The changing landscape of melanoma therapies: indications of better patient outcome

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Published: 24 Jun 2011
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Prof Alexander Eggermont, Dr Caroline Robert, Prof John Haanen and Prof Reinhard Dummer
The panel discuss the significance of some of the key research into melanoma presented at the 2011 ASCO congress in Chicago. The first presentation discussed was a Phase III study demonstrating a statistically significant survival improvement in patients with unresectable, stage III or IV melanoma treated with ipilimumab. A reduction in risk for death and higher estimated overall survival was seen in patients receiving dacarbazine plus ipilimumab when compared to dacarbazine plus placebo. A second major finding was 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 final study was the EORTC 18991 trial which demonstrated that long-term pegylated interferon-á2b therapy had a significant and sustained impact on relapse free survival in stage III melanoma patients, especially those with micro metastases. The panel conclude by outlining the optimal treatment schedules for different melanoma patient sub groups.

This programme was made possible with sponsorship from Bristol-Myers Squibb.

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

The changing landscape of melanoma therapies: indications of better patient outcome


AE: Professor Alexander Eggermont - Institute Gustave Roussy, Villejuif, France
CR: Dr Caroline Robert - Institute Gustave Roussy, Villejuif, France
JH: Professor John Haanen – The Netherlands Cancer Institute, Amsterdam, The Netherlands
RD: Professor Reinhard Dummer – University Hospital Zürich, Switzerland


AE:    So I’d like to start with you, Caroline, because you played an important role in the ipilimumab trial, the first line trial. Perhaps you can tell the audience a bit about how the trial worked out and what are the main points that we can have as take home messages.


CR:    Yes. You remember last year we had this trial that was positive in terms of overall survival. Ipilimumab was tested as a single agent versus a vaccination in patients in second or later line therapy. This year we have the results of a first line treatment for metastatic melanoma patients comparing ipilimumab plus dacarbazine versus dacarbazine, which is the standard chemotherapy we give for melanoma. And we have, this year, the confirmation that ipilimumab, in association this time with chemotherapy, is really efficient in prolonging the survival of the patients. So this is the second trial that is positive with ipilimumab. We have very good confirmation; we still observed some level of toxicity which is slightly different from the drug when it is used as a single agent.


AE:    But it is also because there is a different dose in this trial.


CR:    Exactly, because in the first trial we used a lower dose, 3mg/kg and here we are 10mg/kg. Plus we had DTIC and we know that DTIC has, by itself, a potential hepatotoxicity and surprisingly the toxicity that we observed in this trial is mainly hepatotoxicity but in every case it was manageable and it was going back to normal in ten weeks. We still have to learn a lot about how to optimise this drug; we have a very strong signal of efficacy, this is very good news, but we still need to work and further trials need to be done.


AE:    The other plenary session communication is the result of the early stopping of the BRIM 3 trial because of the interim analysis. It’s the BRAF inhibitor but originally was known as Plexxikon 4032 molecule. So what are the take home messages from that trial?


JH:     I think the most important take home messages from this trial are that the data that were already obtained from the phase I extended cohort and the phase II trial are confirmed in this phase III trial. Where vemurafenib was compared to DTIC and where you see that the response rate is close to 50%, in fact 48.4% in there for the vemurafenib treated group, and that also the progression free survival is maintained for now over five months compared to 1.6 months for the DTIC arm.


AE:    So this basically means that we will not have an adequate read-out any more on overall survival, right? What do you think?


JH:     I’m not sure about that because of the difference in response rates for the DTIC group, it may be that a lot of patients have already passed away before they can be put on the vemurafenib drug. So it could still be that also in the end you will have an overall survival benefit.


AE:    So what percentage of patients do you expect to cross over? More than 25%, less than 25%?


JH:     No, I think it’s maybe a little bit less than 25% of the patients will cross over.


AE:    Reinhard, there was another communication regarding pegylated interferon, so what is your experience with pegylated interferon and how do you read the data of the EORTC 18991 trial?


RD:    First we have to say that interferon is the first immunomodulator that is used in melanoma for decades and I think we all have to admit that we have used this molecule in a very unfocussed way. Actually we have treated patients with metastatic disease, we have treated patients that had surgery and after bulky lymph node involvement they have been treated with interferon, and now over the last five or six years we really start to focus and find a very dedicated indication for this molecule. I think the EORTC trials nicely show that patients with micrometastasis and probably patients with ulcerated tumours are really the best candidates for the treatment. There are many ways to use interferon, there is the high dose application that has a lot of side effects; there is the low dose application and now we have the new molecules and I think the new molecules are an advantage because they make the therapy much easier for the patient. I think we all are convinced that we need a certain time of therapy, so four weeks is too short, probably even one year is too short, so we should treat the patients longer and for this long a period it’s good to have pegylated interferon. And Switzerland is progressive at this time, ahead of other countries.


