Role of vemurafenib in melanoma treatment

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Published: 24 Jun 2011
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Dr Paul Nathan - Mount Vernon Cancer Centre - Northwood, UK
Dr Paul Nathan discusses the array of successful melanoma therapies that have been presented at ASCO 2011, particularly the Phase III BRIM 3 study which compared vemurafenib with dacarbazine in previously untreated patients with unresectable Stage IIIc or Stage IV melanoma. This trial has demonstrated that the BRAF targeting drug vemurafenib halts tumour growth or causes tumour shrinkage in almost half of patients and drastically improves survival. The results were so conclusive that the trial was terminated early and all patients were transferred to vemurafenib. Dr Nathan concludes by considering what role immunotherapy will play in the treatment of melanoma patients and explaining the need for Phase III data for wild type BRAF patients.

ASCO 2011 Annual Meeting, 3—7 June 2011, Chicago

Role of vemurafenib in melanoma treatment

Dr Paul Nathan - Mount Vernon Cancer Centre, Northwood, UK

Paul, thank you very much indeed for coming along, I know it’s a busy time at ASCO. What are the melanoma stories that you are going to take home to the UK and tell people about?

It has to be, and I’m sure you’ve heard, the best ASCO by far for melanoma. Major advances with new agents that have been proven to extend survival in the first line setting; we knew that there was activity in the second line setting last year. And the two areas that are being developed in parallel are genetically or genotypically targeted therapies, particularly with BRAF agents, and the vemurafenib data from BRIM III was shown. And then also data in combination with dacarbazine in the first line with ipilimumab showing a survival benefit as well.

Any place for dacarbazine in the future?

I think that’s unclear at the moment because when you look at the studies with ipilimumab there is a proportion, a small proportion of patients, who do have benefit from dacarbazine, it’s just that we know that we’re useless at identifying which 5-6% of patients do have long-term benefit. All of us who have treated patients with dacarbazine over the years know that there are a tiny sub-population of patients who do have benefits, so I think it would be rash to say that there is no place, but it’s true to say that it’s not going to be a standard of care for the majority of patients in the future.

When temozolomide started working in melanoma, and was used off-label in the US, people were saying, well temozolomide is just dacarbazine, but it’s easier to give. Is it possible that these dacarbazine successes could be related to O6-methylguanine transferase? Has someone looked at it?

Well we know that there’s no improved benefit comparing dacarbazine with temozolomide, and we also know that from the EORTC 1832 study, which showed extended duration temozolomide compared to dacarbazine, that there was no excess benefit of keeping the temozolomide there all the time. So I think that avenue has been fully explored. And what we’re waiting on, I suppose, is some combination data with the PARP inhibitors. But in comparison to the data that we’ve seen at this meeting, that has to be less exciting.

Tell me about the BRIM trials, you were involved in that. Still are.

Still are, and still have patients responding and I think most of us who have been involved were absolutely astonished when we had patients and, at that first response CT scan at six weeks in, we could see massive reductions in tumour bulk. And we’ve never seen anything like that.

That will catch the attention of a lot of people who don’t treat melanoma every day.


What exactly is going on, what’s the BRIM trial?

The BRIM III study, which is the first-line study that has been presented, was a randomised study in BRAF mutant melanoma, carrying the V600 e-mutation of the BRAF oncogene, which comprises about 50% or so of patients with cutaneous melanoma. A randomised study comparing a BRAF-targeted agent with dacarbazine, which was the standard of care. And the study reported in the plenary session by Paul Chapman showed a profound, significant benefit in terms of overall survival and progression-free survival.

With chemotherapy-naïve patients?

First-line with chemotherapy-naïve patients. So compared with dacarbazine.

Give me some numbers on that?

So it was a progression-free survival difference that went from about, from first scan, which was about 1.2 months, up to five or six months, five months for the progression-free survival benefit. And the hazard ratio on the overall survival benefit was about 0.37. So that’s a huge difference.

Impressive. That’s a figure I understand.

Absolutely. So major benefit, and of course the interesting thing is that we don’t yet know about the duration of those responses. So it’s an early report, most of the curve that we’re showing is early follow-up, so we’re not yet sure about the duration of benefit. When you look back to the BRIM I study, which was the phase one study in approximately 32 patients, I think, on the phase one, 25%, seven patients out of those 32 patients, are still on treatment with controlled disease at two years.

On the drug?

On the drug. So although the median progression-free survival seems to be holding up, perhaps at about eight months, but we don’t yet know that from the BRIM III study because it’s too early, there are, I hope, a significant group of patients that will have durable responses.

And there will be a tail to the curve.

We don’t yet know that. Now, we know that melanoma is, in some ways, an atypical cancer, because we know that there are a group of patients in whom we do nothing, they will be long-term survivors; they’re only in the order of 5% or so of the untreated, unselected population. What the tail looks like with anti-BRAF treated patients, we obviously don’t know yet. But that’s an important question because it dovetails very much into how these patients and when these patients should be treated with immunotherapy, with ipilimumab.

What’s your view on that?

Well, the discussants, Kim Margolin and Paul Chapman, when they present the BRIM III data, have been talking very much about the rapid responses to the BRAF agent, and there’s no doubt with melanoma, a proportion of patients arrive with very barky disease, they have very poor prognosis, and are very symptomatic. And you need a rapid response, and we’ve never had an agent that can do that, previously. And it looks as if, if those patients are carrying a mutation in their BRAF oncogene, that they are very likely to have a rapid response, and that would bring profound palliative benefits. The question is about the duration of the responses in that subgroup of patients. We know that the M1C, the worst prognostic group of patients, seem to have as great a chance of responding as the better prognostic patients but the durability of those responses still needs to be teased out.

Ipilimumab takes time to work. So it’s four infusions over a three-month period, and if you look at the first scan from the ipilimumab data, all of those patients have progressed at three months. And so you only see benefits from ipilimumab later on. So if you’ve got rapidly progressive melanoma, you are very unlikely to be able to stand a chance of responding to ipilimumab but you perhaps wouldn’t want to wait until you’ve got progressive disease before giving ipilimumab, so the answer to your question is of course we don’t yet know how to use these drugs in combination.

It sounds like the BRAF is going to split up, as Sledge said in his presidential address, into smart and non-smart; and if you’re not in the smart group where you haven’t got the right mutation, you’re not going to get the BRAF drug and you’ve got the bulky disease, you’ve got no immediate advantage really from either drug.

Yes, so what we haven’t got at the moment is phase III data in wild-type BRAF patients, that shows, well, full stop. But there are candidate drugs that appear to have activity…

What kind of drugs?

So, there’s administering data from Eisai with multi-targeted kinase inhibitor E7080 showing significant activity in an unselected population of patients, many of whom will have wild type. There is interest in some of these multi-targeted kinase drugs used in the wild type setting. And there is pre-clinical data looking at combinations of MEK inhibitors with chemotherapy drugs, with taxanes particularly.


MEK. And which curiously shows activity in the pre-clinical setting in wild type tumours.

Right. That would be nice.

So in the UK we have a study looking at a combination of docetaxel with an Astra Zeneca MEK inhibitor at the moment and there’s plans for a similar study with a probably more potent MEK inhibitor. So obviously a lot of the excitement is around the BRAF mutant tumours, but there is progress being made on the wild type tumours as well.

That sounds fantastic. Paul, thank you very much indeed for taking ten minutes out of your ASCO trip, and safe home to the UK.

Thank you very much.