European Post ASCO Meeting 2011
Recent advances in advanced melanoma: ipilimumab
(Part 2 of 6)
AH: Professor Axel Hauschild – University of Schleswig-Holstein, Kiel, Germany
MM: Professor Michele Maio – University Hospital of Siena, Italy
PL: Professor Paul Lorigan – University of Manchester, UK
DS: Professor Dirk Schadendorf – University Hospital Essen, Germany
AH: Very recently, four weeks ago, there was a meeting of the American Society of Clinical Oncology, shortly ASCO, and some were saying, and it was in the news, that this was an ASCO melanoma meeting because there was some good news out and some highlights of the meetings presented in the plenary session were dedicated to recent developments for the treatment of metastatic melanoma. So let’s talk about this light at the end of the tunnel. So what was the highlight of the meeting for you?
DS: I think after more than two decades, almost three decades of no real progress, we have talked about the limited success of our chemotherapies we have used, now for the first time we have clinical trials demonstrating overall survival benefits. My highlight definitely was the plenary session with two communications on two different drugs demonstrating for the first time survival benefit in a prospective randomised clinical trial.
AH: So this was the highlight for you, the two randomised clinical trials, anything else which was important for you, Paul?
PL: No, I would agree with that but I think we’ve just had a complete shift away from chemotherapy to molecular targeted therapies, both immunotherapy and targeted therapies and I think that’s due to our rapidly increased understanding of the signalling pathways in melanoma, the importance of the immune system and the molecular pathways that control that and then the design of drugs to influence those pathways. Those developments have come through phenomenally quickly in fact, and so in a short period of time we’ve been catapulted into this personalised medicine for melanoma.
AH: So we are facing two different modes of action of the basic drivers of this progress in melanoma treatment. One is dedicated to identifying molecular targets using some gene notation testing and the other one is an immunotherapeutic agent which is improving overall survival. So I would say we should separate the discussion into these two different paths and then we come to combinations. Michele, would you give some comments on the mode of action of this so-called CTLA4 antibody which was considered as one of the highlights at the ASCO meeting?
MM: Yes, of course the CTLA4 was a major breakthrough at ASCO. We had these two compounds that, as Dirk was saying, have finally demonstrated to be able to improve the survival of metastatic melanoma patients. This was very important for me too at ASCO but for me it was also very important that using an anti-CTLA4, so using immunotherapy, we had then additional confirmation that we can treat cancer patients with immunotherapy, that immunotherapy might be effective as compared to the other standard treatments that we have, like chemotherapy, surgery, radiotherapy. It’s finally demonstrating, starting to demonstrate, all its power in treating cancer. The mechanism of action of ipilimumab is quite simple because it practically releases the brake to the immune system as we generally say, meaning that it activates the immune system, making the immune system of cancer patients and of melanoma patients in particular more aggressive against the tumour. So it’s the immune system per se that is able to keep the tumour from growing and in some cases to delay the progression and give some very long term, as normally happens with immunotherapy, very long term clinical responses in the set of patients.
DS: I think, Michele, that’s an interesting aspect because immune system has traditionally very late onset and you are not getting rapid responses, that’s what we have learned over the last decade using vaccines. That’s what we are seeing here as well; we are not seeing rapid shrinkage of the tumour, we are seeing stabilisation of the disease and this is, when you look for the long-term survival of these patients, after one year, after two years, after three years, you see and discover the benefit and the increase in overall survival rate. That’s a fascinating issue of these new treatment options.
AH: Before we go into detail, into the specifics of the findings, I would like to ask you, Dirk, to discuss the findings and the conclusions of the two clinical trials; one was presented last year on ipilimumab, the other one was presented this year. So what were the major findings in terms of survival benefits, in terms of response rate, progression free survival?
DS: Indeed we have two trials using ipilimumab, the antibody against CTLA4. One which was presented at last year’s ASCO was used in a setting of pre-treated patients with advanced melanoma in combination with a peptide plus/minus complicated clinical design. But what turned out that in this three-arm study, in both arms which contained ipilimumab there was a survival benefit of 3.4 or 3.6 months compared to the comparator which was a peptide vaccine arm. This was definitely surprising because this was a poorly selected patient population including almost 15% of melanoma patients who had previous brain metastasis, for example. The excellent news is that in the second trial, this year, ipilimumab was able to demonstrate in patients who had no prior systemic treatment also this overall survival benefit. This was tested in combination with chemotherapy, DTIC, our reference track. The survival benefit in this trial in combination with DTIC was 2.1 months, a little bit less, whatever reason I think we should discuss. But the overall message is it’s again an overall survival benefit and what is comparable between both trials is that the one year survival benefit which is being gained after one year is around 10-15% extra; after two years it’s at10% increased to control and almost 10% or 12% after three years. This is very comparable in the second line pre-treated patient population as well as in the first line.
AH: So to make it as simple as possible, there is a difference, not only in the median overall survival but also in the long run after one, two and three years.
