September 2011 ASCO 2011 Bloom KJ

Background

About 50% of melanomas have an activating V600E BRAF mutation, which suggests that inhibition of the mutated BRAF kinase may be of clinical benefit. Previous phase I and II trials with vemurafenib have shown impressive response rates in V600E BRAF-mutated metastatic melanoma patients.1

At ASCO 2011, Chapman and colleagues presented the results of BRIM-3 — a phase III randomized, openlabel, multicentre trial comparing vemurafenib with dacarbazine (DTIC) in previously untreated patients with V600E BRAF-mutated metastatic melanoma.2

Study design

  • Patients with previously untreated, unresectable stage IIIC or stage IV melanoma (ECOG performance status 0 or 1, with no active CNS metastases) who tested positive for V600E BRAF mutation by the cobas 4800 BRAF V600 Mutation Test were randomized in a one-to-one ratio to oral vemurafenib (960 mg, twice daily) or intravenous DTIC (1,000 mg/m2, three times weekly).
  • Cross-over was not permitted and the trial was a non-blinded randomization.
  • Co-primary endpoints were overall survival (OS) and progression-free survival (PFS) in the intent-to-treat (ITT) population.
  • Secondary endpoints included objective response rates (ORR) and safety.

Key findings

  • From January to December 2010, 675 patients were enrolled from 104 centres worldwide, and the cohorts were well-balanced.
    • Approximately two-thirds of patients in both arms had stage M1c disease, and 42% of patients had elevated LDH levels.
  • The data cut-off for this analysis was December 30, 2010.
  • At the pre-planned interim analysis (50% of deaths needed for final analysis), the hazard ratios (HR) for OS and PFS were 0.37 (95% CI 0.26–0.55; p <0.0001) and 0.26 (95% CI 0.20–0.33; p<0.0001), respectively, both in favour of vemurafenib. (Figures 1 and 2)
  • At six months, the estimated OS was 84% for vemurafenib, versus 64% for DTIC.
    • The median OS could not be analyzed at the time of this analysis.
    • Improvements in OS were seen for all sub-groups examined.
  • The median PFS was 5.3 months for vemurafenib, versus 1.6 months for DTIC, and was highly statistically significant in favour of vemurafenib.
    • All pre-specified subsets of patients showed clear benefits in PFS.
  • The ORR was 48.4% and 5.5% for vemurafenib and DTIC, respectively, among the 65% of patients evaluable for RR, to date.
  • As a result of the promising data, independent data monitoring committee (IDMC) recommended that the DTIC cohort has been allowed to cross over to vemurafenib.
  • At the time of analysis, 66% of vemurafenib patients and 25% of DTIC patients were still on treatment.
  • The most common toxicities associated with vemurafenib that required dose modifications were: arthralgia, rash, photosensitivity, fatigue, and increased liver function tests (LFTs). (Table 1)
  • Adverse events (AEs) of special interest were cutaneous squamous cell carcinoma (grade 3), keratoacanthoma, and skin papilloma (which are a function of vemurafenib and other drugs in this class).
  • For all AEs, grade 3 toxicities were fairly uncommon for both study arms, as was discontinuation.

Key conclusions

  • Vemurafenib is associated with statistically significantly improved OS and PFS compared to DTIC in patients with previously untreated, V600E BRAF-mutated metastatic melanoma.
  • Vemurafenib was associated with a 63% decrease in the hazard ratio of death (p <0.001) and a 74% decrease in the hazard of tumour progression (p <0.001).
  • The benefits of vemurafenib treatment were seen in all sub-groups, including poor prognosis patients.
  • Vemurafenib had a manageable safety profile, with few drug-related discontinuations.
  • This is the first single drug for melanoma to improve response rate, PFS and OS compared with standard chemotherapy.
  • Vemurafenib is a promising new therapy and a foundation upon which to build future combination therapies.

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. Chapman PB, Hauschild A, Robert C, et al. Vemurafenib: Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor vemurafenib with dacarbazine (DTIC) in patients with V600E BRAF-mutated melanoma. J Clin Oncol (ASCO Annual Meeting Abstracts) 2011;29:LBA4.