Validation of an LC-MS/MS method for the determination of sotorasib, a KRAS^G12C inhibitor, in human plasma

Background: Sotorasib (AMG 510) is a first-in-class KRAS^G12C inhibitor that received accelerated US FDA approval in 2021 for the treatment of patients with KRAS-mutated locally advanced or metastatic non-small-cell lung cancer. Method: An LC-MS/MS method was developed and validated for the determination of sotorasib in human plasma to support clinical development studies. Samples were prepared using protein precipitation and analyzed by LC-MS/MS using gradient elution with a calibration standard curve range of 10.0-10,000 ng/ml. Stable isotope labeled [¹³C, D₃]-sotorasib was used as an internal standard. Results & conclusion: The method fully met FDA guidelines for all validation parameters, including precision, accuracy, selectivity, matrix effect, recovery and stability and has been extensively used to support multiple clinical studies.