The KRAS mutation occurs in 13% of non–small cell lung cancers (NSCLC) and leads to worse outcomes in NSCLC.
There are no therapies for tumors with KRAS mutations, but a phase 1 clinical trial of sotorasib (AMG 510) in patients with non–small cell lung cancer (NSCLC) that harbor the KRAS p.G12C mutation showed encouraging antitumor activity.
The findings about the oral agent were published simultaneously in the New England Journal of Medicine and presented at the 2020 ESMO Virtual Congress.
The KRAS mutation occurs in 13% of NSCLCs and in about 1% to 3% of colorectal cancers and other cancers; the KRAS gene is part of the RAS gene family, which is responsible for more than 30% of all human cancers, according to the National Cancer Institute.
This particular protein had been deemed untouchable, but prior work contributed to the finding that sotorasib could bind to the P2 pocket and block the ability of mutated KRAS protein from fueling tumor growth and spread.
The multisite clinical trial included 129 patients with metastatic disease who had received an average of 3 prior therapies. Of the 129, 59 had NSCLC, 42 had colorectal cancer, and 28 had other tumors. The average age was 62, and the median follow-up was 12 months.
The purpose of the trial was to test the safety of sotorasib at 4 different doses: 180 mg, 360 mg, 720 mg and 960 mg.
Nineteen (32.2%) patients with NSCLC had a confirmed objective response and 52 patients (88%) had disease control (objective response or stable disease). The median progression-free survival (PF) was 6.3 months.
Responses were seen at all dose levels, the researchers said; the target dose of 960 mg had a response rate of 35.3%, which was seen as "particularly promising."
In the subgroup with colorectal cancer, 3 patients (7.1%) had a confirmed response and 73.8% (31 patients) had disease control; their PFS was 4 months.
No dose-limiting toxic effects were seen; the most common adverse events affected the gastrointestinal tract and included diarrhea (30%), fatigue (23%) and nausea (21%). Fifteen patients (11.6%) reported grade 3 or 4 treatment-related adverse events.
Treatment was discontinued in 107 patients (83%), mostly because of disease progression; 54 patients died.
At the end of the data collection date for the study, 9 of the 19 patients with NSCLC who had a partial response and 5 patients who had stable disease were still receiving the treatment.
The study was designed, funded, and analyzed by Amgen, which is developing the drug.
Hong DS, Fakih MG, Strickler JH, et al. KRASG12C inhibition with sotorasib in advanced solid tumors. N Eng J Med. Published online September 20, 2020. doi:10.1056/NEJMoa1917239