Continued approval of Lumakras (sotorasib) for adults with KRAS G12C–mutated locally advanced or metastatic non–small cell lung cancer (NSCLC) may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). KRAS G12C is one of the most ubiquitous driver mutations in NSCLC, with about 13% of patients with nonsquamous NSCLC in the United States having the KRAS G12C mutation. Sotorasib, an inhibitor of the RAS GTPase family, exerts its pharmacologic action via forming an irreversible, covalent bond with KRAS G12C that locks the protein in an inactive state, preventing downstream signaling without affecting wild-type KRAS.

The approval was based on data from the single-arm, open-label, multicenter phase I/II CodeBreak 100 trial, the largest clinical trial conducted to date exclusively for patients with the KRAS G12C mutation. The study assessed the efficacy and safety of sotorasib in 124 patients with locally advanced or metastatic KRAS G12C–mutated NSCLC with disease progression after receiving an immune checkpoint inhibitor and/or platinum-based chemotherapy.

The trial demonstrated favorable efficacy and tolerability in 124 patients with KRAS G12C mutation–positive NSCLC who had disease progression after receiving immunotherapy and/or chemotherapy. In the trial, 960 mg of Lumakras administered orally once daily demonstrated an overall response rate (ORR) (a percentage of patients with ≥30% decrease in tumor) of 36% (95% CI: 28-45) with 81% (95% CI:73-87) of patients achieving disease control (percentage of patients who have achieved complete response, partial response and stable disease for more than 3 months).

The average 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 Lumakras occurred in 9% of patients. Lumakras is supplied as 120-mg tablets in cartons containing two bottles of 120 tablets or one bottle of 240 tablets.

In conjunction with the approval of Lumakras, the FDA has also approved the QIAGEN therascreen KRAS RGQ PCR kit (QIAGEN GmbH) and the Guardant360 CDx (Guardant Health, Inc) as companion diagnostics for Lumakras. Patients should be selected for treatment with Lumakras based on the presence of KRAS G12C mutation in tumor or plasma specimens.

In the press release, Bob T. Li, MD, PhD, MPH, principal investigator at Memorial Sloan Kettering Cancer Center, stated, “Sotorasib represents a major advancement in oncology and changes the treatment paradigm for patients with KRAS G12C-mutated non-small cell lung cancer. Patients with non-small celllung cancer who have progressed beyond first-line treatment face a poor prognosis and have limited treatment options available to them. Sotorasib delivers a new option for these patients, and it is the first KRAS-targeted therapy to be approved after nearly four decades of research.”

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