September 2011 ASCO 2011 Dummer R

Background

Melanoma is a common cause of cerebral metastases, and indicates a poor prognosis. In phase I and II studies, vemurafenib has shown dramatic activity in metastatic melanoma harbouring V600-mutated BRAF.1,2 However, these studies excluded patients with active brain metastases and thus to date the activity of vemurafenib — an orally available inhibitor of oncogenic BRAF kinase — for brain metastases has remained unknown.

At ASCO 2011, Dummer and colleagues presented their early findings from an open-label pilot study of vemurafenib in previously treated metastatic melanoma patients with brain metastases.3

Study design

  • The study was an open-label, single-arm trial of vemurafenib designed to evaluate the safety and efficacy of this agent in patients with metastatic melanoma and non-resectable brain metastases.
  • Patients had BRAF V600 mutations (determined by the cobas 4800 BRAF V600 Mutation Test).
  • Patients with an ECOG performance status of 0–2 had to have been pretreated with radiotherapy and/or chemotherapy and were on stable or decreasing doses of steroids, and had brain metastases-related symptoms.
  • Vemurafenib was administered continuously at a dose of 960 mg twice daily, until progressive disease (PD) or toxicity.
  • Staging by magnetic resonance imaging (MRI) brain and computed tomography (CT) of the thorax/abdomen was scheduled every four weeks in the first two months, and then every eight weeks thereafter.
  • Overall survival (OS) was determined, as well as measurements of improvements in physical symptoms.
  • Patients’ serum S100 levels were also determined.
  • Adverse events (AEs), including serious adverse events (SAEs), were assessed.

Key findings

  • Seven patients were enrolled in the study:
    • Median age was 47 years (range 24–50 years);
    • Median number of nine brain metastases in each patient (range: 3–18);
    • All patients had metastases at other organ sites;
    • Patients had an ECOG performance status of 0–2;
    • All patients were on dexamethasone.
  • As of March 2011, patients have received treatment with vemurafenib for one to four months, with one patient on treatment for four months; one patient for three months; three patients for two months; and the remaining two patients for one month.
  • Six patients reported 38 treatment-emergent AEs.
    • All AEs were grade 1 or 2.
    • There were no grade 3 or higher AEs reported.
  • Of the 38 treatment-emergent AEs, 18 were reported by four patients as being possibly drug-related. (Table 1)
    • Four SAEs were reported by two patients, but were not treatment-related.
  • Preliminary evaluation showed that vemurafenib induced tumour regression in brain metastases with similar kinetics to other sites of involvement.
  • Five patients’ staging reports are currently available:
    • Patient 1 presented with a confirmed partial response in brain and body (as assessed by Response Evaluation Criteria in Solid Tumors [RECIST]) associated with a reduction of S100 from 141.6 μg/L (pretreatment) to 4.4 μg/L (day 43). (Figure 1) Dexamethasone and morphine doses were reduced.
  • Partial response was confirmed by brain MRI.
    • Patient 2 showed a minor response in brain and body at week 4 associated with a reduction of S100 from 35.6 μg/L (day 1) to 3.26 μg/L (day 15). (Figure 1)
    • As of March 2011, all other evaluable patients presented stable disease.
    • Serum S100 levels are shown in Figure 1 for Patients 1, 2 and 3.

Key conclusions

  • To date, vemurafenib has been well tolerated in symptomatic patients with melanoma metastatic to the brain.
  • This study provides early, strong results suggesting activity of vemurafenib in brain metastases.

References: 1. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010;363:809–819. 2. Ribas A, Kim KB, Schuchter LM, et al. BRIM-2: an open-label, multicenter phase II study of vemurafenib in previously treated patients with BRAFV600E mutationpositive melanoma. J Clin Oncol (ASCO Annual Meeting Abstracts) 2011;29:8509. 3. Dummer R, Rinderknecht J, Goldinger SM, et al. An open-label pilot study of vemurafenib in previously treated metastatic melanoma patients with brain metastases. J Clin Oncol (ASCO Annual Meeting Abstracts) 2011;29:8548.