A Phase 1 Study of LY3009120, a Pan-RAF Inhibitor, in Patients with Advanced or Metastatic Cancer

Mutations in extracellular signal regulated kinase signaling drive a significant percentage of malignancies. LY3009120, a pan-RAF and dimer inhibitor, has preclinical activity in RAS- and BRAF-mutated cell lines including BRAF-mutant melanoma resistant to BRAF inhibitors. This multicenter, open-label, Phase 1 clinical trial (NCT02014116) consisted of Part A (dose escalation) and Part B (dose confirmation) in patients with advanced/metastatic cancer. In Part A, oral LY3009120 was dose escalated from 50 to 700 mg twice daily (BID) on a 28-day cycle. In Part B, 300 mg LY3009120 was given BID. The primary objective was to identify a recommended Phase 2 dose (RP2D). Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary efficacy. Identification of pharmacodynamic biomarkers was exploratory. In Parts A and B, 35 and sixteen patients were treated, respectively (N=51). In Part A, six patients experienced eight dose-limiting toxicities. The RP2D was 300 mg BID. Common (>10%) any-grade drug-related treatment-emergent adverse events were fatigue (n=15), nausea (n=12), dermatitis acneiform (n=10), decreased appetite (n=7), and maculopapular rash (n=7). The median duration of treatment was four weeks; 84% of patients completed one or two cycles of treatment. Exposures observed at 300 mg BID were above the preclinical concentration associated with tumor regression. Eight patients had a best overall response of stable disease; there were no complete or partial clinical responses. Despite adequate plasma exposure levels, predicted pharmacodynamic effects were not observed.