Relatioship of usage -IL-2 – ipi – vemurafenib

Putting New Melanoma Drugs to Work in Community Practice

Elsevier Global Medical News. 2011 Jul 18, JS MacNeil

Euphoria – there is no better word to describe the mood in the melanoma sessions at ASCO. For the first time ever, oncologists have two new drugs that can prolong the lives of patients with advanced melanoma. They also have a host of questions as to how to bring ipilimumab and vemurafenib into community practice. We asked four experts during the meeting for their thoughts on what comes next:

• Dr. Paul Chapman of Memorial Sloan-Kettering Cancer Center in New York; lead author of the BRIM-3 study of vemurafenib vs. dacarbazine in newly diagnosed patients.

• Dr. Jedd Wolchok of Memorial Sloan-Kettering Cancer Center; lead author of the phase III trial showing the efficacy of ipilimumab plus dacarbazine vs. placebo plus dacarbazine in newly diagnosed patients.

• Dr. Vernon K. Sondak, chair of cutaneous oncology and director of surgical education, H. Lee Moffitt Cancer Center & Research Institute in Tampa.

• Dr. Alexander M.M. Eggermont, general director of the Institut de Cancérologie Gustave Roussy in Villejuif, France.

Question: Should ipilimumab and vemurafenib be used together?

Everyone we asked said no, not outside of a clinical trial at least for now. No one knows whether the combination is safe or effective.

Dr. Chapman: We are about to start a phase III trial combining these to see if it is safe and making sure that vemurafenib does not inhibit the effect of ipilimumab. We all hope that this will result in sustained complete responses. That is what we all are looking for.

Dr. Wolchok: The natural next step that many of us are considering is how to integrate these two forms of therapy together. Vemurafenib directly targets the tumor by inhibiting BRAF kinase; ipilimumab really treats the patient by starting an immune reaction that hopefully will control the disease. These are very different approaches to cancer therapy. They are in no way mutually exclusive, and I believe them to be quite complementary.

I think it is important that the combination be explored in a clinical trial because I could make a list of reasons why these two drugs would work together; I could also create a list of reasons why they might not work well together and may even be antagonists. So, I think before oncologists begin to combine potentially approved medications outside of clinical trials, we [need to] have some idea that this is a safe and effective way to go. Until then, I think monotherapy is the best path forward outside of a clinical trial.

Dr. Sondak: If you combine ipilimumab with something else, sometimes the side effects aren't what you expect. Don't just take a patient and give them both and see what happens. That's not safe. You have to do this in a controlled way a research study as quickly as possible because it is the obvious next question.

Dr. Eggermont: I think at this point they should wait at least for the safety data on the combination.

Question: So which agent would you use first in a patient who has a BRAF mutation?

Again, there was unanimity – with respect to the patient who is very, very sick.

Dr. Chapman: I think that is a question is that is still open. Where I am on this question right now is that for a patient who is relatively well, who has a fairly good performance status, I would think about using ipilimumab first because that person may have time to respond to ipilimumab since it does take 3-6 months to have the full effect. On the other hand, a person who has a poor performance status and is sick and does not have time to respond to ipilimumab I would treat that person up-front with vemurafenib.

Dr. Sondak: I think there is going to be uniform agreement throughout the melanoma community that if you have a BRAF-mutant patient with widespread disease, symptomatic disease, high tumor burden that person is going to go immediately on to vemurafenib because nothing else is going to get a rapid response, a rapid resolution of symptoms.

The question is going to be [what to do] for 80% of patients who are BRAF mutant but have much less acute symptomatic disease. Maybe they have some lung metastases, some subcutaneous nodules, [and] they can't have it all removed surgically but they are still not in dire straits. And I think at our institution we are going to be very motivated to continue to use the immunologic therapies – the IL-2 for some patients, and ipilimumab for many patients because of the possibility that they will get a big benefit at the other end, not an immediate benefit but a long-term benefit. And then if that doesn't work, I think vemurafenib.

