FDA Approves Sotorasib for KRAS G12C+ Locally Advanced or Metastatic NSCLC

The FDA has granted accelerated approval to sotorasib (Lumakras) for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy, according to a press release from Amgen.¹

Based on the objective response rate (ORR) and duration of response (DOR) achieved with the agent in this patient population, the FDA saw fit to approve sotorasib more than 2 months ahead of the Prescription Drug User Fee Act target action date of August 16, 2021. The data that provided supporting evidence for the FDA approval came from the phase 2 CodeBreak 100 trial (NCT03600883).

"Sotorasib represents a major advancement in oncology and changes the treatment paradigm for patients with KRAS G12C-mutated non-small cell lung cancer," said Bob T. Li, MD, PhD, MPH, principal investigator at Memorial Sloan Kettering Cancer Center, in the press release. "Patients with non-small cell lung 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."

The first-in-human, open-label, multicenter study enrolled patients with solid tumors with KRAS G12C mutations who had received at least 1 prior line of systemic anticancer therapy. The NSCLC cohort included 124 patients. All patients in the cohort were treated with 960 mg oral sotorasib once daily. Eighty-one percent of patients had progressed on both platinum-based chemotherapy and PD-1/L1 inhibitors before joining the trial.

A confirmed ORR of 36% (95% CI: 28-45), and the disease control rate was 81% (95% CI: 73-87). According to previously reported at the World Conference on Lung Cancer, among all responders, the median best reduction in tumor size was 60%.² The median time to objective response was 1.4 months and the median DOR was 10 months.^1,2

Further, at a median follow-up of 12.2 months, the median progression-free survival was 6.8 months.

Treatment-related adverse events (TRAEs) observed with sotorasib were predominantly grade 1 or 2 in severity and no treatment-related deaths were reported in the study. Grade 3 TRAEs occurred in 25 (19.8%) patients and 1 patient (0.8%) reported a grade 4 TRAE. The most frequently reported TRAEs of any grade were diarrhea (31.0%), nausea (19.0%), increased alanine aminotransferase (15.1%), and increased aspartate aminotransferase (15.1%). Treatment discontinuation rates due to TRAEs occurred in 7.1% of patients.²

"The FDA approval of Lumakras is a breakthrough moment for patients with KRAS G12C-mutated non–small cell lung cancer because there is now a targeted therapy for this common, but previously elusive, mutation," said David M. Reese, MD, executive vice president of Research and Development at Amgen, in a statement. "KRAS has challenged cancer researchers for more than 40 years with many deeming it as 'undruggable. The Lumakras development program was a race against cancer for Amgen's scientists and clinical trial investigators who together have now successfully delivered this new medicine to patients in less than three years—from first patient dosed to [United States] regulatory approval."

_References:

_{1. FDA approves LUMAKRAS™ (sotorasib), the first and only targeted treatment for patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer. News release. May 28, 2021. Accessed May 28, 2021. https://bit.ly/3wGiklr}

_{2. Li BT, Skoulidis F, Falchook G, et al. CodeBreaK 100: Registrational Phase 2 Trial of Sotorasib in KRAS p.G12C Mutated Non-small Cell Lung Cancer. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; virtual. Abstract PS01.07.}