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Trastuzumab emtansine

FDA-approved
T-DM1; Kadcyla
Sponsor
Genentech/Roche
Indication
HER2+ breast cancer
Target family
Receptor tyrosine kinase
RP2D dose
3.6 mg/kg
Q3WRP2D
01
Multi-organ toxicity

Fingerprint & organ drill-down

Also reported
0%severity100%
0
Assessed · clear
true 0%
No data
never assessed
85 adverse-event terms

Ocular

Any-grade
5%
G3+
0%
RP2D
sagittal schematic · Reversible
↳

Tissues shaded by reported adverse-event rate.

Cornea
AE
-
Express.
46.2%
Limbus
AE
-
Express.
61.99%
Conjunctiva
AE
3.9%
Express.
61.13%
Lens
AE
-
Express.
-
Retina / RPE
AE
-
Express.
5.48%
7.5 nTPM
Dominant tissue
Ocular surface
Surface subtype
Conjunctival (on-target)
Reversibility
Reversible
Reported ocular events
Watering eyes28.83%
non-seriousn=111
Eye disorders26.67%
non-seriousn=15
Blurred vision24.32%
non-seriousn=111
Blurred Vision23.53%
non-seriousn=17
Floaters13.51%
non-seriousn=111
Decreased Peripheral dcreased10%
non-seriousn=10
Decreased Peropheral Vision10%
non-seriousn=10
Eyelid function disorder10%
non-seriousn=10
Visual symptoms - only when she is tired10%
non-seriousn=10
decreased peripheral vision after sugery10%
non-seriousn=10
decreased peripheral vision after surgery10%
non-seriousn=10
decreased peripheral vision after the 2/8 surgery10%
non-seriousn=10
decreased peripheral vision after the surger10%
non-seriousn=10
decreased peripheral vision after the surgery10%
non-seriousn=10
dicreased peripheral vision10%
non-seriousn=10
hyperropia10%
non-seriousn=10
intermittent blurry eye when reads for long time10%
non-seriousn=10
shaking of eyes during C4 infusion10%
non-seriousn=10
shaking of eyes during trastuzumab emtansine infusion10%
non-seriousn=10
shaking of eyes during trastuzumab emtansive10%
non-seriousn=10
stye10%
non-seriousn=10
whipple in the left eye10%
non-seriousn=10
L upper eyelid ptosis10%
non-seriousn=10
Decreased Peripheral Vision10%
non-seriousn=10
Decreased Peripherla Vision10%
non-seriousn=10
Visual Symptoms10%
non-seriousn=10
intermittent blurry eye10%
non-seriousn=10
photosensitivity10%
non-seriousn=10
tired eyes - when reads for a long time10%
non-seriousn=10
visual symptoms - only when tired10%
non-seriousn=10
Keratitis8.33%
non-seriousn=12
Eye disorders - Other, Diplopia8.33%
non-seriousn=12
Eye disorders - Other, L eye twitching8.33%
non-seriousn=12
Eye disorders - Other, Red/tenderness. L eye8.33%
non-seriousn=12
Eye disorders - Other, Twitchy Eye-bilateral8.33%
non-seriousn=12
Eye disorders - Other, sunburn to eyes8.33%
non-seriousn=12
Eye disorders - Other, specify8.11%
non-seriousn=111
Flashing lights6.31%
non-seriousn=111
Lacrimation increased6%
pooledn=138
Dry Eye5.88%
non-seriousn=17
Dry eye4.5%
pooledn=1233
Eye disorders - Other4.23%
non-seriousn=497
Xerophthalmia4.08%
non-seriousn=98
Vision Blurred4.03%
non-seriousn=719
Vision blurred3.9%
pooledn=138
Eye disorder3.85%
non-seriousn=52
LACRIMATION INCREASED3.7%
non-seriousn=1460
Visual impairment3.62%
poolednon-seriousn=138
Conjunctivitis3.5%
pooledn=138
Blepharospasm3.06%
non-seriousn=98
Conjunctival oedema3.06%
non-seriousn=98
Photophobia2.9%
poolednon-seriousn=138
Eye infection2.17%
poolednon-seriousn=138
Conjunctival haemorrhage2.04%
non-seriousn=98
Visual acuity reduced2.04%
non-seriousn=98
Lacrimation decreased2.04%
non-seriousn=49
Conjunctivitis infective1.41%
poolednon-seriousn=71
Diplopia1.41%
poolednon-seriousn=71
Ocular hyperaemia1.12%
non-seriousn=178
Dacryostenosis acquired1.02%
non-seriousn=98
Eyelids pruritus1.02%
non-seriousn=98
Eye pain0.9%
non-seriousn=111
Cataract0.9%
non-seriousn=111
Eye haemorrhage0.56%
non-seriousn=178
Blindness0.56%
non-seriousn=178
Pterygium0.56%
non-seriousn=178
Retinal ischaemia0.56%
non-seriousn=178
Eye contusion0.56%
non-seriousn=178
Eye discharge0.22%
seriousn=451
Meibomianitis0.22%
seriousn=451
Retinal detachment0.2%
non-seriousn=497
Retinal tear0.2%
non-seriousn=497
Retinal vascular disorder0.2%
non-seriousn=497
Visual field defect0.2%
seriousn=497
Rhegmatogenous retinal detachment0.19%
seriousn=518
Chorioretinitis0.14%
seriousn=719
VISION BLURRED0.07%
seriousn=1460
BLINDNESS0.05%
seriousn=2183
RETINAL VEIN THROMBOSIS0.05%
seriousn=2183
CATARACT0.05%
seriousn=2183
Macular hole0%
seriousn=719
Blindness transient0%
seriousn=719
Ocular hypertension0%
seriousn=719
Radiation retinopathy0%
seriousn=719
Periorbital oedema0%
non-seriousn=67
Per-trial detail

