The first KRAS inhibitor, sotorasib (Lumakras)

May 31, 2021

On May 28, 2021, the FDA granted an approval to the first KRAS inhibitor, sotorasib (Lumakras) for the patients with non-small cell lung cancer with KRAS G12C mutations whose disease progressed after more than one therapy including immunotherapy. 

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The KRAS (Kirsten Rat Sarcoma Viral oncogene homologue) gene produces a protein called K-Ras which has a critical role in cell growth and division. KRAS G12C mutation is the most common mutation found in human cancer, and about 13% of NSCLC cancer has this mutation. This mutation leads to a change of amino acid glycine at 12th position to amino acid cysteine in the K-Ras protein, resulting in its constant activation without appropriate signals.

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Not only has there been no targeted therapy for KRAS G12C mutation, but these patients with the mutation tend not to respond to drug therapy. #lungcancer

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Over the last 4 decades, much effort was made to develop a drug targeting KRAS G12C; however, the success was elusive, and KRAS was deemed to be an undruggable target for cancer. Thus, the approval of sotorasib, the first KRAS inhibitor, is such a significant achievement for cancer treatments.

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The approval was based on phase 2 CodeBreaK 100 trial (NCT03600883), in which 36% of the patients (out of 126 patients) responded to the drug for a median 10 months, and 81% of patients had benefits from sotorasib.

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The common adverse effects with sotorasib are diarrhea, musculoskeletal pain, nausea, fatigue, liver damage and cough. Sotorasib could also cause inflammation and eventually fibrosis of the lung called interstitial lung disease.