Advances in the treatment of melanoma

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Published: 20 Jul 2010
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Prof Alexander Eggermont - Erasmus University of Rotterdam, Netherlands

Prof Eggermont talks about the significance of ipilimumab. This monoclonal antibody, although developed to treat melanoma, could have important implications in the fight against many tumours. Ipilimumab affects tumours by modulates the immune system; activating a T-cell response that had been silenced. Considering this mechanism of action, ipilimumab could be effective in a much wider range of patients than personalised medicine and could be used against a number of different types of cancer. Prof Eggermont also discusses recent research into BRAF-inhibitors that has shown extremely high response rates among BRAF mutation-positive melanoma patients.

ASCO 2010 Annual Meeting, 4—8 June 2010, Chicago

Interview with Professor Alexander Eggermont (Erasmus University of Rotterdam, Netherlands)

Advances in the treatment of melanoma

Welcome to ASCO in Chicago. Lex, You’re past President of EORTC, and the past President of ECCO, and tomorrow, at ASCO, you’re going to be made ASCO statesman.
It’s not just showing up your individual brilliance, but the people behind you who you represent—all of European oncology whom you’ve headed.

Thank you. I think it’s a recognition of what EORTC stands for, what ECCO stands for, what European oncology stands for, and so, you know, it’s due time that Europeans get in on the act and pick up some awards in the US.

If you look at the plenary sessions here, there are a great number of European papers. Now, you’re really excited about the big melanoma Phase III trial. Would you like to tell us about that?

Yes, I think, actually, this ASCO meeting, may be the most important of all recent ASCO meetings for a number of reasons. Not only because it’s the first time in 35 years that something really significant is happening in the world of melanoma, but that it is actually a drug that potentially will have an impact on many tumours. It’s such a general principle of getting - in a very innovative way—manipulation of the immune system so that it has to have ramifications for various tumours.

So, this ipilimumab story—, we’re talking about anti-CTLA-4, a monoclonal antibody. We’re talking about a molecule, about a drug that is not directed against tumour cells. It is only modulating an immune response that has gone silent inside the body of a cancer patient—in this case, melanoma patients—and it brings back alive a silenced immune response. What it does is, it restarts, it re-kicks into activity and into expansion a T-cell response which was silenced by suppressor mechanisms in the body of melanoma patients.

And so, this is of fundamental importance. So, the scientific value of this supercedes the fact that this now kicks melanoma into a whole new landscape and a whole new situation,

So, it’s a unique mechanism of action. This is suppressing the suppressor?

Yes, exactly. It’s inhibiting the brake. It’s taking the brake off a system. Inhibit the inhibitor is now the big slogan, and one would not have thought that the differences that it can produce, and this first trial that will now be reported in the plenary session this afternoon but which has gone online, including the New England Journal of Medicine publication online, at the precise moment when the embargo was lifted at ASCO. So, I think that was a very interesting mechanism of how to organise things. It shows that it, in essence, doubles survival in second line at two years and at three years.

Is this in metastatic melanoma?

Yes, in metastatic melanoma. You have melanoma patients, who failed chemotherapy, who failed other regimens. Then, what they got was either (it’s a 3-armed randomised Phase 3 trial) vaccination with just the GP100 peptide, or they got ipilimumab alone—actually at a dose 3mg, which is lower than the optimal dose which was discovered actually later, after the initiation of this trial.  The third arm was the combination of the peptide vaccine plus the monoclonal antibody. And the interesting thing is that it’s completely ipilimumab driven—the results—because the two curves that contain ipilimumab are highly significantly better than the comparator arm with the vaccine alone. The other important piece of information is that the complete responders are all long-term complete responders.

So, if you have a complete response, a very high fraction of the complete responders remain complete responders, and once they’re out two and a half years or three years, you don’t see anybody relapsing after that. The potential of cure is there. So, it’s not just that you are prolonging life, but you are also potentially curing a fraction of patients at a dose of ipilimumab, which we already now know not to be optimal.

Because the optimal dose—and this was published in the Lancet Oncology, I believe, earlier this year,from a very large study—a three arm study where they investigated the effects of three doses of ipilimumab, and where the 10mg dose was really the best dose to give. So, the first line trial in ipilimumab, which is still unblinded because the events are very, extremely slow to come in, is a trial which is at what is considered the right dose—10mg—and which randomises against DTIC, versus DTIC plus ipilimumab.

Now, since the last patient entered that randomised Phase III trial two and a half years ago, , it does not take a statistical wizard such as myself to be able to model that trial the has to be, highly significantly positive. Because in the last large phase three trials with DTIC as a comparator arm—and now I’m talking about 1,200 patients randomised in various trials—the curves of DTIC alone have always been the same, the same, the same. So, it would be highly illogical to think that the first line trial would not be positive and it would resolve a number of issues.

