FDA Approves Sotorasib for KRAS G12C Mutated Metastatic NSCLC

On May 28, 2021, the FDA granted accelerated approval to sotorasib for the treatment of adults with advanced NSCLC with a KRAS G12C mutation, who have received at least one prior systemic therapy. This decision was based on the results of the CodeBreaK 100 trial, a dose escalation and dose expansion study in patients with advanced, KRAS G12C-mutated solid tumors. The trial demonstrated an overall response rate (ORR) of 36% (95% CI 28, 45) in patients with KRAS G12C-mutated NSCLC treated with sotorasib, with a median duration of response (DOR) of 10.0 months (95% CI 6.9, not estimable).

Sotorasib is the first FDA-approved targeted therapy for KRAS G12C-mutated NSCLC, addressing a significant unmet medical need. The KRAS G12C mutation leads to persistent downstream signaling promoting cell growth and division, and has historically been considered an 'undruggable target.' Sotorasib works by irreversibly binding to the P2 pocket in the inactive GDP-bound form of KRAS, locking the protein in an inactive state and thereby blocking KRAS signaling.

The most common adverse reactions observed in patients treated with sotorasib included diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. A dose comparison study is being conducted as a post-marketing requirement to investigate the safety and efficacy of lower doses of sotorasib.

This approval represents a landmark in the treatment of KRAS G12C-mutated NSCLC, offering a new therapeutic option for patients with this genetically distinct form of lung cancer. The FDA's review of sotorasib was conducted under the Real-Time Oncology Review pilot program, highlighting the agency's commitment to expediting the availability of effective treatments for serious conditions.