Adcetris
brentuximab vedotin · CD30Conducted on MMAE: Ames and mouse lymphoma negative; rat micronucleus positive (aneugenic)
Enhertu: genotox, carcinogenicity and repro: done or skipped?
fam-trastuzumab deruxtecan · HER2
Genotoxicity
Not conducted with ADC; DXd clastogenic (rat micronucleus, CHL chromosome aberration), Ames negative
“MAAA-1181a was clastogenic in both an in vivo rat bone marrow micronucleus assay and an in vitro Chinese hamster lung chromosome aberration assay but was not mutagenic in an in vitro bacterial reverse mutation assay.”
Carcinogenicity
Not conducted (not warranted for indication; ICH S9)
“Carcinogenicity studies are not warranted to support the licensing application of fam-trastuzumab deruxtecan-nxki for the proposed indication.”
Instead of carcinogenicity
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.
Instead of genotoxicity
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.
DRG histopathology
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.
Reproductive & developmental
Not conducted (ICH S9: genotoxic payload, HER2 antibody oligohydramnios); fertility assessed from repeat-dose testis findings
“The Applicant did not conduct any reproductive toxicology studies with DS-8201a.”
Safety pharmacology
Standalone telemetered monkey CV/respiratory/CNS study (no effects) plus DXd hERG; QTc prolongation in one monkey in repeat-dose
“In a safety pharmacology study, DS-8201a did not have any significant effects on blood pressure, heart rate, ECG parameters, body temperature, or neurobehavioral function in conscious and unrestrained telemetered male cynomolgus monkeys following a single 78.8 mg/kg dose.”
Genotox: Ames
DXd payload: negative (bacterial reverse mutation)
“DXd, was clastogenic in both an in vivo rat bone marrow micronucleus assay and an in vitro Chinese hamster lung chromosome aberration assay and was not mutagenic in an in vitro bacterial reverse mutation assay.”
Genotox: in vitro mammalian
DXd payload: positive (clastogenic) in Chinese hamster lung chromosome aberration assay
“DXd, was clastogenic in both an in vivo rat bone marrow micronucleus assay and an in vitro Chinese hamster lung chromosome aberration assay and was not mutagenic in an in vitro bacterial reverse mutation assay.”
Genotox: in vivo
DXd payload: positive (clastogenic) in rat bone marrow micronucleus assay
“DXd, was clastogenic in both an in vivo rat bone marrow micronucleus assay and an in vitro Chinese hamster lung chromosome aberration assay and was not mutagenic in an in vitro bacterial reverse mutation assay.”
Carcinogenicity model
Not conducted (ICH S9, advanced cancer indication)
“Carcinogenicity studies have not been conducted with trastuzumab deruxtecan. This is, according to the ICH S9 guideline, not needed for advanced cancer indications, which the current MAA proposed indication indeed is considered to be.”
Carcinogenicity timing
Not required: FDA agreed carcinogenicity studies not needed
“FDA agrees that carcinogenicity studies are not needed to support this BLA submission.”
hERG / QT
DXd: no hERG current inhibition up to 10 µM (IC50 >10 µM)
“In vitro, MAAA-1181a did not have any effects on the hERG channel current up to 10 µmol/L (IC50 > 10 µM).”
Same question, other ADCs
Besponsa
inotuzumab ozogamicin · CD22Conducted: calicheamicin positive in Ames and in vitro micronucleus; ADC clastogenic in mouse micronucleus
Datroway
datopotamab deruxtecan · Trop-2Not conducted with ADC; DXd Ames negative, clastogenic in vitro chromosome aberration and in vivo rat micronucleus
Decnupaz
pivekimab sunirine · CD123Not conducted with ADC (ICH S9); FGN849 positive in Ames TA102, in vitro and in vivo micronucleus
Elahere
mirvetuximab soravtansine · FRαNot conducted with ADC; DM4 and S-methyl-DM4 Ames negative, rat bone marrow micronucleus positive
Emrelis
telisotuzumab vedotin · c-MetNot conducted with ADC; MMAE aneugenic (positive rat micronucleus), Ames and mouse lymphoma negative
Kadcyla
ado-trastuzumab emtansine · HER2Conducted on DM1: Ames negative; rat micronucleus positive (aneugenic/clastogenic); monkey micronucleus inconclusive
Mylotarg
gemtuzumab ozogamicin · CD33Conducted: ADC clastogenic in mouse micronucleus; free calicheamicin DMH mutagenic and clastogenic in vitro
Padcev
enfortumab vedotin · Nectin-4Not conducted with ADC; MMAE Ames and mouse lymphoma negative, rat micronucleus positive (aneugenic)
Polivy
polatuzumab vedotin · CD79bNot conducted with ADC; MMAE Ames and mouse lymphoma negative, rat micronucleus positive (aneugenic)
Tivdak
tisotumab vedotin · Tissue factorNot conducted with ADC; MMAE: Ames and mouse lymphoma negative, rat micronucleus positive (aneugenic)
Trodelvy
sacituzumab govitecan · Trop-2Not conducted with ADC; SN-38 Ames negative, in vitro micronucleus positive (clastogenic)
Zynlonta
loncastuximab tesirine · CD19Not conducted with ADC; SG3199 clastogenic in vitro (micronucleus, chromosome aberration); Ames not assessable (cytotoxicity)