Dr. Eggermont: BRAF-positive patients especially the ones that have rapidly progressive disease or bulky disease that have little time – they will all be treated up front with the BRAF inhibitor. The BRAF-positive patients that have very small disease that is not rapidly progressing could actually also be managed by ipilimumab on first line and only on progression be managed by the BRAF inhibitor because ipilimumab needs more time to work with patients, to kick into activity and into an antitumor effect. … All BRAF-negative patients would see ipilimumab in first line. That is for sure.

Question: The ipilimumab trial paired ipilimumab with dacarbazine. Is DTIC still an option?

Dr. Wolchok: Looking at the result as someone who has been taking care of patients with melanoma using ipilimumab for several years, I think it is still unknown whether dacarbazine should be added. My own opinion would be to oncologists in the community that if they are going to give ipilimumab at 3 mg/kg to stick with the monotherapy label because we really don't have data comparing ipilimumab with dacarbazine alone at that dose. And so I think we stick with what we know produces an overall survival benefit.

There are reasons to imagine the addition of dacarbazine could make results better by killing some cancer cells and releasing some antigenic debris that would serve as a target for the immune system. Chemotherapy can also be thought of as changing the tumor microenvironment, which might be advantageous, but chemotherapy could also be immunosuppressive. So we could really make a case either way that dacarbazine added to or detracted from or left things just the same.

Question: Will interleukin-2 still have a role in melanoma treatment?

Dr. Sondak: I am still going to use IL-2, and it makes the most sense if you have someone who uses IL-2 most of time, you will want to use that first before you use anything else. Why? Ipilimumab is tough on the patient. We want them in as good shape as possible. … We know if they get IL-2 first and then get ipilimumab; the results are just as good, if not better. We don't know the opposite way. And we also know that a lot of people on ipilimumab get side effects. They wind up on steroids and other immunosuppressive drugs that would make it very difficult to put them on IL-2.

Vemurafenib is going to change a lot of things. A lot of people are too far gone to have surgery, too far gone to have IL-2. Now we have BRAF mutant melanoma [patients] who will get vemurafenib, and shrink down… If we could keep a close eye and figure out when is right time, we are going to do more surgery and maybe IL-2 in those patients because we are going to restore them to place where IL-2 is going to have more room to work. But it's not going to be 80% of people getting IL-2. It is going to be a very restricted group of people treated by a very specialized group of doctors.

Dr. Eggermont: I think IL-2 will move down in the options list. IL-2 will remain as an option in second or third line, and IL-2 will also be an option in combination with ipilimumab because [Dr.] Steve Rosenberg already did a trial in 36 patients … and the majority of the complete responders are alive 6 years and longer and are still in complete remission (ASCO 2010, Abstract 8544). The combination of IL-2 and ipilimumab will be relaunched, I am sure.

Question: And interferon – Where will it fit in?

Dr. Sondak: We don't know how long we should treat people, how intensively, and how we should combine the new and the old, and the data that we have just doesn't sort it out. On the other hand, if you look at the whole landscape, it actually makes adjuvant treatment with interferon more important now than it used to be.

It's very clear that interferon treatment does delay recurrences in a substantial fraction of patients. It may not cure many people, but it delays recurrence in quite a few people, and right now today we are so much better off than we were in melanoma 2 years ago and I have no doubt that 2 years from now just with stuff we heard about at this meeting we will be much more clear on how do we use how do we take care of side effects not to mention other new exciting drugs that we hope 2 years from now will start to be available.

In the past we debated, does it even matter that we delay recurrence. The ASCO answer should be, "It absolutely matters to our patients." So interferon and any form of adjuvant therapy is suddenly a bridge. It is a shaky bridge – made with some ropes and a few planks – it isn't very sturdy to walk on, but we're trying to get from here, one place where it was safe to another place where hopefully we are better off and not at the bottom of ravine. It's real exciting – not just the data we already have but for the future and how many patients this will affect positively.

Dr. Eggermont: I think you need to separate the new drugs from the question, what are we going to do in adjuvant? In adjuvant right now, we will still have to wait for about 2.5-3 years for the outcome of the EORTC trial that randomized in double-blind ipilimumab vs. observation in patients with high-risk lymph node positive disease. That answer about ipilimumab in the adjuvant situation will not be there before 2.5 years from now. That means that until then there is only one kid on the block in the adjuvant setting, which is regular interferon, and the currently novel approach of pegylated interferon.