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

January 4, 2021 - A marketing authorization application has been submitted to the European Medicines Agency for the use of sotorasib in patients with KRAS G12C–mutated locally advanced or metastatic non–small cell lung cancer.

A marketing authorization application has been submitted to the European Medicines Agency (EMA) for the use of sotorasib (formerly AMG 510) in patients with KRAS G12C–mutated locally advanced or metastatic non­–small cell lung cancer (NSCLC).1

The application is based on findings from the phase 1/2 CodeBreaK 100 trial (NCT03600883), in which the investigational KRASG12C inhibitor induced deep responses in patients with KRAS G12C­–mutated advanced NSCLC who had progressed after a median of 2 prior lines of therapy.2

The overall response rate (ORR) achieved with sotorasib was consistent with previous data reported from an earlier phase 1 trial that was performed in patients with advanced disease who were administered the agent at a dose of 960 mg per day.3 Moreover, over 50% of patients who responded to the agent, continued to respond and receive treatment at the time of data cutoff.

The data from the trial will be presented in the Presidential Symposium during the 2020 IASLC World Conference on Lung Cancer.

“Just over 2 years since the first patient was dosed, sotorasib is now on track to potentially be the first approved targeted therapy for patients with previously treated NSCLC harboring the KRAS G12C mutation,” David M. Reese, MD, executive vice president of Research and Development at Amgen, stated in a press release. “With this submission to EMA, Amgen is continuing to rapidly advance the KRASG12C inhibitor clinical program to bring this innovative potential therapy to patients globally as quickly as possible.”

In the open-label, multicenter CodeBreaK 100 trial, investigators enrolled patients with solid tumors that harbored the KRAS G12C mutation. To participate, patients had to have previously received a line of systemic therapy that proved to be consistent with their tumor type and stage of disease.

In total, 129 participants were enrolled to the trial; 59 patients had NSCLC, 42 had colorectal cancer (CRC), and 28 had any of 11 other solid tumors. Within the subset of patients with NSCLC, 3 patients were given sotorasib at a dose of 180 mg, 16 received the agent at a dose of 360 mg, and 6 received it at 720 mg. The majority of the patients, or 34, were given sotorasib at a dose of 960 mg.

Notably, reductions in tumor size were observed across all dosing cohorts evaluated. However, the participants who received sotorasib at the highest dose were found to achieve the most benefit from the agent. Despite the higher dose level, the drug showcased acceptable tolerability in this patient subset. As such, the agent was then examined at the 960-mg dose in the expansion phase of the trial.

The primary objective of the phase 1 portion of the trial was safety, and secondary end points comprised ORR, duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS). The primary end point in the phase 2 portion was centrally-assessed ORR. A total of 126 patients with NSCLC were enrolled to the phase 2 portion of the research and 123 of them had centrally-evaluable lesions per RECIST v1.1 criteria at baseline.

In the phase 1 portion of the research, the investigational KRASG12C inhibitor induced a confirmed ORR of 32.2% in a subgroup of patients with heavily pretreated KRAS G12C–mutated NSCLC (n = 59). Moreover, 88.1% of patients (n = 52) achieved disease control, defined as an objective response or disease stability. In this subset, the median PFS was 6.3 months (range, 0.0 months–14.9 months).

Notably, patients with pancreatic, endometrial, and appendiceal cancers, and melanoma all responded to sotorasib.

In the subset of patients with CRC, 7.1% (n = 3) achieved a confirmed response to sotorasib, with 73.8% of patients (n = 31) experiencing disease control. The median PFS in this patient subgroup was 4.0 months (range, 0.0 months–11.1+ months). The phase 2 trial examining the agent in patients with CRC is fully enrolled and topline data are anticipated to read out in 2021.

No dose-limiting toxicities were observed with sotorasib and no deaths linked with the agent were reported. About 19% of participants were found to have treatment-associated toxicities that were grade 3 or higher in severity. However, only 1 participant experienced alanine transaminase that was grade 4.

A new drug application for sotorasib was submitted to the FDA in December 2020 for its use in patients with KRAS G12C­–mutant locally advanced or metastatic NSCLC, as determined by an FDA-approved test, following at least 1 prior systemic therapy.

In the randomized, active-controlled phase 3 CodeBreaK 200 trial (NCT04303780), investigators will examine sotorasib versus docetaxel in patients with KRAS G12C­–mutant NSCLC; this trial is currently recruiting participants. Other phase 1b combination studies (CodeBreaK 101; NCT04185883) are evaluating sotorasib across several advanced solid tumors; these trials are now open for enrollment.


  1. Amgen submit sotorasib marketing authorization application to the European Medicines Agency. News release. Amgen. December 22, 2020. Accessed January 4, 2021.
  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 January 4, 2021.
  3. Hong DS, Fakih MG, Strickler JH, et al. KRASG12C inhibition with sotorasib in advanced solid tumors. N Engl J Med. 2020;383(13):1207-1217. doi:10.1056/NEJMoa1917239