In a clinical trial testing the toxicity of a KRAS inhibitor, the treatment demonstrated early promising antitumor activity and few adverse side effects in patients with advanced non–small cell lung cancer (NSCLC) harboring a KRAS G12C mutation. The research was presented by Govindan et al at the International Association for the Study of Lung Cancer (IASLC) 2019 World Conference on Lung Cancer (WCLC) (Abstract OA02.02).
The KRAS G12C mutation is found in approximately 14% of patients with lung adenocarcinoma and 11% of patients with NSCLC. There are no therapies approved that target this mutation. The KRAS G12C mutation has been identified 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.
Methods
To test the KRAS inhibitor AMG 510 for safety and toxicity, Ramaswamy Govindan, MD, of the Siteman Cancer Center at Washington University School of Medicine, St. Louis, and colleagues enrolled 76 patients with locally advanced or metastatic malignancies who had received 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 enrolled into one of four dose cohorts: 180 mg, 360 mg, 720 mg, and 960 mg, taken orally once a day for 21 days and followed up with radiographs and examinations. Initial data from the phase I trial was presented at the 2019 ASCO Annual Meeting (Abstract 3003). The additional follow-up in a larger group of patients presented at the WCLC includes a subset of 34 patients with NSCLC enrolled, with 23 of the patients being evaluable for efficacy.
“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.”— Ramaswamy Govindan, MD
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Results
Thirteen of the evaluable patients received 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%.
There were no dose-limiting toxicities and no adverse events leading to discontinuation in the 34 patients with NSCLC enrolled. Twenty-seven of these patients remain on treatment. Of the 34 patients, only 9 (26.5%) reported treatment-related adverse events of grade 1 or 2. Three patients reported grade 3 treatment-related adverse effects (anemia and diarrhea). There were no grade 4 or higher treatment-related adverse effects.
“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 Dr. Govindan. “These data continue to show encouraging antitumor activity with AMG 510, underscoring the potential to close the treatment gap for [patients] with previously treated, KRAS G12C–mutated NSCLC.”
Disclosure: For full disclosures of the study authors, visit wclc2019.iaslc.org.
