On May 28, 2021, the FDA accelerated the approval of sotorasib (Lumakras; Amgen), an oral KRAS inhibitor of the RAS GTPase family, for the treatment of adults with locally advanced or metastatic non–small-cell lung cancer (NSCLC) associated with KRAS G12C mutation, as determined by an FDA-approved test, after ≥1 systemic therapies. The FDA granted sotorasib orphan drug and breakthrough therapy designations.
This is the first targeted therapy approved by the FDA for cancer associated with any KRAS mutation, a type of mutation that was thought to be resistant to any drug. Approximately 25% of mutations found in patients with NSCLC are KRAS mutations, and approximately 13% of NSCLC-related mutations are KRAS G12C mutations.
“KRAS mutations have long been considered resistant to drug therapy, representing a true unmet need for patients with certain types of cancer. Today’s approval represents a significant step toward a future where more patients will have a personalized treatment approach,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence.
This approval was based on a study of 124 patients with locally advanced or metastatic NSCLC and KRAS G12C mutation that progressed after treatment with an immune checkpoint inhibitor and/or platinum-based chemotherapy. The study’s primary outcomes were the objective response rate (ORR) and the duration of response with sotorasib therapy. The ORR was 36%, and the response lasted ≥6 months in 58% of the patients who had a response to sotorasib therapy.
The most common (≥20%) side effects reported with sotorasib include diarrhea, musculoskeletal pain, nausea, fatigue, liver damage, and cough. Treatment with sotorasib should be stopped in patients with symptoms of interstitial lung disease and permanently discontinued if interstitial lung disease is confirmed. In patients with liver damage, sotorasib therapy should be withheld, dose reduced, or permanently discontinued.
Sotorasib is contraindicated with acid-reducing agents, drug inducers or substrates of certain liver enzymes, and drugs that are substrates of the P-glycoprotein.
The recommended daily dose of sotorasib is 960 mg. Continued approval of this indication is contingent on confirmatory data from clinical trials regarding the benefit of this medication.