Lumakras

“The Applicant evaluated the safety of sotorasib using Sprague-Dawley rats and Beagle dogs in GLP-compliant repeat-dose toxicology studies of up to 3 months duration.”

“The human metabolites formed in vitro were also produced in the rat and dog in vitro (liver microsomes/hepatocytes).”

“The Applicant evaluated the safety of sotorasib using Sprague-Dawley rats and Beagle dogs in GLP-compliant repeat-dose toxicology studies of up to 3 months duration.”

“The Applicant evaluated the safety of sotorasib using Sprague-Dawley rats and Beagle dogs in GLP-compliant repeat-dose toxicology studies of up to 3 months duration.”

“The Applicant evaluated the safety of sotorasib using Sprague-Dawley rats and Beagle dogs in GLP-compliant repeat-dose toxicology studies of up to 3 months duration.”

“The oral route of administration was chosen for in vivo nonclinical studies based on the intended clinical route of administration.”

“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”

“The mean observed sotorasib clinical exposures from 180, 360, 720, and 960 mg once daily (QD) dosing in subjects (Study 20170543) were lower than the exposures observed at the STD10 of 180 mg/kg in rats in the 3-month GLP repeat-dose toxicology study (Study 150432), but higher than the exposures observed at the HNSTD of 1000 mg/kg/day in dogs”

“In rats, renal toxicity including minimal to marked histologic tubular degeneration/necrosis and increased kidney weight, urea nitrogen, creatinine, and urinary biomarkers of renal tubular injury were present at doses resulting in exposures approximately ≥ 0.5 times the human AUC at the clinical dose of 960 mg.”

“pituitary gland (increased weight and hypertrophy of pituitary basophils of the pars distalis), thymus (decreased weight and decreased lymphoid cellularity), and gallbladder (bile sludge).”

“Following single oral administration, 14C-sotorasib-derived radioactivity distributed widely to rat tissues especially the liver, kidney, thyroid, pancreas, exorbital lacrimal gland, intra-orbital lacrimal gland, and adrenal gland, but brain penetration appeared low.”

“Increases in cysteine S-conjugate β-lyase pathway metabolism in the rat kidney compared to human may make rats more susceptible to renal toxicity due to local formation of a putative sulfur-containing metabolite than humans.”