The current trial in second line had only one restriction for the patient population of melanoma patients, and that was that they had to be HLA-2 positive because of the peptide in that trial design. But we already know from the large database of ipilimumab that there is no HLA restriction for ipilimumab to function.

The second thing is that the outcome of the first line trial will resolve the dose discussion, and the third thing that I think will happen is that ipilimumab is there for all melanoma patients because there were no restrictions on LDH level.

The drug therefore produces objective responses, creates a lot of stable disease, and slows down the disease and, I think, even the patients who are progressors are much slower progressors. So, it’s phenomenally important, and who would think that in the age of, perhaps, a little bit overselling of personalised medicine as the only philosophy to go by, that the drug that would now change the whole landscape of melanoma would be a drug that’s got nothing to do with the tumour cell itself directly, but is only an innovative way of modulating the immune system. So I think this drug goes into renal cancer now, and it goes into prostate, and it goes into colorectal.

There’s a communication about a lung cancer trial at the meeting, a very interesting randomised Phase II, three arms, where actually, it shows that if you give the chemo—I believe it’s a Taxane—up front, followed by the administration of ipilimumab, you get the best results, which, theoretically, could make sense. You induce a response and apoptosis and the shedding of antigens, and the boosting of the immune response by ipilimumab then provides the beneficial effect.

What are the side effects?

It’s not an easy drug to handle, because the side effects are very novel, they’re very different from what we have been used to. So, because of rekicking T-cells responses into existence and maintaining them, this will also happen with some of the slumbering T-cell responses that you and I may carry. And what happens is that, so you see colitis—which resembles, to some degree, Crohn’s colitis, that has been silenced by immune suppression,  in a substantial proportion of patients. Most of it is diarrhoea and it’s grade 2, but if it’s grade 3 or 4, you need immediately to stop ipilimumab and intervene with high dose corticosteroids.

And other autoimmune related events are reported—such as thyroiditis, dermatitis—all these are immune T-cell mediated events-  and a rare, previously unknown suppression of the pituitary gland , knocked out by a similar type of response , and demanding substitution therapy. This only happens in some 3% of patients, but, nevertheless you need to take care of it. It must be recognised.

Instruction of the patient is crucial because  in the experience of over 600 patients in the Phase 2 programme of ipilimumab, have been patients who had a drug related death traced back to diarrhoea, grade 3, 4, not immediately treated with high dose corticosteroids. And a number of cases where the patient did not go to the ipilimumab prescribing physician, but to a gastroenterologist, led to serious illness

The instruction of the patients is key , that (s)he should always go first to the ipilimumab prescribing physician, and then you also have to instruct the physicians,  in order to avoid calamities.

It’s clearly going to be nail biting to see how it gets on in prostate and lung as well. You’ve mentioned personalised medicine, you know, being a bit disappointing and so on. But, in melanoma we are beginning to crack open too. You have to tell me about that.

There is another very big story, of course, in melanoma, and that is in the mutation driven drug development arena, and, this is within the premises of personalised medicine. The Braf story was first highlighted by the Plexxikon drug 4032. Keith Flaherty is the principle investigator of that programme and showed in an expanded Phase II that in some 80 patients you see an 80% response rate. 80% response rate in melanoma is, of course, unheard of, but It’s, of course, only in Braf mutated tumours, which is about 60% of the melanoma patient population.

He presented about 50% short lived responses—shorter than six months but a50% of that patient population going into long term responses.

There’s another drug, and that’s being reported on at ASCO this year, and it’s a study from, Rick Kefford from Sydney who reported another highly selective Braf inhibitor by GSK, which looks very much like Plexxikon. High response rates in the extended Phase I experience, same type of side effects, , interesting new side effectssuch as the initiation of keratoacanthomas, not so aggressive, but occasional invasive squamous cell carcinomas. These can appear very rapidly after the administration of these drugs, within three, four months.

This, potentially, of course, is a problem in terms of development of these drugs for the adjuvant setting, where, if you’re going to have to administer this fora year or two years in an adjuvant setting where already a fraction of your patient population are cured in the first place. But these Braf inhibitors are going to make it in melanoma, alone or in combination say with ipilimumab.

For you who’s been committed to translational oncology in melanoma for as long as I’ve known you—20, 25 years—it must be immensely satisfying?

That’s right. In 1985, I went to Steve Rosenberg’s lab, and it’s been totally fantastic, in terms of the outcome of randomised Phase III trials, investigating biochemotherapy. Very satisfying.

Also, that the criticism that immunotherapy would never lead to anything is now a discussion you cannot maintain anymore.