Adverse events by trial

A Study of Trastuzumab Emtansine in Participants With Human Epidermal Growth FacPHASE3real-worldn=2183CTCAE NR (ClinicalTrials.govPooledC
ClinicalTrials.gov NCT01702571 posted results, adverse events module (non-serious; 200/2183 pooled across arms)
402 adverse-event terms · 22 systems · expand a system below
Infections70
URINARY TRACT INFECTION
7.38%non-serious
161/2183
NASOPHARYNGITIS
6.6%non-serious
144/2183
Respiratory tract infection
6.12%non-serious
134/2183
Urinary tract infection
6.12%non-serious
134/2183
UPPER RESPIRATORY TRACT INFECTION
4.31%non-serious
94/2183
Pneumonia
4.08%non-serious
89/2183
Bronchitis
2.04%serious
45/2183
Lower respiratory tract infection
2.04%serious
45/2183
Lung infection
2.04%serious
45/2183
Influenza
2.04%serious
45/2183
Paronychia
2.04%non-serious
45/2183
Viral Upper Respiratory Tract Infection
2.04%non-serious
45/2183
PNEUMONIA
1.37%serious
30/2183
LOWER RESPIRATORY TRACT INFECTION
0.41%serious
9/2183
SEPSIS
0.41%serious
9/2183
CELLULITIS
0.37%serious
8/2183
DEVICE RELATED INFECTION
0.27%serious
6/2183
ERYSIPELAS
0.18%serious
4/2183
BRONCHITIS
0.14%serious
3/2183
INFECTION
0.14%serious
3/2183
OTITIS MEDIA
0.14%serious
3/2183
VASCULAR DEVICE INFECTION
0.14%serious
3/2183
BREAST CELLULITIS
0.09%serious
2/2183
ENDOCARDITIS
0.09%serious
2/2183
GASTROENTERITIS
0.09%serious
2/2183
HERPES ZOSTER
0.09%serious
2/2183
MASTITIS
0.09%serious
2/2183
PERITONITIS
0.09%serious
2/2183
PHARYNGITIS
0.09%serious
2/2183
PYELONEPHRITIS
0.09%serious
2/2183
STAPHYLOCOCCAL INFECTION
0.09%serious
2/2183
STAPHYLOCOCCAL SEPSIS
0.09%serious
2/2183
ABSCESS
0.05%serious
1/2183
ACINETOBACTER INFECTION
0.05%serious
1/2183
ARTHRITIS INFECTIVE
0.05%serious
1/2183
BACTERAEMIA
0.05%serious
1/2183
BACTERIAL INFECTION
0.05%serious
1/2183
BACTERIAL SEPSIS
0.05%serious
1/2183
BRAIN ABSCESS
0.05%serious
1/2183
CATHETER SITE INFECTION
0.05%serious
1/2183
CLOSTRIDIUM DIFFICILE COLITIS
0.05%serious
1/2183
CYSTITIS
0.05%serious
1/2183
ENCEPHALITIS
0.05%serious
1/2183
GASTROENTERITIS NOROVIRUS
0.05%serious
1/2183
GASTROENTERITIS VIRAL
0.05%serious
1/2183
GASTROINTESTINAL VIRAL INFECTION
0.05%serious
1/2183
INFECTIOUS PLEURAL EFFUSION
0.05%serious
1/2183
INFECTIVE EXACERBATION OF BRONCHIECTASIS
0.05%serious
1/2183
INTERVERTEBRAL DISCITIS
0.05%serious
1/2183
KLEBSIELLA BACTERAEMIA
0.05%serious
1/2183
LISTERIOSIS
0.05%serious
1/2183
LIVER ABSCESS
0.05%serious
1/2183
MENINGITIS
0.05%serious
1/2183
PNEUMOCOCCAL INFECTION
0.05%serious
1/2183
PNEUMONIA STREPTOCOCCAL
0.05%serious
1/2183
PNEUMONIA VIRAL
0.05%serious
1/2183
PYELONEPHRITIS ACUTE
0.05%serious
1/2183
PYELONEPHRITIS CHRONIC
0.05%serious
1/2183
RESPIRATORY TRACT INFECTION
0.05%serious
1/2183
RESPIRATORY TRACT INFECTION VIRAL
0.05%serious
1/2183
SEPTIC SHOCK
0.05%serious
1/2183
SKIN INFECTION
0.05%serious
1/2183
SOFT TISSUE INFECTION
0.05%serious
1/2183
STAPHYLOCOCCAL BACTERAEMIA
0.05%serious
1/2183
STREPTOCOCCAL INFECTION
0.05%serious
1/2183
TRACHEOBRONCHITIS
0.05%serious
1/2183
VIRAL INFECTION
0.05%serious
1/2183
VIRAL UPPER RESPIRATORY TRACT INFECTION
0.05%serious
1/2183
VULVAL ABSCESS
0.05%serious
1/2183
DENGUE HAEMORRHAGIC FEVER
0.05%serious
1/2183
GI50
Neurologic (other)33
Pulmonary33
General28
Injury28
Musculoskeletal26
Investigations21
Metabolic15
Neoplasms12
Other12
Hepatic11
Psychiatric11
Cardiac10
Hematologic9
Dermatologic9
Vascular9
Renal7
Ocular3
BLINDNESS
0.05%serious
1/2183
RETINAL VEIN THROMBOSIS
0.05%serious
1/2183
CATARACT
0.05%serious
1/2183
Endocrine2
Immune2
Ear1
02
Construct

