Lumakras: genotox, carcinogenicity and repro: done or skipped?

“Though both sotorasib and the M24 metabolite showed some potential for induction of micronuclei in vitro, neither was mutagenic in in vitro bacterial reverse mutation (Ames) assays and sotorasib was not genotoxic in the in vivo erythrocyte micronucleus test and alkaline comet assay in rats.”

“The Applicant did not conduct carcinogenicity or fertility studies to support the currently proposed indication (NSCLC), and these studies are not needed to support a marketing application for a drug intended to treat patients with advanced cancer.”

“In rat and rabbit embryo-fetal development studies, oral sotorasib did not cause adverse developmental effects or embryo-lethality at exposures up to 4.6 times the human exposure at the 960 mg clinical dose”

“The sotorasib hERG IC50 was 54.8 µM (Study 150431); no clinically significant interaction with the hERG channel is expected over the proposed clinical dose range. In vivo, sotorasib at doses up to 300 mg/kg did not result in changes to qualitative ECG, quantitative ECG, or haemodynamic parameters”

“Sotorasib was negative for genotoxicity in the GLP bacterial mutation assay (Study 150436) and the combined in vivo mammalian erythrocyte micronucleus test and alkaline comet assay in the rat (Study 150435).”

“Although sotorasib was positive for the induction of micronuclei in this exploratory in vitro assay, sotorasib was negative for genotoxicity in the GLP in vitro Ames assay (Study #150436)”

“Sotorasib was negative for genotoxicity in the GLP bacterial mutation assay (Study 150436) and the combined in vivo mammalian erythrocyte micronucleus test and alkaline comet assay in the rat (Study 150435).”

“FDA agrees that carcinogenicity studies are not needed to support the use of sotorasib in the currently proposed indication per ICH S9.”

“FDA agrees that carcinogenicity studies are not needed to support the use of sotorasib in the currently proposed indication per ICH S9.”

“The IC50 value of 54.8 μM (n=3) determined in this GLP-compliant in vitro hERG channel study suggests minimal risk of QT prolongation through this pathway in humans given sotorasib.”