Datroway
datopotamab deruxtecan
Species
MonkeyRat
Longest study
13 wk
Genotox
Partial / alternative Partial / alternative
Carcinogenicity
Not conducted Not conducted
Repro
Partial / alternative Partial / alternative
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat (non-binding) and cynomolgus monkey (relevant); DXd payload in rat and monkey
“Though datopotamab deruxtecan did not bind rat Trop2 in an in vitro assay, the monkey is a pharmacologically relevant species considering datopotamab deruxtecan demonstrated similar binding to human and monkey Trop2.”
Why that species
Similar binding to human and monkey Trop2; weak to no binding to mouse and rat Trop2
“Datopotamab deruxtecan bound to human and monkey Trop2 similarly in an ELISA-based assay but demonstrated weak to no binding to mouse and rat Trop2.”
Surrogate molecule
No surrogate; clinical ADC in rat and monkey; DXd payload in GLP 1-month rat and monkey studies
“The toxicity of DXd was also evaluated in GLP-compliant 1-month repeat-dose toxicology studies in rats and monkeys.”
Species: general tox
Rat and cynomolgus monkey (3-month IV studies)
“In 3-month repeat-dose toxicology studies evaluating the safety of datopotamab deruxtecan administered intravenously, the intended route of administration, there were no mortalities at doses up to 200 mg/kg in rats or doses up to 80 mg/kg in monkeys.”
Species: DART
Not conducted (DXd is genotoxic and affects dividing cells)
“The Applicant did not conduct fertility or embryo-fetal development toxicology studies with datopotamab deruxtecan as DXd is genotoxic and affects actively dividing cells, and therefore, these studies are not warranted to support the proposed indication.”
Species: carcinogenicity
Not conducted
“Carcinogenicity studies are not warranted to support the current application.”
Surrogate used in
No surrogate used; cynomolgus monkey is a pharmacologically relevant species for the clinical ADC
“Given similar binding to human and monkey Trop2, the cynomolgus monkey is supported as a pharmacologically relevant species for datopotamab deruxtecan.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“Datopotamab deruxtecan was administered i.v. to cynomolgus monkeys at doses of 10, 30 or 80 mg/kg every three weeks on five occasions in a GLP-compliant 3-month toxicity study with a 2-month recovery period, no deaths or moribundity were noted up to 80 mg/kg.”
Pivotal GLP studies
GLP 3-month q3w IV: rat (20, 60, 200 mg/kg) and monkey (10, 30, 80 mg/kg), 2-month recovery; DXd 1-month rat and monkey
“Datopotamab deruxtecan was administered i.v. to cynomolgus monkeys at doses of 10, 30 or 80 mg/kg every three weeks on five occasions in a GLP-compliant 3-month toxicity study with a 2-month recovery period, no deaths or moribundity were noted up to 80 mg/kg.”
Route in tox
IV (clinical route)
“In 3-month repeat-dose toxicology studies evaluating the safety of datopotamab deruxtecan administered intravenously, the intended route of administration, there were no mortalities at doses up to 200 mg/kg in rats or doses up to 80 mg/kg in monkeys.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted with ADC; DXd Ames negative, clastogenic in vitro chromosome aberration and in vivo rat micronucleus
“In genetic toxicology studies, deruxtecan was not mutagenic in an Ames assay but demonstrated clastogenic potential in an in vitro Chinese hamster lung chromosome aberration assay and an in vivo rat bone marrow micronucleus assay.”
Carcinogenicity
Not conducted (not warranted, advanced cancer)
“Carcinogenicity studies are not warranted to support the current application.”
Reproductive & developmental
Not conducted (genotoxic payload); testis/ovary findings in rat; embryo-fetal toxicity warning
“The Applicant did not conduct fertility or embryo-fetal development toxicology studies with datopotamab deruxtecan as DXd is genotoxic and affects actively dividing cells, and therefore, these studies are not warranted to support the proposed indication.”
Safety pharmacology
Stand-alone monkey CV/respiratory/neuro study plus repeat-dose endpoints; DXd hERG negative up to 10 µM
“Datopotamab deruxtecan did not have significant effects on cardiovascular, respiratory, or neurobehavior in safety pharmacology studies in monkeys.”
Genotox: Ames
DXd payload: negative in Ames assay
“In genetic toxicology studies, deruxtecan was not mutagenic in an Ames assay but demonstrated clastogenic potential in an in vitro Chinese hamster lung chromosome aberration assay and an in vivo rat bone marrow micronucleus assay.”
Genotox: in vitro mammalian
DXd payload: positive (clastogenic) in Chinese hamster lung chromosome aberration assay
“In genetic toxicology studies, deruxtecan was not mutagenic in an Ames assay but demonstrated clastogenic potential in an in vitro Chinese hamster lung chromosome aberration assay and an in vivo rat bone marrow micronucleus assay.”