Molecular anatomy

Antibody
IgG1
Humanized
Linker
Non-cleavable
Non-cleavable
3.5
DAR
Payload
Lys-SMCC-DM1
Tubulin inhibitor
Linker structureC16H18N2O6
[H]C1=C([H])C(=O)N(C([H])([H])C2([H])C([H])([H])C([H])([H])C([H])(C(=O)ON3C(=O)C([H])([H])C([H])([H])C3=O)C([H])([H])C2([H])[H])C1=O
Payload structureC53H75ClN6O15S
CC1C2CC(C(C=CC=C(CC3=CC(=C(C(=C3)OC)Cl)N(C(=O)CC(C4(C1O4)C)OC(=O)C(C)N(C)C(=O)CCSC5CC(=O)N(C5=O)CC6CCC(CC6)C(=O)NCCCCC(C(=O)O)N)C)C)OC)(NC(=O)O2)O
03
Antibody

Antibody & Fc engineering

Antibody
trastuzumab
Isotype
IgG1
Origin
Humanized
Fc modifications
Noneinferred
Glycoengineering
Standardinferred
Effector silencing
Noneinferred
FcγR binding
Retained
C1q binding
Retainedinferred
Target KD (nM)
0.5
Epitope / domain
HER2 extracellular subdomain IV
04
Linker & conjugation

Linker chemistry

Linker profile
Linker
SMCC
Class
Non-cleavable
Cleavage
Non-cleavable
Attachment
Lysine
Conjugation
Conventional Lys (SMCC)
Symmetry
Asymmetric
DAR (mean)
3.5
DAR homogeneity
Heterogeneous
Plasma t½
4.0 d
Cleavage trigger
Non-cleavable
Release control
Unconditional
Hydrophilicity mask
Noneinferred
Platform
Random lysine amine conjugationunver.
Conjugation site
92 possible sites
DAR distribution
DAR0-8 mixture, average 3.53 +/- 0.05 by intact MS
%HMW aggregate
1.64 %
Formula
C16H18N2O6
Linker MW
334.328 Da
Linker TPSA
101.06 Ų
Linker xLogP
0.325
ADCdb linker
LIN0EBJON
In-vitro stability
-
Stability note
acAb t½ 3.94 d; SMCC is the highest intrinsic plasma stability among clinical linkers — non-cleavable thioether to charged Lys-MCC-DM1 catabolite (no bystander); deconjugation is not a significant pathway
05
Payload

