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”