Genotox: in vivo
DXd payload: positive (clastogenic) in rat bone marrow micronucleus assay
“In genetic toxicology studies, deruxtecan was not mutagenic in an Ames assay but demonstrated clastogenic potential in an in vitro Chinese hamster lung chromosome aberration assay and an in vivo rat bone marrow micronucleus assay.”
Carcinogenicity model
Not conducted (not warranted for advanced cancer application)
“Carcinogenicity studies are not warranted to support the current application.”
Carcinogenicity timing
Not required: carcinogenicity studies not warranted for this application
“Carcinogenicity studies are not warranted to support the current application.”
hERG / QT
DXd: no hERG inhibition up to 10 µM
“In an in vitro hERG potassium channel assay, DXd did not inhibit hERG at concentrations up to 10 µM.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Datroway don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for ADCs
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”
This product's starting point
NOAEL / key findings: Monkey NOAEL 10 mg/kg for lung, cornea, skin, liver, thymus (intestinal toxicity at ≥10); rat NOAEL 20-60 mg/kg; ADA limits margins (FDA multi-discipline review, p. 66)
NOAEL / key findings
Monkey NOAEL 10 mg/kg for lung, cornea, skin, liver, thymus (intestinal toxicity at ≥10); rat NOAEL 20-60 mg/kg; ADA limits margins
“The NOAELs for pulmonary, corneal, dermal, hepatic, and lymphoid (thymic) toxicity was concluded to be 10 mg/kg.”
Risksopen answer page →
Immune & cytokine safety
ADA in 5/6 monkeys at 10 mg/kg reducing exposure; minimal in vitro cytokine release; transient CRP increases
“Five of 6 monkeys given 10 mg/kg showed ADA positive responses after the 3-month dosing period, and there was a reduction in Dato-DXd exposure after the 4th dose compared to the 1st dose.”
Biodistribution & persistence
14C-DXd rapid wide distribution without retention (highest intestine, bladder, kidney); low DXd release in plasma (≤6.5%); biliary/fecal excretion
“Tissues with the highest concentrations of radioactivity included the small and large intestines, urinary bladder, and kidney.”
Modality-specific risk
Interstitial lung disease (Trop2 in alveolar epithelium), ocular surface/corneal toxicity, GI and hematologic DXd payload toxicity
“Lung toxicity noted in monkeys is consistent with expression of Trop2 in the lung, and Trop2 staining was noted on the plasma membrane of the alveolar epithelium in humans and monkeys with similar frequency and intensity in a tissue-cross reactivity study.”
Anti-drug antibodies: animals
ADA in 5 of 6 monkeys at 10 mg/kg, reducing ADC exposure after the 4th dose
“Five of 6 monkeys given 10 mg/kg showed ADA positive responses after the 3-month dosing period, and there was a reduction in Dato-DXd exposure after the 4th dose compared to the 1st dose.”
Anti-drug antibodies: patients
17% (223/1333) ADA-positive; 17% of these neutralizing
“During the median 5.8-month treatment period across 6 clinical studies in patients with NSCLC or breast cancer who received DATROWAY 6 mg/kg once every 3 weeks, 17% (223 out of 1333) of patients developed anti-datopotamab deruxtecan-dlnk antibodies with 17% (37 out of 223) of these patients developing neutralizing antibodies against datopotamab deruxtecan-dlnk.”
Label warnings
- Interstitial Lung Disease/Pneumonitis
- Ocular Adverse Reactions
- Stomatitis
- Embryo-Fetal Toxicity
Immune-mediated reactionsPulmonary toxicityOcular toxicityGastrointestinalEmbryo-fetal toxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Datroway don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for ADCs
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”
This product's starting point
NOAEL / key findings: Monkey NOAEL 10 mg/kg for lung, cornea, skin, liver, thymus (intestinal toxicity at ≥10); rat NOAEL 20-60 mg/kg; ADA limits margins (FDA multi-discipline review, p. 66)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
3-month rat and cynomolgus monkey IV studies (every 3 weeks, five doses) with 2-month recovery
“To assess the general toxicity profile, 3-month intermittent intravenous dose toxicity studies (every 3 weeks (Q3W), five times in total) in rats and monkeys were conducted. The reversibility of toxic changes was also evaluated following a 2-month recovery period in the intermittent dose toxicity studies.”
Pivotal GLP studies
GLP 3-month q3w IV: rat (20, 60, 200 mg/kg) and monkey (10, 30, 80 mg/kg), 2-month recovery; DXd 1-month rat and monkey
“Datopotamab deruxtecan was administered i.v. to cynomolgus monkeys at doses of 10, 30 or 80 mg/kg every three weeks on five occasions in a GLP-compliant 3-month toxicity study with a 2-month recovery period, no deaths or moribundity were noted up to 80 mg/kg.”
