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

• Published in: Molecular cancer therapeutics Vol. 19; no. 2; pp. 460 - 467
• Main Authors: Sullivan, Ryan J., Hollebecque, Antoine, Flaherty, Keith T., Shapiro, Geoffrey I., Rodon Ahnert, Jordi, Millward, Michael J., Zhang, Wei, Gao, Ling, Sykes, Amanda, Willard, Melinda D., Yu, Danni, Schade, Andrew E., Crowe, KrisAnne, Flynn, Daniel L., Kaufman, Michael D., Henry, James R., Peng, Sheng-Bin, Benhadji, Karim A., Conti, Ilaria, Gordon, Michael S., Tiu, Ramon V., Hong, David S.
• Format: Journal Article
• Language: English
• Published: United States 01.02.2020
• Subjects: Adult; Aged; Aged, 80 and over; Cell Line, Tumor; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasms - drug therapy; Phenylurea Compounds - pharmacology; Phenylurea Compounds - therapeutic use; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Young Adult
• ISSN: 1535-7163; 1538-8514; 1538-8514
• DOI: 10.1158/1535-7163.MCT-19-0681

Mutations in ERK 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 I 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 a day on a 28-day cycle. In part B, 300 mg LY3009120 was given twice a day. The primary objective was to identify a recommended phase II 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 16 patients were treated, respectively (N = 51). In part A, 6 patients experienced eight dose-limiting toxicities. The RP2D was 300 mg twice a day. 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 4 weeks; 84% of patients completed one or two cycles of treatment. Exposures observed at 300 mg twice a day 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.