The FDA announced the approval on March 30 of ipilimumab (Yervoy ™) for the treatment of patients with newly diagnosed or previously treated unresectable or metastatic melanoma.

"The results of the O20 study on which the FDA based their decision represents the first time ever that a drug has been shown to increase overall survival in advanced melanoma," said Dr Paul Lorigan, a consultant oncologist from the Christie Hospital NHS Foundation Trust who has been involved in the trials.

"The approval of ipilimumab by the FDA means that for the first time in 40 years there's a new treatment option in melanoma," said Dr James Larkin, a consultant medical oncologist from The Royal Marsden NHS Foundation Trust, another of the centres involved in the trials. The current standard treatment for melanoma, he added, is dacarbazine that has a response rate of 5 to 10% and has not been shown to improve overall survival. "Melanoma affects a lot of young people and represents an unmet medical need that needs to be tackled urgently."

Ipilimumab is an antibody that activates the body's immune system to fight melanoma by inhibiting the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) molecules found on T cells. CTLA-4 has been characterized as a "brake" that binds to co-stimulatory molecules on antigen-presenting cells, preventing their interaction with CD28 on T cells, thereby generating a signal that prevents further T cell activation. The analogy most commonly used for the CTLA-4 inhibition by ipilimumab is that you are disconnecting the brake and allowing the accelerator to work unchecked.

The FDA approval was based on the 020 study, where 676 patients with unresectable or metastatic melanoma (who had received at least one prior systemic treatment) were randomised 3:1:1 to one of three treatment arms consisting of ipilimumab, 3 mg/kg intravenously in combination with the tumour vaccine (n=403); ipilimumab plus vaccine placebo (n=137); and tumour vaccine with placebo (n=136). Results showed that overall survival was 10 months for ipilimumab alone versus 6 months for vaccine alone (HR 0.66 95% CI: 0.51-0.87, p=0.0026). Additionally the study demonstrated a statistically significant improvement in overall survival for the combination of ipilimumab plus tumour vaccine compared to tumour vaccine alone.

"An experimental vaccine comparator arm was used since it was considered unethical to offer placebo to patients suffering from a disease with a poor prognosis," explained Larkin.

In the 020 study, the most common adverse events were immune-related and occurred in around 60% of patients treated with ipilimumab and 32% treated with the comparator arm. Immune related adverse events were treated with the use of supportive care and systemic steroids using established protocol specific treatment guidelines. "There has been a suggestion that response to ipilimumab is correlated with toxicity, and that toxicity is a surrogate for the immune stimulation," said Lorigan

The approved dose for ipilimumab is 3mg/kg administered intravenously over 90 minutes every three weeks for a total of four doses.

Bristol Myers Squibb have also announced that study 024, comparing ipilimumab 10 mg/kg in combination with dacarbazine to dacarbazine alone, has met its primary endpoint of improving overall survival in previously untreated patients with unresectable stage III or IV melanoma.

"The study was event driven, i.e. a certain number of deaths had to be reported to reach the primary endpoint. The fact that 024 reported twelve months later than expected offers an impressive indication that overall survival in the ipilimumab arm increased markedly," said Lorigan, cautioning that the extent of benefit will only be fully appreciated when the study reports. An abstract of the 024 data has been submitted to the American Society of Clinical Oncology (ASCO) for potential presentation in June.

Additional on-going studies in ipilimumab include an EORTC adjuvant study looking to determine if the agent is effective in preventing or delaying recurrence and prolonging survival after complete resection of high risk stage III melanoma. The study is recruiting well and is expected to report in 2014. Other studies are exploring use of ipilimumab in kidney cancer, prostate cancer and lymphoma.

Also expected to be registered soon is Roche's Vemurafenib (PLX4032/RG7204/RO5185426), a BRAF inhibitor interfering with internal signalling in the cell. There will need to be trials, said Lorigan, looking at how these drugs will be used in combination. "For those patients who don't have BRAF mutations it's likely that we'll use ipilimumab upfront; while for those who have BRAF mutations we'll use vemurafenib upfront and ipilimumab second line," said Lorigan, adding that around half of melanoma patients have BRAF mutations.

"For someone who treats a lot of patients with advanced melanoma it's an incredibly exciting time to have two treatment options come along in the space of a few months that clearly prolong survival," said Larkin.