AH: And this is comparable in the two clinical trials which were presented in the last two years so this is confirmatory data. So there is no treatment without any side effects, was there any learning session from one to the other one, is there any difference in the dosing between the trial which was presented last year and this year? Would you like to comment on the study design and toxicity, Paul?
PL: Well to pick up on Michele’s point about how the drug works, the drug works to stimulate the immune system and that is a non-specific effect . So it’s not just the immune system attacking the cancer cells and melanoma cells, it’s the immune system in general and so can unearth immune activity elsewhere in the body. The main side effects seen with the CTLA4 antibody are, in fact, immune related adverse events, so they’re related to stimulation of the immune system. So those are skin rash, which is common but not usually very severe; inflammation of the bowel, which can be a major problem in a small proportion of patients, and then problems related to effects on the liver, which with single agent treatment are low, and other effects on other endocrine glands – thyroid, pituitary gland. So in the second line study, which was the first study that was published last year and that was using the lower dose of treatment, the main significant toxicity was colitis, so was inflammatory colitis related to the treatment. That severe toxicity, so grade 3 or grade 4, occurred in about 7 or 8% of people; diarrhoea occurred in 25-30% of people, so that was mild diarrhoea but severe diarrhoea in 7-8% of people. There were treatment related deaths, which was a very salutary lesson for us.
Now, I think we’ve learnt a lot from that and we’ve learnt how to manage the adverse events and we’ve got very good treatment algorithms now for managing patients. The company, BMS, who have ipilimumab have put a lot of time and effort into educating investigators, as we have done as well. It was interesting to see in the first line study, which was at a higher dose of the drug and given with chemotherapy, in fact the toxicity rates were the same. There was one extra toxicity that we weren’t expecting, so it was this hepatic transaminitis, so raised liver function tests, we’re not quite sure why that is, whether it was a direct toxic effect of the combination or whether it’s an immune mediated event. But in general toxicity in the confirmatory study was less of an issue, which I think is reassuring.
DS: And no death.
PL: And no deaths, yes, absolutely. Very important, no deaths.
AH: It’s matching your expectations from your own experience in Siena?
MM: It is actually because I think that, as Paul was saying and the comment from Dirk also, that the centres that have been using ipilimumab in the past three, four, five years have acquired their own learning curve on how to manage the side effects. Of course the company and the community have discussed a lot, have developed specific algorithms but I think the experience, our experience in Siena, and I think we can share this type of feeling, is that you have to have a sense of the side effects that patients are starting to experience because we clearly know that the sooner we treating the side effects like diarrhoea or skin irritation and so on, the better the patients will do. So the length of the side effects and the intensity of the side effects will be much lower and eventually patients will be able to continue their treatment according to the standard schedule of treatment. So it has been very important for the centres who have been using ipilimumab; it will be even more important once the drug is available to a larger community that this type of information is given, not only to the treating physicians, but also to the patients who have to be aware of these types of side effects and refer immediately. Because as soon as they refer, as soon as the treatment for the side effects is started, this decreases a lot the intensity and the time of the side effects themselves.
DS: Compliance will be definitely an issue for patients, eventually.
MM: It will be very crucial. I think we all have experience with patients who don’t call you because they say, when you ask them, why didn’t you call, they say, because I didn’t want to disturb. So they start calling you three, four, five days after they started with diarrhoea. Of course we all know that that is the worst thing you can do because it takes then longer to solve the side effects.
AH: Ipilimumab was approved under the trade name of Yervoy in March 2011 by the FDA and it’s approved for first and second line stage 4 melanoma treatment, which is a very important message. The dose which is approved is 3mg/kg body weight, so what is expected regarding the approval in Europe? When will the drug be approved and what is known about the pricing, because there was an issue in the United States, it’s not a cheap drug?
DS: Yes, I think the file which was submitted to the agency also in Europe was based on last year’s ASCO presentation, the second line trial using also 3mg. So we expect to have approval and licensing of the drug with the 3mg label and the European authorities have ruled already, in May, and announced on the website that there will be positive feedback to the company regarding the 3mg and that it will be approved in July in Europe. Definitely the pricing in the US is definitely challenging, whether this price will also be the price in Europe needs to be determined. There is no official announcement by the company about the pricing and the reimbursement politics. The different European countries will also be different, there will be mechanisms in countries like the UK which will re-evaluate that. Similarly this will be done also in Germany, there is a new agency now which evaluates the pricing after one year of no price binding, it’s up to the company, but after this one year there will be a value dossier and negotiation with the company on the real price in Germany. Similarly mechanisms in other countries will probably modulate the price.
AH: You wanted to comment on this?
PL: Yes, I think it’s going to be a real challenge. The second line clinical trial completed last year and the publication of the… well, before that one on publication of the data at ASCO, an extended access programme was opened by BMS and most countries have put a lot of patients, nearly 3,000 patients in Europe gone into that. So there is a real need for this treatment for patients but we haven’t seen the cost on it yet.