Amgen’s KRAS Inhibitor Registers Long-Lasting Performance in Solid Tumors

By Pavel Ryzhov, Ph.D.

Amgen recently announced updated data from the Phase 1 cohort of the CodeBreaK 100 clinical trial [1] that aims to evaluate sotorasib in patients with advanced solid tumors. Sotorasib (AMG 510) is an orally available medicine, which acts as a KRASG12C inhibitor.

KRAS (Kirsten RAt Sarcoma virus) protein, a member of the RAS family, is a small GTPase that is able to relay proliferation signals from the outside to the inside of the cell. It is one of the most prevalent oncogenes in human cancers and it is also the most frequently mutated isoform of RAS oncogenes. Due to the lack of traditional binding pockets on the KRAS protein, various attempts to develop small molecule-based therapies failed, giving it an “undruggable” tag. The common mutations found in the KRASgene are primarily at codons 12, 13, or 61.

Mutation of the glycine 12 amino acid to any of the six possible amino acids, leads to RAS activation and eventually cancer growth. Among those six, Glycine to Cysteine (KRAS-G12C) mutation is one of the most common, constituting 10%–20% of all KRAS G12 mutations found in cancers. Its G12C mutation, which is adjacent to the binding site, has been widely regarded as one of the major tumor drivers in multiple solid tumors, including non-small cell lung cancer (NSCLC), colorectal cancer, and others.

According to the press-release, Amgen’s latest clinical trial data on sotorasib was published in the New England Journal of Medicine (NEJM) [2] and an NSCLC-related subset of the data also recently presented at the virtual European Society for Medical Oncology Conference (ESMO 2020). Results (as of June 1st, 2020) from the trial showed that 34 pretreated NSCLC patients that were administered with a daily dose of 960 mg of sotorasib, had an objective response rate (ORR) of 35.3% and disease control rate (DCR) of 91.2%. In addition, other reported outcomes included 10.9 months for a median duration of response to the therapy, 6.3 months for median progression-free survival, and tumor shrinkage for 71.2% of patients. In regards to tolerability and safety of sotorasib, the announced results were in line with previously reported data for the CodeBreaK study.

The lead author of the NEJM paper, Dr. David S. Hong, emphasized that “sotorasib continues to demonstrate encouraging clinical benefit in heavily pretreated patients with KRAS G12C-mutant tumors” and in his opinion, results “also establish a compelling trend in tumor shrinkage and median progression-free survival with a positive benefit-risk profile.” Along with the data from the paper, the virtual presentation included data about biomarkers of sotorasib’s clinical activity, which included PD-L1 expression levels in tissues, KRAS G12C mutant allele frequencies (MAFs), and others.

The data from the Phase 1 part of the CodeBreak 100 study is a part of the larger evaluation strategy of sotorasib in other clinical trials. It also includes a Phase 2 trial for NSCLC and CRC indications, which are now fully enrolled and results expected in late 2020 or 2021. Furthermore, other studies began recruiting: a randomized active-controlled confirmatory Phase 3 study (CodeBreaK 200) that compares sotorasib to docetaxel in NSCLC patients and 6 Phase 1b (CodeBreaK 101) combination studies in other advanced solid tumors.

Editor: Rajaneesh K. Gopinath, Ph.D.

Related Article: Amgen’s Efficacy of AMG 510 to KRAS G12C Mutant Critical for Future Directions and Business Investments

References

1. https://clinicaltrials.gov/ct2/show/NCT04185883
2. https://www.nejm.org/doi/full/10.1056/NEJMoa1917239

Author

Pavel Ryzhov