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P2.15-C Phase 1 Trial Evaluating Safety, Efficacy, and PK of AMG 510, a Novel KRASG12C Inhibitor, in Non-Small Cell Lung Cancer

2019; Elsevier BV; Volume: 14; Issue: 11 Linguagem: Inglês

10.1016/j.jtho.2019.09.181

1556-1380

Ramaswamy Govindan, Marwan Fakih, T. Price, Gerald S. Falchook, Jayesh Desai, James Kuo, John H. Strickler, John C. Krauss, Bob T. Li, C.S. Denlinger, Greg Andrew Durm, Jude Ngang, Haby Henary, Gataree Ngarmchamnanrith, Erik Rasmussen, Phuong K. Morrow, David S. Hong,

Peptidase Inhibition and Analysis

Currently, no approved therapy targets KRASG12C mutation, which occurs in approximately 13-14% of non-small cell lung cancer (NSCLC). AMG 510, a novel small molecule, specifically and irreversibly inhibits KRASG12C by locking it in an inactive GDP-bound state. This is a phase 1, first-in-human, open-label, multicenter study of AMG 510 in patients with locally advanced or metastatic KRASG12C mutant solid tumors, including NSCLC. The primary endpoint is safety; key secondary endpoints include objective response rate, assessed every 6 weeks, duration of response, progression-free survival, and PK. Key inclusion criteria: KRASG12C mutation identified through DNA sequencing; measurable or evaluable disease; progression on standard therapy; and ECOG PS ≤ 2. Patients with active (untreated) brain metastases and myocardial infarction within 6 months of study initiation were excluded. Once maximum tolerated dose is identified during dose escalation, additional patients will be enrolled in the dose expansion part. AMG 510 is given orally once daily until disease progression, intolerance, or consent withdrawal. As of 4 April 2019, 13 patients (8 females; median age: 63 years [range: 53–77]) with NSCLC were enrolled into 4 dose escalation cohorts. Median number of prior lines of therapy was 3 (range: 1–5). Median duration of treatment was 59 days (range: 9–192). No dose-limiting toxicities were identified. The most frequently reported adverse events (AEs) were decreased appetite and diarrhea, observed in 4 and 3 patients, respectively. Six patients reported 10 treatment-related adverse events (TRAEs) (6 grade 1; 2 grade 2; 2 grade 3). Two grade 3 TRAEs were anemia in a patient with baseline grade 2 anemia and diarrhea that lasted 2 days in another patient. 10 patients were evaluable for tumor response: 5 patients had a partial response (2 of which were confirmed), 4 had stable disease, and 1 had progressive disease (PD). Of all 13 patients enrolled, 11 remained on study, and 2 discontinued due to PD. AMG 510 is well tolerated at all 4 dose levels and showed antitumor activity in patients with advanced KRASG12C mutant NSCLC. Enrollment is ongoing (ClinicalTrials.gov identifier: NCT03600883).