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

Per the US FDA sotorasib approval summary, mutation is found in approximately 14% of adenocarcinoma of the lung, primarily in patients with a history of smoking. Until recently, targeted therapies against have been largely unsuccessful due to the small protein size of and thus lack of binding pockets in and rapid hydrolysis of GTP to GDP by enzymes from abundance of GTP in the cytoplasm. Sotorasib, a first-in-class covalent inhibitor that binds to the switch pocket II in the -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 + 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.