A phase 1a/1b study of aurora kinase A inhibitor VIC-1911 as monotherapy and in combination with sotorasib for the treatment of KRAS G12C-mutant non–small-cell lung cancer.

Abstract

TPS9140 Background: Activity of direct covalent KRAS G12C inhibitors in NSCLC is limited by mutational and adaptive resistance. AURKA has roles in centrosome maturation and cytokinesis. AURKA amplification/overexpression is reported in multiple tumors, including NSCLC, and AURKA signaling may mediate adaptive resistance to KRAS inhibition. VIC-1911 is a highly selective, orally active small molecule inhibitor of AURKA. VIC-1911 demonstrated monotherapy activity in vitro in KRAS G12C-mutant human NSCLC cells with intrinsic and acquired resistance to the KRAS G12C inhibitor sotorasib, and combination VIC-1911 and sotorasib showed synergy in the same cell lines. Combination VIC-1911 and sotorasib delayed the emergence of adaptive resistance in vitro. These findings suggest that 1) AURKA activation is present in both intrinsic and acquired resistance to sotorasib in KRAS G12C-mutant NSCLC and 2) the combination of VIC-1911 and sotorasib is a potential therapeutic approach for KRAS G12C-mutant NSCLC with intrinsic or acquired resistance to sotorasib monotherapy. In addition, in vivo data suggest both sotorasib and adagrasib are synergistic in combination with VIC-1911 in human KRAS G12C-mutant NSCLC cell line xenograft models. Methods: A non-randomized, open-label Phase 1a/1b study of VIC-1911, an aurora kinase A inhibitor, administered as monotherapy and in combination with sotorasib for the treatment of advanced KRAS G12C-mutant NSCLC is in progress. Participants ≥18 years, with locally advanced or metastatic KRAS G12C-mutant NSCLC, prior treatment with at least 1 line of PD-1/PD-L1 inhibitor therapy with or without platinum-based chemotherapy and have adequate organ function are eligible. Both KRAS G12C inhibitor naïve and experienced patients are eligible. VIC-1911 monotherapy is given at oral doses of 25 – 90 mg twice daily in dose escalation and at the VIC-1911 maximum tolerated dose (MTD) in the expansion cohort in patients who are refractory/relapsed on prior KRAS G12C inhibitor therapy. The combination regimen includes dose escalation with VIC-1911 at oral doses of 75, 150 or 200 mg twice daily on days 1-4, 8-11 and 15-18 every 28-day cycle plus sotorasib 960 mg daily in patients who are refractory/relapsed or naïve to prior KRAS G12C inhibitor therapy. In dose escalation, a 3+3 schema is followed with dose limiting toxicity (DLT) criteria for toxicity and a sample size ≤ 36. For expansion cohorts, the sample size is based on Simon 2-stage optimal design, with a sample size ≤ 104. VIC-1911 and sotorasib dose modification criteria are provided. Supportive medications are allowed and early stopping rules for toxicity will be followed. VIC-1911 pharmacokinetics will be assessed. Pharmacodynamics will be determined from ctDNA and tumor biomarker analysis. Clinical trial information: NCT05374538 .