September 2011 ASCO 2011 Ribas A

Background

Most agents tested in large phase II trials in patients with metastatic melanoma have response rates of 10–20%. Approximately 50% of melanomas harbour a V600E-activating mutation in the BRAF gene, which can now be targeted with investigational inhibitors. In a previous phase I study, treatment with vemurafenib led to a high incidence of tumour regressions in BRAFmutant melanoma.1

At ASCO 2011, Ribas and colleagues presented results of the BRIM-2 study — a pivotal phase II trial of vemurafenib in previously treated patients with BRAFmutant metastatic melanoma.2 The goal of the study was to confirm the best overall response rate (ORR) of vemurafenib in previously treated patients with BRAF V600-mutated melanomas.

Study design

  • The trial was a single-arm, multicentre, open-label phase II trial in patients with stage IV disease who had received one or greater prior systemic therapy.
    • Patients had brain metastases controlled for at least three months following local therapy.
  • The primary endpoint was ORR as assessed by an independent review committee (IRC).
  • Secondary endpoints were duration of response, progressionfree survival (PFS), overall survival (OS), and safety.
  • BRAF mutation status was determined using a PCR-based investigational, companion diagnostic assay (cobas 4800 BRAF V600 Mutation Test, Roche Molecular Systems).
  • Patients received oral vemurafenib at a dose of 960 mg twice daily until progressive disease (PD), unacceptable toxicity, or death.

Key findings

  • The trial included 132 patients with a median age of 51.5 years, who were enrolled between October 2009 and March 2010 for a median follow up of 10 months (range: 0.6–14.7 months).
    • 54% of patients had an ECOG performance status of 1, and 61% had M1c stage disease; 49% of patients had elevated lactate dehydrogenase (LDH); and 49% had received more than one line of prior therapy (i.e., poor prognostic factors.)
  • The ORR was 53% as assessed by independent review committee (IRC).
    • 29% of patients had stable disease (SD).
    • 14% of patients had PD. (Figure 1)
    • There were no differences in response rates according to age, gender, performance status, disease stage, number of prior therapies or prior therapy with high-dose interleukin- 2 (IL-2).
    • There was a difference in response rates based on baseline LDH levels with higher response rates in patients with a normal LDH and a lower response rate in patients with a baseline LDH of greater than 1.5 times the upper limit of normal (ULN).
  • The median duration of response was 6.8 months (95% CI: 5.6–not reached).
  • The median PFS by intent-to-treat-analysis was 6.7 months (95% CI: 5.5–7.8 months) and the PFS at six months was 54%. (Figure 2)
  • The median OS has not yet been reached after a median follow-up of 10 months. (Figure 3)
    • The OS at six months was 77% (95% CI: 70–85) and at 12 months was 58% (95% CI: 49–67).
  • Adverse events (AEs) were generally reversible (with dose modification or interruption).
  • The most common AEs (all grades) were arthralgia (seen in 59% of patients), rash (52%), and photosensitivity reaction (52%).
  • The most common grade 3 AE was cutaneous squamous cell carcinoma (seen in 26% of patients), the majority of which were centrally reviewed as keratoacanthoma-type.
  • 45% of patients required dose reductions, most commonly for rash, arthralgia, and liver function test abnormalities.
  • 64% of patients had dose interruptions due to AEs.
  • The median daily dose was 91% of the intended total dose.
  • Only four patients discontinued therapy due to drug-related AEs.

Key conclusions

  • Based on positive results as assessed by the primary endpoint of ORR, the BRIM-2 trial confirms that vemurafenib is an active agent in patients with BRAF mutation-positive melanoma who have completed prior systemic therapy.
  • The trial met its primary endpoint, with an ORR of 53% and a 95% CI that excludes an ORR of 20%.
  • The toxicity profile of vemurafenib at 960 mg twice daily is manageable, with most AEs being reversible with dose modification or interruption.
  • The longer follow up of this study is complementary to the benefits in OS seen in the BRIM-3 trial: together, these trials provide evidence that vemurafenib is an effective agent for the treatment of patients with BRAF V600 mutation–positive melanoma.

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 RG7204 (PLX4032) in previously treated patients with BRAF V600E mutation-positive metastatic melanoma. J Clin Oncol (ASCO Annual Meeting Abstracts) 2011;29:8509.