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 conducted GLP-compliant embryo-fetal development studies in Sprague-Dawley rats and New Zealand White rabbits.”

“No carcinogenicity studies have been conducted nor are any planned in accordance with International Council for Harmonisation (ICH) S9 (ICH, 2009).”

“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”

“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.”

“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.”

“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 the GLP 3-month rat toxicology study with a 2-month recovery, higher dose levels were evaluated (60, 180, and 750 mg/kg/day), which were associated with systemic exposure that exceeded the human clinical exposures.”

“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 conducted GLP-compliant embryo-fetal development studies in Sprague-Dawley rats and New Zealand White rabbits.”

“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”

“Prenatal and postnatal development studies were not conducted or needed to support the use of sotorasib in the currently proposed indication (NSCLC) per ICH S9.”

“No carcinogenicity studies have been conducted nor are any planned in accordance with International Council for Harmonisation (ICH) S9 (ICH, 2009).”

“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 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.”

“In vivo, sotorasib induced dose-dependent inhibition of ERK1/2 phosphorylation and tumor growth in mice bearing subcutaneously (SC)-implanted human tumor cell lines (including NSCLC) expressing KRASG12C but not KRASG12V or KRASG12D mutations”

“Overall, in vitro and in vivo primary pharmacology data support the intended clinical use. Moreover, the in vivo models and the sotorasib dose range studied are considered mostly relevant for the clinical situation.”