CodeBreaK 200: Sotorasib (AMG510) Has Broken the KRAS G12C+ NSCLC Enigma Code

Per the US FDA sotorasib approval summary, KRAS G12C mutation is found in approximately 14% of adenocarcinoma of the lung, primarily in patients with a history of smoking. Until recently, targeted therapies against KRAS G12C have been largely unsuccessful due to the small protein size of KRAS and thus lack of binding pockets in KRAS and rapid hydrolysis of GTP to GDP by KRAS enzymes from abundance of GTP in the cytoplasm. Sotorasib, a first-in-class covalent KRAS G12C inhibitor that binds to the switch pocket II in the KRAS G12C-GDP "off" state, received US FDA accelerated approval on May 21, 2021 in the US, based on a Phase II dose expansion cohort of CodeBreaK 100 trial. Sotorasib at 960 mg once daily achieved an ORR of 36% (95% CI: 28%, 45%), with a median response duration of 10 months (range 1.3+, 11.1) in 124 KRAS G12C+ NSCLC. At the European Society of Medical Oncology (ESMO) 2022 annual meeting, sotorasib achieved a statistically significant improved PFS over docetaxel (HR = 0.66; 95% CI: 0. 51-0.86; P = 0.002). The modest magnitude of PFS improvement of 1.1 months (from 4.5 months to 5.6 months) and the ORR of 28% led to a vigorous debate on whether sotorasib was indeed a true breakthrough. In this pros and cons debate, we argue thatsotorasib has achieved a true breakthrough.