Payload & physicochemistry

Payload profile
Payload
Lys-SMCC-DM1
Class
Maytansinoid
Mechanism
Tubulin inhibitor
Released catabolite
Lys-MCC-DM1 (lysine-Nε-MCC-DM1; = Lys-SMCC-DM1 in literature), the principal charged catabolite; MCC-DM1 and free DM1 also detected at low levels in plasma
Mechanistic subtype
Tubulin-maytansinoid
Stereochem / salt
Free thiol maytansinoid; neutralunver.
Bystander
No
PAMPA rank
5
MW
1103.7 Da
XLogP3
-0.2
logD₇.₄
-0.5
TPSA
312 Ų
pKa
2.2 pKa
Charge pH 7.4
Zwitterion
H-bond donors
5
H-bond acceptors
17
IC50 (HCEC)
-
Formula
C53H75ClN6O15S
PubChem CID
74832310
ADCdb payload
PAY0JCIBW
Potency IC50 (nM)
1
Hydrophobicity · logD₇.₄
hydrophilic −2-0.5+4 lipophilic
Bioactivity note
ADCdb lists T-DM1 cellular IC50 values spanning ~0.04 nM (high HER2-expressing lines) to >500 nM (low/negative HER2 lines), HER2-expression dependent. No isolated free-payload (DM1) IC50 is given on the ADCdb ADC page; DM1 is a potent antimitotic maytansinoid that inhibits tubuli
06
Dosing & regimen

Dosing

RP2D dose
3.6 mg/kg
Schedule
Q3W
Route
IV
Fractionated
No
n at RP2D
490
Dose basis
TBW
Trial phase
Approved
Dose-OAE available
No
Tox summary basis
RP2D
ADA rate (%)
5.3 %
07
Pharmacology

Clinical pharmacokinetics

By analyte · FDA label §12.3 + Drugs@FDA clinical-pharmacology reviews
Intact ADCTotal antibodyFree payload
Cmax
83.4ug/mL+1
86.3ug/mL
4.61ng/mL+1
AUC
489ug*day/mL
816ug*day/mL
9.11ng*day/mL
Tmax
end of infusionh
—
end of infusionh
t½
~4days
7.8days
—
CL
0.68L/day
5.4mL/day/kg
—
Vd
3.13L
45.2mL/kg
—
FDA label §12.3 Drugs@FDA reviewhover a value for dose / population / source · “+N” marks additional reported values
08
Ocular & expression

