FDA Approval Sought for Sotorasib in Patients With KRAS G12C+ Locally Advanced or Metastatic NSCLC

A New Drug Application was submitted to the FDA seeking approval of the investigational KRAS G12C inhibitor sotorasib as treatment of patients with KRAS G12C-mutated locally advanced or metastatic non–small cell lung cancer, as determined by an FDA-approved test, following at least 1 prior systemic therapy.

A New Drug Application (NDA) was submitted to the FDA seeking approval of the investigational KRAS G12C inhibitor sotorasib (AMG 510) as treatment of patients with KRAS G12C-mutated locally advanced or metastatic non–small cell lung cancer (NSCLC), as determined by an FDA-approved test, following at least 1 prior systemic therapy, announced Amgen, in a press release.1

The NDA is supported by findings from the phase 2 CodeBreaK 100 clinical trial, for which updated data are planned to be presented during the upcoming 2020 World Conference on Lung Cancer (WCLC) Presidential Symposium in January 2021.

"Sotorasib was the first KRAS G12C inhibitor to enter the clinic and now is on track to potentially be the first approved targeted therapy for patients with advanced NSCLC harboring the KRAS G12C mutation. In the United States, about 13% of patients with NSCLC have the KRAS G12C mutation and face a significant unmet need," said David M. Reese, MD, executive vice president of Research and Development at Amgen, in a statement.

Topline results from CodeBreaK 100 were announced in October 2020 showing a satisfactory objective response rate (ORR) that was consistent with the prior phase 1 data. At the time, it was reported that more than half of the patients who responded to sotorasib still on treatment and responding at the time of data cutoff.2

The phase 1 data showed an ORR of 32.2% in 34 heavily pretreated patients with KRAS G12C–mutant NSCLC treated across all dose levels of sotorasib. The disease control rate observed was 88.1%, and the median duration of response (DOR) was 10.9 months. Additionally, 71.2% of patients had tumor shrinkage after 6 weeks of treatment with sotorasib. The median progression-free survival (PFS) in the phase 1 portion of the study was 6.3 months.3

Data from the initial safety analysis of the NSCLC cohort in CodeBreaK 100 trial showed no dose-limiting toxicities and no treatment-related adverse events (TRAEs) leading to death. The most common TRAEs observed were diarrhea (25.4%), alanine aminotransferase (ALT) increase (20.3%), aspartate aminotransferase (AST) increase (20.3%), fatigue (10.2%), and nausea (10.2%). Eleven cases of grade 3 or higher TRAEs were seen, which were mostly mainly ALT and AST increases. Grade 3 TRAEs led to treatment discontinuation in only 1 patient.

The goal of phase CodeBreaK 100 is to evaluate the safety and efficacy of sotorasib in metastatic NSCLC and other KRAS G12C-mutated advanced solid tumors. The primary end point is ORR and the secondary end points are DOR, PFS, and duration of stable disease.

As of October 2020, the study achieved its target enrollment of 533 participants with KRAS G12C-mutant advanced solid tumor. A phase 3 clinical trial was also initiated to confirm the phase 1 and 2 results.1,2

To be eligible for inclusion in the study, patients were required to be aged 18 or older and have pathologically documented, locally advanced, or metastatic malignancy with a KRAS G12C mutation. Patients with active brain metastases from non-brain tumors, myocardial infarction within 6 months of the study start date, and gastrointestinal tract disease that interferes with a patient’s ability to take the study drug were not eligible to enroll.

The NDA for sotorasib as treatment of this patient population will be reviewed under the FDA’s Real-Time Oncology Review (RTOR) pilot program, a program the allows for a more efficient review of the safety and efficacy data for a drug.


1. Amgen submits sotorasib New Drug Application to U.S. FDA for advanced or metastatic non-small cell lung cancer with KRAS G12C mutation. News release. Amgen. December 16, 2020. Accessed December 17, 2020. https://bit.ly/37t5H3B

2. Amgen announces positive topline phase 2 results for investigational KRAS G12C inhibitor sotorasib in advanced non-small cell lung cancer. News release. Amgen. October 5, 2020. Accessed December 17, 2020. https://bit.ly/38jRm8W

3. Hong DS, Fakih MG, Desai J, et al. KRASG12C inhibition with sotorasib in advanced solid tumors.N Engl J Med. 2020; 383:1207-1217. doi: 10.1056/NEJMoa1917239