Trastuzumab deruxtecan

FDA-approved

T-DXd; Enhertu; DS-8201a

Target

HER2 · ERBB2

Sponsor

Daiichi Sankyo/AstraZeneca

Indication

HER2+ breast/gastric/NSCLC

Target family

Receptor tyrosine kinase

RP2D dose

5.4 mg/kg (breast/NSCLC); 6.4 mg/kg (gastric)

Q3WRP2D

Multi-organ toxicity

Fingerprint & organ drill-down

Also reported

0%severity100%

Assessed · clear

true 0%

No data

never assessed

2 adverse-event terms

Ocular

Any-grade

11%

G3+

0.4%

RP2D

sagittal schematic · Reversible

↳

Tissues shaded by reported adverse-event rate.

Cornea

Express.

46.2%

Limbus

Express.

61.99%

Conjunctiva

Express.

61.13%

Lens

Express.

Retina / RPE

Express.

5.48%

7.5 nTPM

Dominant tissue

Ocular surface

Surface subtype

Conjunctival (on-target)

Reversibility

Reversible

Reported ocular events

Dry eye11%

G3+ 0.4%n=234

Vision blurred3.5%

n=257

Per-trial detail

Adverse events by trial

DS8201-A-J102 (QT/QTc study)Phase 16.4 mg/kg IV q3wn=51CTCAE NR (any-grade; CT.gov B

ClinicalTrials.gov posted results - Other (non-serious) AEs >=0% NCT03366428

148 adverse-event terms · 21 systems · expand a system below

Infections25

Nasopharyngitis

31.4%

16/51

Upper respiratory tract infection

9.8%

5/51

Lung infection

7.8%

4/51

Ginsivitis

5.9%

3/51

Influenza

5.9%

3/51

Gastroenteritis

3.9%

2/51

Paronychia

3.9%

2/51

Pharyngitis

3.9%

2/51

Rhinitis

3.9%

2/51

Angular cheilitis

1/51

Cellulitis

1/51

Cystitis

1/51

Dacryocystitis

1/51

Folliculitis

1/51

Hordeolum

1/51

Infection

1/51

Laryngitis

1/51

Oral candidiasis

1/51

Periodontitis

1/51

Sinusitis

1/51

Skin infection

1/51

Urinary tract infection

1/51

Vaginal infection

1/51

Skin candida

1/51

Oral herpes

1/51

GI20

Investigations17

Dermatologic13

Injury9

Pulmonary9

General8

Ocular7

Conjunctivitis allergic

3.9%

2/51

Dry eye

3.9%

2/51

Punctate keratitis

3.9%

2/51

Blepharitis

1/51

Cataract

1/51

Chalazion

1/51

Corneal disorder

1/51

Metabolic7

Musculoskeletal7

Neurologic (other)7

Immune3

Psychiatric3

Renal3

Vascular3

Other2

Hematologic1

Cardiac1

Ear1

Hepatic1

Neoplasms1

Construct

Molecular anatomy

Antibody

IgG1

Humanized

Linker

Cleavable

DAR

Payload

DXd

TopoI inhibitor

Linker structureC25H31N5O8

[H]OC(=O)C([H])([H])N([H])C(=O)[C@@]([H])(N([H])C(=O)C([H])([H])N([H])C(=O)C([H])([H])N([H])C(=O)C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])N1C(=O)C([H])=C([H])C1=O)C([H])([H])c1c([H])c([H])c([H])c([H])c1[H]

Payload structureC26H24FN3O6

CC[C@@]1(C2=C(COC1=O)C(=O)N3CC4=C5[C@H](CCC6=C5C(=CC(=C6C)F)N=C4C3=C2)NC(=O)CO)O

Antibody

Antibody & Fc engineering

Antibody

trastuzumab

Isotype

IgG1

Origin

Humanized

Fc modifications

None

Glycoengineering

Standard

Effector silencing

None

FcγR binding

Retained

C1q binding

Retained

Target KD (nM)

Epitope / domain

HER2 extracellular subdomain IV

Linker & conjugation

Linker chemistry

Linker profile

Linker

GGFG tetrapeptide

Class

Cleavable

Cleavage

Cleavable

Attachment

Cysteine (interchain)

Conjugation

Conventional interchain Cys

Symmetry

Symmetric

DAR (mean)

DAR homogeneity

Heterogeneous

Plasma t½

5.7 d

Cleavage trigger

Cathepsin B/L (GGFG tetrapeptide)

Release control

Conditional

Hydrophilicity mask

Hydrophilic-linker

Cell line

Chinese Hamster Ovary

Formula

C25H31N5O8

Linker MW

529.55 Da

Linker TPSA

191.08 Å²

Linker xLogP

-1.3675

ADCdb linker

LIN0ECMCR

In-vitro stability

>97%@21d/human-plasma

Stability note

acAb t½ 7–8 d in clinical (Yin Clin Pharmacokinet 2021); GGFG is exceptionally plasma-stable cleavable linker (1–2% DXd released at 21 d in rat/mouse/human plasma per Nakada 2019); profiles of T-DXd and total antibody nearly superimposable, indicating linker stability in circulation

Payload

Payload & physicochemistry

Payload profile

Payload

DXd

Class

Topoisomerase I inhibitor

Mechanism

TopoI inhibitor

Released catabolite

DXd

Mechanistic subtype

TopoI

Stereochem / salt

Free base (conjugate formulated with no payload salt counterion); DXd payload is a single (1S,9S) stereoisomer (exatecan derivative)

