Amgen Plans to Submit NDA for KRAS G12C Inhibitor Sotorasib to FDA by Year-End

Amgen plans to submit a marketing application for its KRAS G12C inhibitor, sotorasib, to the FDA by the end of this year. This move would position Amgen as the first company to bring a KRAS inhibitor to market, as no such therapies are currently available worldwide.

KRAS mutations occur in approximately 25% of cancer cases, predominantly in lung cancer, pancreatic cancer, and colorectal cancer, and are associated with extremely poor prognosis. Among these, the KRAS G12C mutation is one of the most common KRAS mutations, specifically referring to the substitution of glycine by cysteine at position 12 of the KRAS protein. This mutation is present in ~13% of lung adenocarcinomas, ~3% of colorectal cancers, ~2% of uterine cancers, and ~1% of mesotheliomas. Low frequencies of KRAS G12C mutations are also observed in pancreatic cancer (<1%), cervical cancer (<1%), bladder cancer (<1%), and gastric cancer (<1%).

Unfortunately, no effective KRAS inhibitors have been approved over the past 40 years, leading to a widespread belief that the KRAS oncoprotein is an “undruggable” target. This perception persisted until the emergence of sotorasib (AMG 510) from Amgen, the first KRASG12C inhibitor, which demonstrated that targeted therapy for KRAS mutations is no longer a distant dream.

The results of the Phase II clinical trial, codenamed CodeBreaK100 and published this September, showed that in patients with KRAS G12C-mutated non-small cell lung cancer (NSCLC) who had experienced disease progression after prior chemotherapy and/or immunotherapy, sotorasib achieved an objective response rate (ORR) of 32.2% and a disease control rate (DCR) of 88.1%, with a median progression-free survival of 6.3 months. The study also indicated that monotherapy with sotorasib led to tumor shrinkage in some patients. These findings position Amgen to develop sotorasib as a new treatment option for NSCLC, potentially in combination with other anticancer agents to enhance therapeutic efficacy.

Amgen outlined its next steps on Tuesday, planning to submit a marketing application for sotorasib by the end of 2020. The company had previously stated that it would discuss future plans with regulatory authorities and expected to begin commercial sales of sotorasib the following year.

Amgen’s interactions with the FDA secured regulatory advantages for sotorasib, with the agency granting it Breakthrough Therapy Designation for the treatment of locally advanced or metastatic KRAS G12C–mutated non-small cell lung cancer (NSCLC) in patients who have previously received at least one systemic therapy. Amgen is collaborating with Guardant Health and Qiagen to develop blood- and tissue-based companion diagnostics.

Benefiting from Breakthrough Therapy designation, the marketing application for sotorasib will receive accelerated approval from the FDA, and the FDA will evaluate sotorasib through the Real-Time Oncology Review (RTOR) pilot program. Projects included in the RTOR may take only a few weeks from the completion of data submission to approval.

The inclusion of sotorasib in the RTOR program represents the outcome of communications between Amgen and the FDA to date; however, whether sotorasib qualifies for this program will be determined only after the FDA reviews its top-line data. This decision is expected to be made within days or weeks following the FDA’s receipt of the top-line data.

Once a drug product is included in the RTOR program, the FDA will schedule a teleconference to discuss specific details such as the timeline for early submission of data. Within 6 to 9 weeks following communication with the FDA, the sponsor is required to dynamically submit reports to the FDA as part of the early data submission, including top-line efficacy data and toxicology study reports. The FDA will arrange meetings based on these early submissions to request additional analytical data from the sponsor or to provide preliminary feedback.

By reviewing data submitted in advance, the FDA can conduct its review more efficiently than if it were to begin only after receiving a complete marketing application. However, the purpose of the RTOR program is not merely to accelerate approval timelines. Rather, the FDA views it as a working approach that facilitates earlier patient access to drugs while enhancing review quality and balancing the workload of review teams.

Nevertheless, Amgen remains ahead of its competitors in bringing KRAS inhibitors to market. Mirati Therapeutics, trailing closely behind, announced preliminary data for the treatment of NSCLC this October and plans to submit a marketing application in the second half of next year. The timeline indicates that Amgen’s sotorasib will receive FDA approval around the time Mirati submits its marketing application for MRTX849 next year.