A clinical trial testing the toxicity of a KRAS inhibitor demonstrated early promising antitumor activity and few adverse side effects in patients with advanced non-small cell lung cancer harboring KRAS G12C mutation, according to research presented today at the IASLC 2019 World Conference on Lung Cancer, host by the International Association for the Study of Lung Cancer.
Non small cell lung cancer
The KRASG12C mutation is found in approximately 14% of patients with lung adenocarcinoma and 11% of patients with non-small cell lung cancer but there are no therapies approve that target this mutation. KRAS G12C mutation has identify as an oncogenic driver of tumorigenesis. KRAS is a guanine-nucleotide-binding protein that acts as a molecular switch inside cells and links to receptor tyrosine kinase activation to intracellular signaling.
To test this therapy, AMG 510, for safety and toxicity, Ramaswamy Govindan, M.D.; from the Siteman Cancer Center at Washington University School of Medicine, St. Louis and colleagues enroll 76 patients with locally advance or metastatic malignancies who had receive previous standard therapy. The research group’s primary endpoint was toxicity and secondary research endpoints were objective response rate, duration of response, disease control rate, progression free survival and duration of stable disease.
Patients were enroll in four dose cohorts: 180 mg, 360 mg; 720 mg and 960 mg, taken orally once a day for 21 days and follow up with radiographs and examinations. Initial data from the Phase one study were present at the 55th Annual Meeting of the American Society of Clinical Oncology earlier this year.
Dose limiting toxicities
The additional follow-up in a larger group of patients being present at WCLC includes a subset of 34 NSCLC patients enrolled; with 23 of the patients being evaluable for efficacy. Thirteen of the evaluable patients receive the target dose of 960 mg once daily; with seven (54%) achieving a partial response at one or more time points and six (46%) achieving stable disease; for a disease control rate of 100%.
Hence there were no dose limiting toxicities and no adverse events leading to discontinuation in the 34 NSCLC patients enroll. Twenty-seven of these patients remain on treatment. So the 34 patients, only nine (26.5%) report treatment relate; adverse events (TRAEs) of grade one or two. Three patients report grade three treatment relate adverse effects (anemia and diarrhea).
So there were no grade four or higher TRAEs. “KRAS G12C mutant lung adenocarcinoma is one of the largest subsets of NSCLC potentially amenable to target therapies. So they please that we have a promising new oral therapy for this group of patients,” Govindan said. “These data continue to show encouraging anti-tumor activity with AMG 510; so underscoring the potential to close the treatment gap for non-small cell lung cancer patients with previously treat KRAS G12C-mutate NSCLC.”