On May 28, the U.S. Food and Drug Administration (FDA) approved sotorasib (Lumakras) as the first treatment for adult patients with non–small cell lung cancer (NSCLC) whose tumors have a KRAS G12C genetic mutation and who have received at least one prior systemic therapy. This is the first approved targeted therapy for tumors with any KRAS mutation.
KRAS G12C is one of the most prevalent driver mutations in NSCLC, with about 13% of patients with nonsquamous NSCLC in the United States having the mutation.
Richard Pazdur, MD
“KRAS mutations have long been considered resistant to drug therapy, representing a true unmet need for patients with certain types of cancer,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence and Acting Director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research. “[This] approval represents a significant step toward a future where more patients will have a personalized treatment approach.”
The FDA approval of sotorasib is based on results from a subset of patients in CodeBreaK 100, the largest clinical trial conducted to date exclusively for patients with the KRAS G12C mutation. The trial demonstrated favorable efficacy and tolerability in 124 patients with KRAS G12C mutation–positive NSCLC who had disease progression after receiving an immunotherapy and/or chemotherapy.
In the trial, 960 mg of sotorasib administered orally once daily demonstrated an overall response rate (a proportion of patients with ≥ 30% decrease in tumor) of 36% (95% confidence interval [CI] = 28%–45%), with 81% (95% CI = 73%–87%) of patients achieving disease control. The median duration of response was 10 months. The most common adverse reactions (≥ 20%) were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. Adverse reactions resulting in permanent discontinuation of sotorasib occurred in 9% of patients.
Sotorasib was approved using the Accelerated Approval pathway, under which the FDA may approve drugs for serious conditions where there is an unmet medical need and a drug is shown to have certain effects that are reasonably likely to predict a clinical benefit to patients. Further study is required to verify and describe anticipated clinical benefits of sotorasib.
The FDA granted this application Fast Track, Priority Review, and Breakthrough Therapy designations. Sotorasib also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, the FDA collaborated with the Australian Therapeutic Goods Administration, the Brazilian Health Regulatory Agency, Health Canada, and Medicines and Healthcare products Regulatory Agency (MHRA; United Kingdom). The application reviews are ongoing at the other regulatory agencies.