Adcetris
brentuximab vedotin · CD30Conducted on MMAE: Ames and mouse lymphoma negative; rat micronucleus positive (aneugenic)
Tivdak: genotox, carcinogenicity and repro: done or skipped?
tisotumab vedotin · Tissue factor
Genotoxicity
Not conducted with ADC; MMAE: Ames and mouse lymphoma negative, rat micronucleus positive (aneugenic)
“Genetic toxicology studies were not conducted with tisotumab vedotin; rather, the applicant submitted studies that evaluated the payload.”
Carcinogenicity
Not conducted (ICH S9)
“Carcinogenicity studies were not conducted with tisotumab vedotin in accordance with ICH S9 guidance.”
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 with ADC (ICH S9); MMAE rat EFD teratogenic/embryolethal; male repro toxicity in monkey
“MMAE was teratogenic and embryo lethal when administered to pregnant rats via two intravenous doses of 0.2 mg/kg during the period of organogenesis on gestational days 6 and 13.”
Safety pharmacology
Incorporated into repeat-dose monkey studies (ICH S9); MMAE hERG in vitro
“Additionally, safety pharmacology endpoints for tisotumab vedotin representative of the cardiovascular (ECG and heart rate), central nervous (cageside observations) and respiratory systems (breaths per minute) were assessed as part of the repeat-dose toxicity studies as outlined in ICH S9 guideline.”
Genotox: Ames
MMAE: negative in Ames assay
“MMAE was not mutagenic in the bacterial reverse mutation (Ames) assay or the L5178 TK +/- mouse lymphoma forward mutation assay.”
Genotox: in vitro mammalian
MMAE: negative in L5178Y TK+/- mouse lymphoma forward mutation assay
“MMAE was not mutagenic in the bacterial reverse mutation (Ames) assay or the L5178 TK +/- mouse lymphoma forward mutation assay.”
Genotox: in vivo
MMAE: positive in rat bone marrow micronucleus (aneugenic)
“MMAE was positive for genotoxicity in the in vivo rat bone marrow micronucleus study through an aneugenic mechanism.”
Carcinogenicity model
Not conducted (ICH S9)
“Carcinogenicity studies were not conducted with tisotumab vedotin in accordance with ICH S9 guidance.”
Carcinogenicity timing
Not required for advanced cancer (ICH S9); FDA agreed
“The FDA agrees with the Applicant’s position; carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer in accordance with ICH S9.”
hERG / QT
ADC not tested; MMAE <50% hERG inhibition up to 100 µM
“In vitro inhibition of the hERG channel was not evaluated with tisotumab vedotin; however, up to 100 µM MMAE had limited (<50%) inhibition on hERG potassium channel.”
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
Enhertu
fam-trastuzumab deruxtecan · HER2Not conducted with ADC; DXd clastogenic (rat micronucleus, CHL chromosome aberration), Ames 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)
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)