Amgen Reports First-in-Human Clinical Trial Results of AMG 510, a First-in-Class KRAS G12C Inhibitor, at ASCO 2019

On June 3, Amgen presented the first KRAS oral report at the ASCO 2019 conference.^G12CResults of the First-in-Human Clinical Trial of the Inhibitor AMG 510.

This open-label Phase I study enrolled 35 patients with KRAS G12C mutations who had previously received at least two lines of therapy, including 14 patients with non-small cell lung cancer (NSCLC), 19 patients with colorectal cancer (CRC), and 2 patients with other tumor types. Patients were divided into four cohorts based on dosage and received AMG 510 once daily at doses of 180 mg, 360 mg, 720 mg, or 960 mg. The primary endpoint was safety, while secondary endpoints included pharmacokinetics, objective response rate (assessed every 6 weeks), duration of response, and progression-free survival.

The results showed that among 10 evaluable patients with non-small cell lung cancer (NSCLC), 5 (50%) achieved a partial response (PR) and 4 had stable disease (SD), resulting in a disease control rate of 90% (9/10). At the time of data cutoff, the 5 patients who achieved PR had been receiving treatment for 7.3–27.4 weeks and were still on therapy. Notably, one of these patients continued to improve after the data cutoff and achieved a complete response (CR) at week 18.

Among the 18 evaluable patients with colorectal cancer, 13 achieved stable disease (SD), most of whom received the drug at dose levels of 180 mg or 360 mg. To date, 26 patients remain on treatment, while 9 have discontinued therapy.

In terms of safety, no dose-limiting toxicities of AMG 510 were observed at the four dose levels tested in this Phase I study. Treatment-related adverse events associated with AMG 510 were primarily mild (Grade 1), with an incidence rate of 68%. There were two cases of Grade 3 treatment-related adverse events, including anemia and diarrhea. No serious treatment-related adverse events of Grade 4 or higher were reported.

David M. Reese, Executive Vice President and Head of Research and Development at Amgen, stated that KRAS was the first oncogene discovered in humans more than 30 years ago and has since become one of the most active areas of research in cancer studies. However, due to the lack of a traditional small-molecule binding pocket on this protein target, it has long been considered “undruggable.” AMG 510 works by binding to a hidden groove on the surface of the KRAS protein, forming an irreversible covalent bond with the cysteine residue on mutant KRAS proteins, thereby rendering KRAS inactive. Given its high selectivity for KRAS G12C, we believe AMG 510 holds significant therapeutic potential and can be used either as monotherapy or in combination with other targeted therapies and immunotherapies.

The RAS gene family represents the human oncogenes with the highest mutation frequency, among which KRAS mutations are the most prevalent. KRAS mutations are commonly observed in solid tumors. The incidence of the specific KRAS G12C mutation is approximately 13% in non-small cell lung cancer (NSCLC), 3%–5% in colorectal cancer, and 1%–2% in other solid tumors.

Probability of RAS Gene Mutations in Common Human Cancers

There are approximately 30,000 newly diagnosed patients with KRAS G12C-mutant tumors in the United States each year. AMG 510 is the first KRAS G12C candidate drug to enter clinical development after 30 years of research into the RAS pathway, and it has been granted orphan drug designation by the FDA for the treatment of KRAS G12C mutation-positive non-small cell lung cancer (NSCLC) and colorectal cancer.

Original Title: ASCO 2019 | After a Long 30 Years, KRAS Inhibitors See the Light of Day