FDA Grants Sotorasib Breakthrough Therapy Designation for Advanced KRAS G12C-Mutant NSCLC

The FDA granted a Breakthrough Therapy designation to sotorasib for the treatment of patients with locally advanced or metastatic non–small cell lung cancer who harbored a KRAS G12C mutation following at least 1 prior line of systemic therapy.

The FDA has granted a Breakthrough Therapy designation to the KRAS G12C inhibitor sotorasib for the treatment of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) who harbored a KRAS G12C mutation as detected by an FDA-approved test and following at least 1 prior line of systemic therapy, announced Amgen, developer of the drug, in a press release.

"Breakthrough Therapy designation and Real-Time Oncology Review bring Amgen closer to potentially providing a targeted therapy to patients with a KRAS G12C mutation and establishing sotorasib as the foundational therapy in KRAS G12C-driven cancers," said David M. Reese, MD, executive vice president of Research and Development at Amgen, in a statement. "We are pleased to receive these regulatory designations and plan to submit a new drug application by end of year as we rapidly work to get sotorasib to the patients who need it." 

The most common KRAS mutation in NSCLC is the KRAS G12C mutation, but the treatment options for the patients with NSCLC harboring the KRAS G12C mutation are limited. The current therapies produce suboptimal outcomes, with response rates in the range of 9% to 18% and a median progression-free survival of about 4 months in the second-line setting. The unmet need in this setting for new therapeutic approaches remains high.

"For more than 40 years, scientists have been trying to target KRAS. Today's news is a welcome update for the many non-small cell lung cancer patients with the KRAS G12C mutation, who currently have no targeted therapies," stated Bonnie J. Addario, cofounder and board chair of the GO2 Foundation for Lung Cancer. "We are pleased that the FDA and Amgen recognize the unmet need for these patients and are working to make new treatment options available as quickly as possible."

Sotorasib is the first KRAS G12C inhibitor that has entered the clinic and is being explored in the broadest clinical program, which is evaluating 10 combinations across sites in 4 continents around the world. The clinical program for sotorasib, CodeBreaK, has established the deepest set of clinical data in just over 2 years, and since its inception, more than 600 patients and 13 tumor types have been enrolled.

This designation, which will expedite the development and regulatory review process, and the drug’s inclusion in the Real-Time Oncology Review pilot program are supported by findings from the phase 2 CodeBreaK 100 clinical trial (NCT03600883), which demonstrated durable anticancer activity and a positive benefit-risk profile. This first-in-human, open-label, multicenter study included patients with solid tumors who harbored a KRAS G12C mutation in an attempt to address the longstanding unmet need for these patients.

The global phase 3 CodeBreaK 200 study (NCT04303780) is currently recruiting and will compare treatment with sotorasib to docetaxel in patients with NSCLC who harbor a KRAS G12C mutation. The trial is expected to enroll 650 patients who will be randomized to either therapy in an open-label, active-controlled trial design. The primary end point is progression-free survival, and secondary end points include overall survival, objective response rate, patient-reported outcomes, quality of life, duration of response, time to response, and disease control rate.

To be included in CodeBreaK 200, patients must be at least 18 years old with a previously treated, locally-advanced, and unresectable, or metastatic NSCLC with a KRAS G12C mutation and an ECOG performance status of ≤ 1. Patients with active brain metastases from non-brain tumors, myocardial infarction within 6 months of the first day on the study, or gastrointestinal tract disease causing the patient to be unable to take oral medication are excluded from the study.


Amgen's sotorasib granted breakthrough therapy designation for advanced or metastatic non-small cell lung cancer patients with KRAS G12C mutation. News Release. Amgen. December 8, 2020. Accessed December 8, 2020. https://prn.to/3gsrBGV