Sotorasib Granted Priority Review for KRAS G12C–Mutated Advanced or Metastatic NSCLC


The FDA has granted priority review to sotorasib for the treatment of patients with KRAS G12C–mutated locally advanced or metastatic non–small cell lung cancer, after at least 1 previous systemic therapy.

The FDA has granted priority review to sotorasib (formerly AMG 510) for the treatment of patients with KRAS G12C–mutated locally advanced or metastatic non–small cell lung cancer (NSCLC), after at least 1 previous systemic therapy.1

The decision was based on data from the phase 2 CodeBreaK 100 trial (NCT03600883), which showed that treatment with KRAS G12C inhibitor elicited a 6.8-month median progression-free survival (PFS) in patients with KRAS G12C–mutated NSCLC.2

Moreover, at a median follow-up of 12.2 months, sotorasib induced an objective response rate (ORR) of 37.1% (95% CI, 28.6%-46.2%) and a disease control rate (DCR) of 80.6% (95% CI, 72.6%-87.2%). The median duration of response (DOR) was 10 months.

The FDA is slated to make a decision on the agent by August 16, 2021 per the Prescription Drug User Fee Act; this is 4 months earlier than the standard review cycle, according to Amgen, the drug developer.

“These results are encouraging and clinically meaningful for patients with advanced disease harboring the KRAS G12C mutation,” Bob T. Li, MD, PhD, MPH, lead study author and medical oncologist a Memorial Sloan Kettering Cancer Center, said during a presentation of the data delivered at the International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer. “These are the patients who have progressive disease after standard treatment, so they need additional treatments, and the fact that we are seeing rapid tumor shrinkages and durable responses in these patients, is for me, a step forward and a win for patients.”

The phase 2 CodeBreaK 100 trial enrolled a total of 126 patients with locally advanced or metastatic NSCLC with a KRAS G12C mutation assessed per central testing of tumor biopsies. Patients had to have progressed on previous standard therapies and they could not have active brain metastases.

In the trial, patients were given oral sotorasib at a dose of 960 mg until progressive disease. Radiographic scans were performed every 6 weeks up to week 48 and once every 12 weeks thereafter.

The primary end point of the trial was ORR per RECIST v1.1 criteria by blinded independent central review, while key secondary end points included DOR, DCR, time to recovery, PFS, overall survival, and safety. The examination of biomarkers served as an exploratory end point.

The median age of participants at baseline was 63.5 years and the majority, or 92.9% were either current or former smokers. Moreover, 69.8% of patients had an ECOG performance status of 1. Just under half, or 42.9%, of patients received 1 prior line of systemic treatment, while 34.9% received 2 lines, and 22.2% received 3 lines. About 90% of patients received previous platinum-based chemotherapy, 91.3% received PD-1/PD-L1 inhibitors, and 81.0% received both. Eighty-one percent of patients had progressed on previous platinum-based chemotherapy and PD-1/PD-L1 inhibitors.

Additional results revealed that of those who achieved a response with sotorasib, 2.4% experienced a complete response, 34.7% had a partial response, and 43.5% had stable disease. Additionally, 16.1% experienced disease progression and 3.2% of patients were not evaluable or were missing a scan.

Moreover, responses achieved with the agent proved to be durable. The median time to objective response was 1.4 months. Seventy-two percent of responses were observed at the time of the first assessment. Just under half, or 43% (n = 20/46), of those who responded continued to receive treatment without experiencing progressive disease at the time of the data cutoff, which was December 1, 2020.

Tumor shrinkage of any magnitude was reported in 81% of patients (n = 101/124) and the median percentage of best tumor shrinkage among all patients who responded to treatment with sotorasib was 60%.

Results from the exploratory biomarker analyses showed that the clinical activity to sotorasib was observed across a range of biomarker subgroups, including those with PD-L1–negative or –low status, and also those with STK11 mutations. STK11 mutations are generally linked with poorer outcomes in patients with NSCLC who previously received treatment with checkpoint inhibitors and chemotherapy.

Regarding safety, 69.8% of patients experienced any-grade treatment-related toxicities, while 19.8% experienced grade 3 effects. The majority of these effects were grade 1 or 2 in severity.

The most frequently reported treatment-related adverse effects (TRAEs) included diarrhea (31.0%, any grade; 4.0% grade 3), nausea (19.0%, any grade), alanine aminotransferase (15.1%, any grade; 6.3%, grade 3), aspartate aminotransferase (15.1%, any grade; 5.6%, grade 3), fatigue (11.1%, any grade), vomiting (7.9%, any grade), increased blood alkaline phosphatase (7.1%, any grade; 0.8%, grade 3), and maculopapular rash (5.6%, any grade).

TRAEs resulted in treatment discontinuation in 7.1% of patients, while 22.2% of patients experienced TRAEs that led to dose modification.

Previously, in December 2020, the FDA granted a breakthrough therapy designation for the drug for use as a potential treatment in patients with KRAS G12C–mutated locally advanced or metastatic NSCLC, as determined via an FDA-approved test, after at least 1 prior systemic treatment.


  1. FDA grants sotorasib priority review designation for the treatment of patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer. News release. Amgen. February 16, 2021. Accessed February 16, 2021.
  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.

This article was originally published on OncLive as, "FDA Grants Priority Review to Sotorasib for KRAS G12C–Mutated Advanced or Metastatic NSCLC."

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