September 2011 ASCO 2011 Sharfman WH


RAF265 is an oral small molecule multi-kinase inhibitor of mutant BRAF V600E and vascular endothelial growth factor receptor 2 (VEGFR2). It displays dose-dependent inhibition of tumour growth and regression in mutant BRAF V600E tumour xenografts, including primary human melanoma models.

At ASCO 2011, Sharfman and colleagues presented results from the first in-human phase I study of the oral RAF inhibitor RAF265 administered daily to patients with advanced cutaneous melanoma.1

Study design

  • The trial was designed as a dose escalation study to identify the maximum tolerated dose (MTD), safety, pharmacokinetic profile, progressive disease and anti-tumour activity of RAF265, and to develop a phase II dose expansion restricted to BRAF mutant melanoma patients.
  • Various administration schedules of RAF265 were used: daily, weekly, and intermittent.
  • Only the results for daily dosing in the arm 2 dose escalation schema were presented during this session, where patients were treated by a loading dose followed by continuous daily RAF265 oral solution at escalated dose levels (there were seven dose levels in this study).
  • A Bayesian logistic regression model with overdose control guided the dose escalation.
  • Patients who were 18 years of age or older, with histologically confirmed melanoma and measurable, locally advanced or metastatic disease, with a minimum four weeks having elapsed since any major surgery or prior investigational therapy were eligible for this study.

Key findings

  • 76 patients were enrolled with a median age of 60 years (range: 26–83 years).
  • RAF265 was rapidly absorbed, with the maximal plasma concentration (Cmax) observed at approximately three hours after drug administration (range: 1–8 hours).
  • Cmax and area under the curve (AUC0-last) increased proportionally with increasing dose.
  • The mean elimination half-life (t1/2) of RAF265 was 11 days. (Figure 1)
  • Pre-clinical studies had indicated that 4,127 ng/mL was the effective concentration (Ceff), which fell between dose levels six and seven; however, the MTD was declared to be dose level six.
  • Plasma angiogenesis markers showed decreases of soluble VEGFR2 (sVEGFR2) and increases in placental growth factor (PlGF) across dose levels.
    • Statistically significant changes in angiogenesis marker levels were seen over time (p<0.0001) and across dose levels.
  • There were limited grades 3 or 4 drug-related adverse events (AEs) at dose levels one to five. Adverse events at dose levels 6 and 7 are shown in Table 1.
  • Seven dose-limiting toxicities (DLTs) were noted in six patients:
    • Pulmonary embolism (two patients), visual disturbances (one patient), hyperlipasemia (one patient), diarrhea (one patient) and ataxia (one patient).
    • Grade 3 thrombocytopenia (five patients) and 4 (two patients) occurred at 67 mg daily in the second cycle and was also considered dose limiting.
    • The MTD was declared at 48 mg once daily, at dose level six.
  • 64 patients were evaluable for response:
    • The overall response rate (ORR) was 11% across all dose levels, and the median duration of response was approximately four months.
    • Patients with responses were seen across all the dose levels, and one complete response was seen at dose level seven.
    • Responses were seen in patients with both BRAF mutant tumours (n = 39, three partial responses), and BRAF wildtype tumours (n = 27, two PR and one CR).

Key conclusions

  • In this first in-human phase I study, the MTD of oral RAF265 on a continuous daily schedule was defined at 48 mg.
  • The main dose-limiting toxicities were thrombocytopenia and visual AEs.
  • Clinical activity was observed at multiple dose cohorts in patients with BRAF mutant and wild type melanoma.
  • Statistically significant changes were observed in angiogenesis markers, PIGF and sVEGFR2, over time across all dose levels.
  • Due to the long half-life of RAF265, an intermittent schedule is being explored to improve its therapeutic index.

Reference: 1. Sharfman WH, Hodi FS, Lawrence DP, et al. Results from the first-in-human (FIH) phase I study of the oral RAF inhibitor RAF265 administered daily to patients with advanced cutaneous melanoma. J Clin Oncol(ASCO Annual Meeting Abstracts) 2011;29:8508.