Lumakras: what was done before first-in-human, and what came after?

“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.”