Research Reveals a Promising New KRAS Inhibitor for Lung Cancer

Although the KRAS G12C mutation is harbored by 11% of patients with non–small-cell lung cancer (NSCLC) and 14% of those with lung adenocarcinoma, no treatments are approved to target this mutation. However, hope for patients with this mutation may be on the horizon, according to research presented at the International Association for the Study of Lung Cancer (IASLC) 2019 World Conference on Lung Cancer (WCLC) held in Barcelona. In a phase I trial, researchers demonstrated that KRAS inhibitor AMG 510 demonstrated safety and antitumor activity in advanced NSCLC patients.

“KRAS G12C mutant lung adenocarcinoma is one of the largest subsets of NSCLC potentially amenable to targeted therapies. I am pleased that we have a promising new oral therapy for this group of patients,” said Ramaswamy Govindan, MD, a medical oncologist at the Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri. “These data continue to show encouraging anti-tumor activity with AMG 510, underscoring the potential to close the treatment gap for non-small cell lung cancer patients with previously treated KRAS G12C-mutated NSCLC.”

In the study, 76 patients with metastatic or locally advanced cancer were enrolled. These patients had previously been given standard therapy. The primary outcome was toxicity; secondary outcomes included duration of response, objective response rate, progression-free survival, and duration of stable disease.

The researchers. assigned the patients to four experimental cohorts taking different doses of the AMG 510, including 180 mg, 360 mg, 720 mg, and 960 mg. The drug was taken once a day, by mouth for 21 days, followed by X-rays and examinations.

Data on the trial were first presented at American Society of Clinical Oncology (ASCO) 55th Annual Meeting. The follow-up at IASCLC 2019 WCLC focused on a subsample of 34 NSCLC patients of whom 23 were assessed for drug efficacy. In total, 13 of 23 patients who were given a target dose of 960 mg demonstrated a disease control rate of 100%, with 54% attaining a partial response and 46% attaining stable disease.

Among the 34-participant subset, no adverse events resulting in discontinuation occurred, and there were no dose-limiting toxicities. Furthermore, only 9 of these patients had grade 1-2 treatment-related adverse events (TRAEs) and 3 patients had grade 3 TRAEs (ie, diarrhea and anemia).

The KRAS G12C mutation is an oncogenic driver, with KRAS a guanine-nucleotide-binding protein, which functions as a molecular switch inside cells and connects receptor tyrosine kinase activation to intracellular signaling.

“AMG 510 represents a novel, first-in-class small molecule that specifically binds to the mutant protein of KRAS,” Govindan said. “It binds to the cysteine component and irreversibly locks it in the inactive state so that KRAS activity is restrained. This is very specific and customized to the mutant protein; therefore, we expect fewer normal-tissue toxicities.”

Govindan also said the early results of the trial were impressive.

“The very first patient went on this study just about a year ago,” he said. “All these results [that] were accumulated have come on just within a year of research.”