FDA Approval Sought for Sotorasib for KRAS G12C–Mutated Advanced or Metastatic NSCLC

December 16, 2020 - A new drug application has been submitted to the FDA for sotorasib for the treatment of patients with KRAS G12C–mutant locally advanced or metastatic non–small cell lung cancer, as determined by an FDA-approved test, after at least 1 previous systemic therapy.

A new drug application has been submitted to the FDA for sotorasib (formerly AMG 510) for the treatment of patients with KRAS G12C–mutant locally advanced or metastatic non–small cell lung cancer (NSCLC), as determined by an FDA-approved test, after at least 1 previous systemic therapy.1

The application follows the breakthrough therapy designation that was granted earlier this month, and is based on findings from the phase 2 CodeBreaK 100 trial (NCT03600883). Here, sotorasib resulted in deep responses in patients with KRAS G12C–mutant advanced NSCLC who had experienced disease progression following a median of 2 previous lines of treatment.2

The agent elicited an overall response rate (ORR) that proved to be consistent with prior data that read out from a phase 1 trial conducted in patients with advanced disease who received sotorasib at a daily dose of 960 mg. More than half of participants who experienced responses with the treatment continued to respond and had still been on the agent at the time of data cutoff.

Results from the trial will be shared at the IASLC 2020 World Conference on Lung Cancer.

“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,” David M. Reese, MD, executive vice president of Research and Development at Amgen, stated in a press release. “In the United States, about 13% of patients with NSCLC have the KRAS G12C mutation and face a significant unmet need. This submission, along with these other important regulatory achievements, underscore Amgen’s commitment to bringing this potential treatment option to patients has quickly as possible.”

The first-in-human, open-label multicenter phase 1/2 CodeBreaK 100 trial enrolled patients with KRAS G12C­–mutant solid tumors. To be eligible for enrollment, patients had to have received a previous line of systemic treatment that was consistent with their tumor type and disease stage.

A total of 129 patients were enrolled to the trial; of these patients, 59 had NSCLC, 42 had colorectal cancer, and 28 had any of 11 other solid tumors. Four cohorts within the NSCLC subset received a different daily dose of sotorasib. Three patients received the agent at a dose of 180 mg, 16 received 360 mg, 6 had 720 mg, and 34 received 960 mg. Across all doses examined, tumor reductions were observed.

Notably, however, patients given the 960-mg dose of the agent yielded the most benefit with adequate tolerability. Based on this, sotorasib was evaluated at a dose of 960 mg in the expansion portion of the research.

The primary end point of the trial was safety, while key secondary end points included ORR, duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS). At a median follow-up of 11.7 months, 14 patients were still on sotorasib treatment. The majority of the 45 patients who discontinued treatment with the agent cited the reason of progressive disease.

Data from a subgroup of 59 heavily pretreated patients with KRAS G12C–mutated NSCLC examined in the phase 1 portion of the trial, presented during the 2020 ESMO Virtual Congress, showed that sotorasib elicited a confirmed ORR of 32.2%. Notably, 88.1% of patients achieved disease control with the agent.3

Additionally, 71.2% of patients (n = 42) experienced tumor reduction of any magnitude at the time that the first series of scans were done. Among the 19 participants who received the 960-mg dose, sotorasib induced an ORR of 35.3% with a median DOR of 10.9 months. Ten of 19 responders were still responding to sotorasib at the June 1, 2020 data cutoff. Additionally, the DCR was 91.2% with the agent with a median duration of stable disease of 4.0 months.

No patients experienced a complete response with the agent. A stable disease rate of 55.9% was experienced in the entire population and the subgroup of patients who received the agent at the 960-mg dose. The median PFS with sotorasib was 6.3 months in the NSCLC subset.

Regarding safety, no dose-limiting toxicities and no deaths associated with sotorasib were reported. Almost 19% of patients experienced treatment-related adverse effects that were grade 3 or higher, but only 1 patient experienced a grade 4 event of alanine transaminase.

In the active-controlled phase 3 CodeBreak 200 trial (NCT04303780), investigators will compare the use of sotorasib with docetaxel in patients with KRAS G12C–mutated NSCLC. The trial is currently recruiting patients.


  1. Amgen submits sotorasib new drug application to US FDA for advanced or metastatic non-small cell lung cancer with KRAS G12C mutation. New release. Amgen. December 16, 2020. Accessed December 16, 2020. http://prn.to/3mva6qS.
  2. Amgen announces positive topline phase 2 results for investigational KRAS G12C inhibitor sotorasib in advanced non-small cell lung cancer. News release. October 5, 2020. Accessed December 16, 2020. https://bit.ly/2HVviYs.
  3. Hong DS, Fakih MG, Strickler JH, et al. KRASG12C inhibition with sotorasib in advanced solid tumors. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract 1257O.