Patients with metastatic melanoma have a median survival of 6 to 10 months. Few patients have a response to systemic therapies. Ipilimumab blocks cytotoxic T-lymphocyte–associated antigen 4 (CTLA4) on lymphocytes, and has recently been associated with median overall survival of 10.1 months among previously treated patients and 11.2 months among previously untreated patients. However, the majority of patients do not have a response to anti- CTLA4 antibody therapy and still need effective therapeutic options.

Mutations in the gene encoding the serine–threonine protein kinase B-RAF (BRAF) have been identified in over 60% of melanomas initially tested. Melanomas carrying a BRAF V600E mutation activate the protein kinase (MAPK) pathway, promoting cell proliferation and preventing apoptosis. Vemurafenib was developed as a potent kinase inhibitor with specificity for the BRAF V600E mutation within cancer cells. It produced tumour regressions in patients with BRAF V600– mutant metastatic melanoma in a phase 1 trial and improved overall survival in a phase III trial. The median duration of follow-up in the phase III trial was slightly less than 4 months, inadequate to address long term outcomes.

This phase II trial in 132 patients with previously treated BRAF V600–mutant metastatic melanoma reported in the New England Journal of Medicine had a much longer follow-up period (median 12.9 months; range, 0.6 to 20). The primary end point was the overall response rate; overall survival was a secondary end point. The following findings were reported:

• The confirmed overall response rate was 53% (95% CI, 44 to 62) of which 6% had a complete response and 47% a partial response).

• The median duration of response was 6.7 months (95% CI, 5.6 to 8.6).

• The median progression-free survival was 6.8 months (5.6 to 8.1).

• Primary progression was observed in 14% of patients.

• Some patients had a response after receiving vemurafenib for more than 6 months.

• The median overall survival was 15.9 months (11.6 to 18.3).

• The most common adverse events were grade 1 or 2 arthralgia, rash, photosensitivity, fatigue, and alopecia. Cutaneous squamous-cell carcinomas (the majority, keratoacanthoma type) were diagnosed in 26% of patients.

The researchers conclude that this trial showed a clinical response to vemurafenib in more than half of patients with previously treated BRAF V600–mutant metastatic melanoma; and the long follow-up period provided critical information on long-term overall survival, not yet shown in the phase III trial comparing vemurafenib with dacarbazine.