For the first time, physicians 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 practice. We asked four experts 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
• 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?
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 physicians 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?
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.