Ocular profile & eye-tissue target expression

Target profile
OAE any-grade
5 %
OAE grade 3+
0 %
OAE data status
reported
Severity (weighted)
1.5
Keratopathy
-
Conjunctival
3.9 %
Dry eye
3.9 %
Blurred vision
4.5 %
Dominant tissue
Ocular surface
Surface subtype
Conjunctival (on-target)
Grading scale
CTCAE v3.0
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: CTCAE v3Denominator: RP2D
Dose & schedule → ocular toxicity · keratopathy (any-grade) by cohort
2.4 mg/kg
weekly
18.75%
n=16 · First-in-human Ph1
3.6 mg/kg
q3w
11.76%
n=51 · T-DM1 QT study
3.6 mg/kg
q3w
11.49%
n=383 · ATEMPT
3.6 mg/kg
q3w
9.82%
n=112 · TDM4374g
3.6 mg/kg
q3w
8.7%
n=69 · TDM4450g/BO21976
3.6 mg/kg
q3w
8.22%
n=912 · KAITLIN
3.6 mg/kg
q3w
8.18%
n=110 · TDM4258g
3.6 mg/kg
q3w
7.81%
n=64 · T-DM1+pertuzumab Ph1b/2
3.6 mg/kg
q3w
7.17%
n=223 · KRISTINE (TRIO-021)
3.6 mg/kg
q3w
6.93%
n=361 · MARIANNE
3.6 mg/kg
q3w
6.67%
n=15 · First-in-human Ph1
3.6 mg/kg
q3w
6.08%
n=148 · T-DM1 Ph2
3.6 mg/kg
Q3W
6%
n=740 · KATHERINE
3.6 mg/kg
Q3W
4.5%
n=490 · EMILIA
3.6 mg/kg
q3w
0.25%
n=403 · TH3RESA (TDM4997g/BO25734)
3.6 mg/kg
q3w
0.14%
n=740 · KATHERINE (BO27938)
3.6 mg/kg
q3w
0.05%
n=2002 · KAMILLA (TDM4529g/BO28407)
—
39.8%
n=98 · A Study of Trastuzumab Emtansine (T-DM1) in Combination With Docetaxel, and Pote
—
28.99%
n=138 · A Study of Trastuzumab Emtansine, Paclitaxel, and Pertuzumab in Patients With HE
—
28.83%
n=111 · ATOP TRIAL: T-DM1 in HER2 Positive Breast Cancer
—
26.67%
n=15 · THELMA
—
23.53%
n=17 · BYL719 + T-DM1 in HER2(+) Metastatic Breast Cancer Pts Who Progress on Prior Tra
—
16.67%
n=24 · An Open-Label, Phase Ib/II Clinical Trial Of Cdk 4/6 Inhibitor, Ribociclib (Lee0
—
15%
n=20 · A Study Of Pembrolizumab In Combination With Trastuzumab-DM1
—
13.33%
n=135 · A Study of the Efficacy and Safety of Trastuzumab Emtansine (Trastuzumab-MCC-DM1
—
11.36%
n=44 · HKI-272 for HER2-Positive Breast Cancer and Brain Metastases
—
11.11%
n=18 · 4-1BB Agonist Monoclonal Antibody PF-05082566 With Trastuzumab Emtansine or Tras
—
10.39%
n=231 · A Study of Tucatinib vs. Placebo in Combination With Ado-trastuzumab Emtansine (
—
10.07%
n=1838 · A Study of Trastuzumab Emtansine (Kadcyla) Plus Pertuzumab (Perjeta) Following A
—
10%
n=10 · Copper Cu 64-DOTA-Trastuzumab PET in Predicting Response to Treatment With Ado-T
—
9.86%
n=497 · T-DM1 vs Paclitaxel/Trastuzumab for Breast (ATEMPT Trial)
—
9.86%
n=71 · Corrected QT Interval Effects of Trastuzumab Emtansine (T-DM1) in Patients With
—
9.32%
n=719 · A Study of Trastuzumab Emtansine (T-DM1) Plus Pertuzumab/Pertuzumab Placebo Vers
—
8.96%
n=67 · A Study of Trastuzumab Emtansine (Trastuzumab-MCC-DM1, T-DM1) in Combination Wit
—
8.33%
n=12 · T-DM1 Alone Versus T-DM1 and Metronomic Temozolomide in Secondary Prevention of
—
8.27%
n=133 · KATE2
—
6.87%
n=451 · IMpassion050
—
6.79%
n=442 · A Study Evaluating Trastuzumab Emtansine Plus Pertuzumab Compared With Chemother
—
5%
n=20 · KAMELEON
—
4.48%
n=67 · MyTACTIC
—
3.85%
n=52 · T-DM1
—
3.7%
n=1460 · A Study of Trastuzumab Emtansine Versus Trastuzumab as Adjuvant Therapy in Patie
—
2.04%
n=49 · A Study to Evaluate the Efficacy and Safety of Trastuzumab Emtansine Versus the
—
1.62%
n=1233 · ProHer
—
1.12%
n=626 · EMILIA
—
1.01%
n=497 · TH3RESA
—
0.56%
n=178 · TRAXHER2
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
09
Identity & registry

Identifiers, registry & notes

ADC id
trastuzumab-emtansine
Approval status
FDA-approved
Approval year
2013
UniProt
P04626
ADCdb ADC
DRG0CYMEB
ADCdb antibody
ANI0FIZAK
ADCdb target
TAR0THKZD
Primary source
KADCYLA DailyMed label; EMILIA NEJM 2012
Aliases & development codes
T-DM1; Kadcyla
Notes
V3.1: Non-cleavable SMCC + charged Lys-MCC-DM1 catabolite → no bystander → low OAE despite high HER2 cornea expression. oae_any_pct=5.0 is DERIVED (sum of decomposed AEs); label gives individual Eye AEs only: conjunctivitis 3.9%, dry eye 3.9%, blurred vision 4.5%, lacrimation 3.3%. oae_g3plus_pct=0 derived (G3-4 not separately specified).