The pace of discovery in metastatic melanoma in the last couple of years has been remarkable. The approval of Bristol-Myers Squibb’s ipilimumab (Yervoy) a couple of months ago is almost certainly to be followed by a green light for Roche and Daiichi Sankyo’s vemurafenib, possibly towards the end of this year, and researchers are hopeful that further advances are on the way (ASCO – Melanoma hopes lie in combination approaches, June 6, 2011).
Data presented at this year’s Asco reinforced the excitement around these two agents. They are not a cure, and metastatic melanoma remains a devastating disease. But doctors are increasingly optimistic that more patients can be kept alive for longer, and a swift uptake of both agents – where they can be afforded – is expected.
The trial of vemurafenib, BRIM 3, presented at the conference’s plenary spot, is still ongoing and results are likely to continue emerging next year. The study started in January 2010 and recruited 672 patients with previously untreated, BRAF mutation positive metastatic melanoma; enrolment took less that 12 months.
About 10% of patients are still alive and definitive overall survival data is not yet available, but the investigators estimate six month survival in the vemurafenib plus dacarbazine arm at 84%, compared to 64% for those solely on the chemotherapy.
Life expectancy for these patients is less than a year, so progression free survival data has been generated. Those given vemurafenib on top of dacarbazine lived significantly longer before their tumours progressed – 5.3 months – compared to a median 1.6 months in the dacarbazine group.
The hazard ratios – which describe relative risk – are also impressive: vemurafenib reduced the risk of death by 63% and the risk of tumour progression by 74%. Patients who respond to the drug do so quickly and dramatically.
“It is unprecedented to see this level of activity. We have seen patients get on vemurafenib and their symptoms improve in 72 hours. Pain medicine can be reduced. Patients have an improved quality of life,” said Dr Lynn Schuchter, professor of haematology-oncology at the Abramson Cancer Center at the University of Pennsylvania.
A review of the study given by Dr Kim Allyson Margolin of the University of Washington at the conference’s plenary session was equally positive. “[Vemurafenib’s] rapid onset of anti-tumour activity can lead to symptomatic relief in a very short time, which is something melanoma specialists have never previously been able to offer, and that really feels fantastic,” she told the conference.
Duration of response
The data from the first-line ipilimumab trial presented showed overall survival was significantly extended by adding the immunotherapy to dacarbazine, by just over two months – to 11.2 from 9.1 months.
Unlike vemurafenib, ipilimumab takes longer to have an effect. The antibody works by essentially taking the brakes off the immune system, and the impact on the cancer builds more slowly.
However, the trial confirmed that ipi can have a sustained effect in some patients. After three years, 20.8% of patients in the group that received ipi plus dacarbazine were still alive, compared to 12.2% of the group that received the chemotherapy agent and a placebo.
It is this duration of response in certain patients that is getting doctors excited. Working out which subsets of patients respond well, as well as refining optimum dosage schedules, are the next steps for this agent, Dr Margolin believes.
As only the third drug to win approval to treat metastatic melanoma – after dacarbazine was approved in 1975 and high dose interleukin-2 in 1998 – take up of ipilimumab is likely to be swift, where it is reimbursed.
Analysts believe the drug, branded Yervoy by BMS, could generate $141m this year with sales reaching $1.36bn by 2016, according to forecast data from EvaluatePharma.
And although vemurafenib will likely be indicated for the same patient group when it reaches the market, few believe the agents will actually compete for patients with the BRAF mutation.
“Vemurafenib is appropriate for patients who have symptoms and need to respond fast,” Dr Margolin said. “For those patients whose tumour burden is relatively limited, minimally symptomatic and whose long term goal is durable benefit and who are not in urgent need of the physical and emotional relief associated with quick tumour regression, ipi may well be the preferred choice.”
Dr Paul Chapman, lead author of the study and an oncologist at Memorial Sloan-Kettering Cancer Center in New York, agreed. “I would treat patients with enough time to respond with ipi first. But it can take a long time to work. If a patient might not have enough time to respond, I would try vemurafenib first,” he said.
Consensus forecasts for vemurafenib, previously called RG7204, currently sit at $537m by 2016. That figure that could head north following this conference although the drug will not address such a large population as ipi. BRAF mutations are associated with just under half of all melanomas and vemurafenib targets a BRAF subset, meaning analysts believe only a third of all melanoma patients will qualify for the drug.
The excitement around these drugs is tempered by the fact that they are not a cure – the median time for melanoma tumours to become resistant to vemurafenib is seven months. Considering their high cost – vemurafenib is unlikely to be cheap and a three month course of Yervoy costs $120,000 – and the fact the survival benefit for many patients can be counted in weeks, reimbursement will be hard to come by in many regions of the world.
This makes finding out which patients are likely to benefit a hugely important next step, particularly for ipilimumab. Meanwhile evidence that vemurafenib has utility as a “bridging” therapy, to get patients to a stage where their disease can be treated with more durable and definitive solutions such as surgery or radiotherapy, should also be sought, Dr Margolin said.
But while they might not be a cure, doctors agree these two new agents represent a big leap forward and provide a platform for further research. Particularly with combination therapies, that many believe hold the key to help more melanoma patients live longer.
“What’s important to my patients is – what’s my chance of being alive long term, or in five years time?,” said Dr Chapman. In five years time “I’m hoping that will be a substantial proportion of patients.”