DART package
Species: DART
Not conducted (DXd is genotoxic and affects dividing cells)
“The Applicant did not conduct fertility or embryo-fetal development toxicology studies with datopotamab deruxtecan as DXd is genotoxic and affects actively dividing cells, and therefore, these studies are not warranted to support the proposed indication.”
Reproductive & developmental
Not conducted (genotoxic payload); testis/ovary findings in rat; embryo-fetal toxicity warning
“The Applicant did not conduct fertility or embryo-fetal development toxicology studies with datopotamab deruxtecan as DXd is genotoxic and affects actively dividing cells, and therefore, these studies are not warranted to support the proposed indication.”
PPND / ePPND: when
PPND not conducted (ICH S9)
“In accordance with ICH guideline S9 no prenatal and postnatal development, including maternal function studies were conducted.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Carcinogenicity studies are not warranted to support the current application.”
Carcinogenicity model
Not conducted (not warranted for advanced cancer application)
“Carcinogenicity studies are not warranted to support the current application.”
Carcinogenicity timing
Not required: carcinogenicity studies not warranted for this application
“Carcinogenicity studies are not warranted to support the current application.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey NOAEL 10 mg/kg (lung, cornea, skin, liver, thymus): margin of exposure 0.25 (below human exposure)
“The NOAEL for pulmonary, corneal, dermal, hepatic and lymphoid (thymic) toxicity was concluded to be 10 mg/kg corresponding to a margin of exposure of 0.25.”
NOAEL / key findings
Monkey NOAEL 10 mg/kg for lung, cornea, skin, liver, thymus (intestinal toxicity at ≥10); rat NOAEL 20-60 mg/kg; ADA limits margins
“The NOAELs for pulmonary, corneal, dermal, hepatic, and lymphoid (thymic) toxicity was concluded to be 10 mg/kg.”
Efficacy evidenceopen answer page →
Efficacy evidence
Nude mouse xenografts of human pancreatic cancer, NSCLC and breast cancer
“Four in vivo studies were performed with datopotamab deruxtecan (Dato-DXd) administered intravenously to nude mouse xenograft models of human pancreatic cancer, non-small cell lung cancer (NSCLC) and breast cancer, with the two latter being in line with the sought indications.”
Why that model
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Reviewer's view of the efficacy data
EMA: adequate evidence of anti-tumour activity in Trop2-positive models in vitro and in vivo
“Overall, the primary pharmacodynamic studies provided adequate evidence that datopotamab deruxtecan showed anti-tumour activity against TROP2 positive cancer models in vitro and in vivo.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted
No fertility, embryo-fetal or pre- and postnatal development studies; fertility assessed from repeat-dose studies
Why: Payload DXd is genotoxic and toxic to actively dividing cells · Within the guideline · Pharmacology or kinetics
“The Applicant did not conduct fertility or embryo-fetal development toxicology studies with datopotamab deruxtecan as DXd is genotoxic and affects actively dividing cells, and therefore, these studies are not warranted to support the proposed indication.”
“The FDA agrees with the Applicant’s conclusions. Because DXd is genotoxic and is toxic to actively dividing cells, reproductive toxicology studies are not warranted to support this application.”
Safety marginAccepted
Monkey NOAEL for lung, cornea, skin, liver and thymus toxicity gave a margin of exposure of 0.25; no margin for intestinal toxicity
Why: Sought indication is within the scope of ICH S9 · Within the guideline · Serious disease
“In monkeys, slight intestinal toxicity was observed at ≥10 mg/kg, and no exposure margin was determined (margin of exposure <0.25). The NOAEL for pulmonary, corneal, dermal, hepatic and lymphoid (thymic) toxicity was concluded to be 10 mg/kg corresponding to a margin of exposure of 0.25.”
“Considering the sought indication low margins of exposure are acceptable and within the scope of the ICH guideline S9.”
Safety pharmacologyAcceptedBeyond the letter
Safety pharmacology study in male monkeys only
Why: No significant gender differences in exposure or target organs of toxicity · Pharmacology or kinetics
“Only male monkeys were used in the safety pharmacology study; however, this was sufficiently justified and supported by a lack of significant gender differences in exposure or target organs of toxicity.”
Similar precedents
TrodelvyADCs · sacituzumab govitecan · Trop-2Monkey + rodent · 13 wkAdcetrisADCs · brentuximab vedotin · CD30Monkey + rodent · 26 wkBesponsaADCs · inotuzumab ozogamicin · CD22Monkey + rodent · 26 wkDecnupazADCs · pivekimab sunirine · CD123Monkey + rodent · 13 wkElahereADCs · mirvetuximab soravtansine · FRαMonkey + rodent · 10 wkEmrelisADCs · telisotuzumab vedotin · c-MetMonkey + rodent · 13 wk