Bystander

Yes

PAMPA rank

493.5 Da

XLogP3

logD₇.₄

1.4

TPSA

129 Å²

pKa

9.2 pKa

Charge pH 7.4

H-bond donors

H-bond acceptors

IC50 (HCEC)

Formula

C26H24FN3O6

PubChem CID

117888634

ADCdb payload

PAY0UXDSB

Plasma protein binding (%)

97 %

Hydrophobicity · logD₇.₄

hydrophilic −2+1.4+4 lipophilic

Bioactivity note

Free DXd payload: TOP1 (DNA topoisomerase I) inhibitor; in vitro IC50 ~0.5 nM (MDA-MB-468) and ~4 nM (KPL-4) per ADCdb. T-DXd ADC IC50 0.7 ng/mL (SK-BR-3), 8.1 ng/mL (NCI-N87); cell-kill ranges ~0.7 to >3000 ng/mL by HER2 expression. Source: ADCdb PAY0UXDSB / DRG0ERKBH.

Dosing & regimen

Dosing

RP2D dose

5.4 mg/kg (breast/NSCLC); 6.4 mg/kg (gastric)

Schedule

Q3W

Route

Fractionated

n at RP2D

234

Dose basis

TBW

Trial phase

Approved

Dose-OAE available

Tox summary basis

RP2D

ADA rate (%)

2.2 %

Pharmacology

Clinical pharmacokinetics

By analyte · FDA label §12.3 + Drugs@FDA clinical-pharmacology reviews

	Intact ADC	Free payload
Cmax	132ug/mL+1	4.7ng/mL+1
AUC	772ug*day/mL+1	29ng*day/mL+1
Tmax	1.8-2.1hours	3.8-23.8hours
t½	5.4-5.7days	5.4-6.1days
CL	0.4L/day	18L/h
Vd	2.7L	—

FDA label §12.3 Drugs@FDA reviewhover a value for dose / population / source · “+N” marks additional reported values

Ocular & expression

Ocular profile & eye-tissue target expression

Target profile

OAE any-grade

11 %

OAE grade 3+

0.4 %

OAE data status

reported

Severity (weighted)

3.58

Keratopathy

Conjunctival

Dry eye

11 %

Blurred vision

3.5 %

Dominant tissue

Ocular surface

Surface subtype

Conjunctival (on-target)

Grading scale

Mixed

Reversibility

Reversible

Target expression in eye tissues (HCA detection · HPA bulk)

Cornea (central)

46.2 %

Cornea (limbal)

61.99 %

Conjunctiva

61.13 %

RPE

5.48 %

Retina (HPA)

7.5 nTPM

Cross-trial comparability · source-verified

Ascertainment: Symptom-driven reportingScale: MixedDenominator: RP2D⚠ Not comparable: symptom-driven ascertainment + mixed grading scale

Dose & schedule → ocular toxicity · keratopathy (any-grade) by cohort

5.4 mg/kg

IV q3w + pertuzumab

11%

n=381 · DESTINY-Breast09

5.4 mg/kg

IV q3w

11%

n=234 · DESTINY-Breast01 + Study DS8201-A-J101

5.4 mg/kg

11%

n=234

5.4 mg/kg

IV q3w

7.3%

n=41 · DESTINY-Lung01

5.4 mg/kg

IV q3w

6.5%

n=434 · DESTINY-Breast06

5.4 mg/kg

IV q3w

n=50 · DS8201-A-J101 (first-in-human)

5.4 mg/kg

IV q3w + ritonavir

5.9%

n=17 · DS8201-A-A104 (drug-drug interaction)

5.4 mg/kg

IV q3w

5.7%

n=404 · DESTINY-Breast02

5.4 mg/kg

IV q3w

5.3%

n=283 · DESTINY-Breast11

5.4 mg/kg

Q3W IV infusion

3.5%

n=257 · DESTINY-Breast03

5.4 mg/kg

IV q3w

0.8%

n=130 · DESTINY-Breast01

6.4 mg/kg

IV q3w

8.8%

n=91 · DESTINY-Lung01

6.4 mg/kg

IV q3w

8.3%

n=12 · DS8201 Phase 1 (HER2+ cancer)

6.4 mg/kg

IV q3w

7.6%

n=66 · DS8201-A-J101 (first-in-human)

6.4 mg/kg

IV q3w

3.9%

n=51 · DS8201-A-J102 (QT/QTc study)

5.4-6.4 mg/kg

IV q3w

1.7%

n=59 · DS8201-A-J101 (first-in-human)

6.4 mg/kg

IV q3w

0.8%

n=125 · DESTINY-Gastric01

Per-cohort rates from the per-trial extraction, sorted by dose. Cross-trial comparison is subject to ascertainment / scale differences (see comparability above) — e.g. an early symptom-driven trial can read lower than a later systematic-exam trial at a higher dose.

Ocular AE grading reference — interspecialty consensus · 6 scales + dose modification

Identity & registry

Identifiers, registry & notes

ADC id

trastuzumab-deruxtecan

Approval status

FDA-approved

Approval year

2019

UniProt

P04626

ADCdb ADC

DRG0ERKBH

ADCdb antibody

ANI0FIZAK

ADCdb target

TAR0THKZD

Primary source

ENHERTU PI (pooled DB01+J101, N=234)

Aliases & development codes

T-DXd; Enhertu; DS-8201a

Notes

V3.1: Dry eye 11 / G3 0.4 in pooled DB01+J101 (ENHERTU PI). G3+ corrected 0.5→0.4.