AE:    Not only in this respect.


RD:    And our authorities have admitted this drug, I think also as a reaction because nobody was really comfortable with the high dose use of interferon. I think it was for the benefit of the patients. I have to say, also, that the registration did not really translate in the treatment that was developed by the EORTC because the packages label in Switzerland did not meet the necessities of the dose intensity so we just used pegylated interferon flat, right from the beginning. And we teach the patients very openly and tell them how to use it. I always warn them that in the first weeks they might suffer severe side effects so they should wait at least six to eight weeks and then they can decide how they feel. I am very convinced that patients who really suffer a lot should not really try to go through two years, they should stop after a certain time, but if the tolerability is good, I think interferon is an adequate treatment today.


AE:    One abstract that hit me as a fairly interesting one because of the response rate was the combination of ipilimumab and bevacizumab. Ipi has been combined in a number of ways already, or tremelimumab, either with high dose interferon and high dose also. So John, what’s your impression there because we’re moving into combinations of a monoclonal antibody of which the mechanism of action we only partially understand, and then we just choose now another cytokine to go with it, and we choose actually an antiangiogenic to go with it, without really knowing too much up front what the mechanism of action is that we’re after. But the interesting thing is that all studies do show something. What’s your takeaway there?


JH:     I think there are two important points to consider; I think it’s important to have some idea what the combination could do, although maybe in some trial cases it’s just hypothetically and just scientifically interesting. And the other thing is the side effects. I was amazed by the side effects that were seen in the combination of ipilimumab and bevacizumab; it was interesting in terms of a response rate, absolutely, but also the number of side effects that were seen were impressive. So I think we really have to be careful in how we continue with combining ipilimumab with other drugs.


AE:    How do you start? With which drug and which dose would you advocate?


JH:     Ah, there you go.


AE:    This is good. We can all have a different opinion, you start.


JH:     OK, I will start with ipi, 3mg/kg and then after one dose I would start with the PS.


AE:    OK, you upload with ipi and then you give the BRAF inhibitor?


JH:     Yes.


RD:    Actually, I would first see what type of patients are in, so in patients with aggressive disease, high tumour load, high LDH, I would definitely start with vemurafenib and when the remission is in sight then you can add ipi and I would also favour the lower dose of ipi.


AE:    So Caroline, please tell them what they should do.


CR:    I think spontaneously I would have begun with a BRAF inhibitor but I would not wait very long because the effect is very rapid, so maybe fifteen days after I would begin ipilimumab.


AE:    So what are we going to do with BRAF negative patients?


CR:    We have three challenges, I think. The people who don’t respond to ipilimumab, let’s not forget it’s the majority of the patients who don’t respond to ipilimumab. The patients who relapse after BRAF efficacy and the patients who are BRAF negative, like three big challenges.


AE:    What could our first line combination development potentially be for BRAF negative patients?


JH:     Well of course we will treat these patients with ipilimumab, the question is do you need to combine it with something else or should you also start with adoptive cell therapy. Of course we know also that patients that fail ipilimumab appear to have a high response rate also in the adoptive cell therapy, so I think that would be my answer.


RD:    There are so many kinase inhibitors out there and there are multi-kinase inhibitors. Today we had the presentation about RAF265, actually the side effects are a problem, but these kinase inhibitors will also work in wild type, they have shown that they can do it. And you can also combine a molecule like this with a MEK kinase inhibitor and then you have a very strong pressure on the RAF/MEK kinase pathway and this might also work in wild type cells. So I would follow this and certainly I don’t see a lot of light for chemotherapy any more, I think this will disappear more and more in melanoma, and we will go into molecular target therapy in combination with immuno. But we have to keep in mind that our molecular target therapy does not kill our antigens and this is one of the concerns that is in my head, that if you inhibit the cells they will definitely change their antigen repertoire and we don’t know which are the important antigens yet, so there might be even negative interactions.


CR:    Yes, I agree Going after new targets like MEK or ERP on the same MAP kinase pathway or exploring the PI3 kinase pathway and trying to develop blockers of these different pathways, combining with other immunotherapy, ipilimumab or the new PD1 blocker also. So we see that the future is going to be good.


AE:    I would like to thank the panel, I think it has been an informative session with a lot of new and creative thinking, and that’s what we’re all for for electronic cancer medical science, and we’ll be back at the ECCO/ESMO meeting in Stockholm later this year.