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FDA Approves Sotorasib for KRAS G12C-Mutated NSCLC

Non-small cell lung cancer.

The FDA granted accelerated approval to sotorasib (Lumakras™, Amgen) for patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC) who have received at least one prior systemic therapy.

"Outcome in patients with advanced NSCLC on second- or third-line therapies is poor," wrote Bob Li, MD, PhD, MPH, Medical Oncologist at Memorial Sloan Kettering Cancer Center, and colleagues, in the primary analysis of their registrational phase 2 CodeBreaK 100 clinical trial (NCT03600883), on which the approval was based. "Sotorasib is a first-in-class small molecule that specifically and irreversibly inhibits KRAS G12C."

In this study, 126 patients with locally advanced or metastatic NSCLC with KRAS G12C mutations were enrolled. Efficacy was measured in 124 patients whose disease had progressed on or after at least one prior systemic therapy. Patients received 960 mg of sotorasib orally once daily until disease progression or unacceptable toxicity. The primary end point was the objective response rate. Secondary endpoints included duration of response, disease control rate, progression-free survival, and safety.

Sotorasib produced an overall response rate was 36%. The median duration of response was 10 months. At a median follow up of 6.9 months, 55.2% remained on treatment without progression, disease control rate was 80.5%, and median progression-free survival was 6.7 months. Treatment-related adverse events of any grade occurred in 69.8% of patients.

The most common adverse reactions, occurring in at least 20% of patients, were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. The most common laboratory abnormalities, occurring in at least 25% of patients, were decreased lymphocytes, decreased hemoglobin, increased aspartate aminotransferase, increased alanine aminotransferase, decreased calcium, increased alkaline phosphatase, increased urine protein, and decreased sodium.

"In the phase 2 CodeBreaK 100 trial, sotorasib provided deep responses and durable clinical benefit with a favorable safety profile in patients with pretreated NSCLC harboring KRAS p.G12C," concluded Dr. Li and colleagues. "After four decades of scientific effort, sotorasib may have the potential to be the first targeted treatment option for this patient population with a high unmet need."

The recommended dose of sotorasib is 960 mg orally once daily, with or without food. However, the FDA is requiring a postmarketing trial in order to see if a lower dose of sotorasib will provide a similar clinical benefit.

For More Information

Li B, Skoulidis F, Falchook G, et al (2021). Registrational phase 2 trial of sotorasib in KRAS p.G12C mutant NSCLC: first disclosure of the Codebreak 100 primary analysis. J Thorac Oncol (WCLC 2020 Virtual Presidential Symposium), 16(suppl_3):S61. Abstract PS01.07. DOI:10.1016/j.jtho.2021.01.321

ClinicalTrials.gov (2021). A phase 1/2, study evaluating the safety, tolerability, PK, and efficacy of AMG 510 in subjects with solid tumors with a specific KRAS mutation (CodeBreaK 100). NLM identifier: NCT03600883.

Lumakras™ prescribing information (2021). Amgen Inc. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214665s000lbl.pdf

US Food & Drug Administration (2021). FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-sotorasib-kras-g12c-mutated-nsclc

Image credit: Librepath. Licensed under CC BY-SA 3.0


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