Enigma.

Top Line: KRAS-mutated lung adenocarcinoma has been considered “undruggable.”

The Study: The most common mutations in lung adenocarcinoma involve KRAS and affect 25-30% of patients. KRAS mutation is associated with poor prognosis and poor response to molecular targeted therapy. Until now, there has been no targeted therapy for KRAS mutated NSCLC. The most common KRAS mutation is the p.G12C point mutation and single-handedly affects 13% of lung adenocarcinomas. Sotorasib (or “Lumakras”) is an irreversible, small molecule inhibitor of KRAS-G12C. CodeBreaK100 is a phase 2 study evaluating the efficacy and safety of sotorasib in 124 patients with advanced KRAS p.G12C-mutated adenocarcinoma that progressed on prior immunotherapy and/or platinum chemotherapy. The objective response rate was 37.1% (3.2% CR, 33.9% PR) and the disease control rate was 80.6%. Nearly half of patients were still receiving therapy at 6 months and nearly a third at 12 months. Median PFS was 6.8 months and median OS was 12.5 months. Ramucirumab and docetaxel are used in a similar line of therapy and have an ORR of 23% and median PFS of 4.5 months. The most common side effects of sotorasib were diarrhea, nausea, fatigue, arthralgias, and elevated liver enzymes. CodeBreaK200 will be comparing sotorasib to docetaxel-based chemo in a phase 3 format.

TBL: Sotorasib is the first molecular targeted therapy for KRAS-mutated lung adenocarcinoma. | Skoulidis, N Engl J Med 2021