IHC 1+, 2+, or 3+), and HER2-mutant NSCLC

Trial Identifier

NCT04042701

Phase

Ib

Regimen

T-DXd + pembrolizumab

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GEMINI-PeriOp Gastric trial overview

Tumor

Locally advanced resectable GEJ adenocarcinoma

Trial Identifier

NCT07069712

Phase

II

Stage

Locally advanced resectable gastric, GEJ, or esophageal adenocarcinoma

Regimen

Sonesitatug vedotin + rilvegostomig and 5-FU or capecitabine; T-DXd + rilvegostomig and 5-FU or capecitabine; rilvegostomig + FLOT chemotherapy

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PETRA trial overview

Tumor

Advanced solid tumors (advanced/metastatic ovarian cancer, HR+/HER2- breast cancer, TNBC, pancreatic cancer, prostate cancer, NSCLC, SCLC, gastric cancer, biliary cancer, cervical cancer, endometrial cancer, CRC, bladder cancer)

Trial Identifier

NCT04644068

Phase

I/IIa

Regimen

Saruparib; saruparib + paclitaxel; saruparib + carboplatin ± paclitaxel; saruparib + T-DXd; saruparib + Dato-DXd; saruparib + camizestrant

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SubQ (NCT07015697) trial overview

Tumor

HER2-expressing metastatic solid tumors

Trial Identifier

NCT07015697

Phase

I

Regimen

Subcutaneous T-DXd + hyaluronidase

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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

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