AMG 510 is the First KRASG12C Inhibitor to Reach Clinical Stage After Three Decades of
First-In-Human Results Show Preliminary Safety, Tolerability Data and Anti-Tumor Activity in KRAS Mutant Solid Tumors
FDA Grants AMG 510 Orphan Drug Designation for KRASG12C-Positive Non-Small Cell Lung and Colorectal Cancers
"KRAS has been a target of active exploration in cancer research since it was identified as one of the first oncogenes more than 30 years ago, but it remained undruggable due to a lack of traditional small molecule binding pockets on the protein. AMG 510 seeks to crack the KRAS code by exploiting a previously hidden groove on the protein surface," said
The Phase 1, first-in-human, open-label multicenter study enrolled 35 patients with various tumor types (14 non-small cell lung cancer [NSCLC], 19 colorectal cancer [CRC] and two other). Eligible patients were heavily pretreated with at least two or more prior lines of treatment, consistent with their tumor type and stage of disease. The primary endpoint is safety, and key secondary endpoints include pharmacokinetics, objective response rate (assessed every six weeks), duration of response and progression-free survival. Patients were enrolled in four dose cohorts - 180 mg, 360 mg, 720 mg and 960 mg, taken orally once a day.
Five out of 10 evaluable patients with NSCLC experienced a partial response (PR), and another four had stable disease (SD), for a disease control rate (DCR) of 90 percent (9/10).1 All five patients with response to therapy had a treatment duration of 7.3-27.4 weeks at data cutoff and remain active on treatment. One patient with PR improved further to a complete response of the target lesions at week 18, post data cutoff.
In addition, 13 of 18 evaluable patients with CRC achieved SD, with the majority of CRC patients treated at the first two dose levels. Twenty-six patients remain on study and nine have discontinued.
Treatment-related adverse events (AEs) were primarily grade 1 events (approximately 68 percent). Two grade 3 treatment-related AEs were reported (anemia and diarrhea). No grade 4 treatment-related AEs and no serious treatment-related AEs were reported. Enrollment into dose expansion is underway.
"While there's been significant progress in treating solid tumor cancers overall with targeted therapies, patients with the KRASG12C mutation have not benefited from these advances," said
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The subject of more than three decades of research, the RAS gene family are the most frequently mutated oncogenes in human cancers.2,3 Within this family, KRAS is the most prevalent variant and is particularly common in solid tumors.3 A specific mutation known as KRASG12C accounts for approximately 13 percent of non-small cell lung cancers, three to five percent of colorectal cancers and one to two percent of numerous other solid tumors.4 Approximately 30,000 patients are diagnosed each year in
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