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Pr Jedd Wolchok: treatment of advanced melanoma

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A breakthrough in the treatment of advanced melanoma





Hello! You’re on MD-FM INSIGHT, the first medical web radio. Today we’ll be devoting our "Question & Answer" program to the treatment of advanced melanoma.


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At the 2013 meeting of the American Society of Clinical Oncology, we interviewed Prof. Jedd Wolchok, from the Memorial Sloan-Kettering Cancer Center in New York, who presented his phase 1 results on a combination therapy, using ipilimumab and the investigational antibody nivolumab, to treat stage III and IV metastatic melanoma patients, who had undergone up to three prior therapies. The results also came out in June in the NEJM.



Tell us Dr. Wolchok, what led you up to this study:


Wolchock-1: “So we launched a phase 1 clinical trial of the combination of nivolumab and ipilimumab in patients with melanoma. And this was based on several lines of rational: the first is that each one of those medicines has activity in melanoma. And data was presented at this meeting and at past ASCO meetings demonstrating that ipilimumab impacts overall survival in patients with melanoma. In addition, nivolumab, while earlier in development, is showing signs of durable activity in patients with advanced melanoma. Together with that, we have a body of preclinical evidence showing that blocking both the CTLA-4 pathway, which is the target for the ipilimumab, and the PD-1 pathway, the target for nivolumab, is a very potent combination in animal models of cancer –both colorectal cancer and melanoma, in mice, can be more effectively treated with a combination of antibodies than with either one alone. ”



So... tell us about your findings:


Wolchock-2: “So looking at the combination of nivolumab and ipilimumab, we first of all established a safety profile for the combination and showed that there is a maximal tolerated dose of 1 mg per kg of nicolumab, and 3 mg per kg of ipilimumab, which has an acceptable safety profile. There are some adverse events, they can be grade 3 or 4 adverse events in 53 percent of patients, but these are reversible with standard protocol algorithms and, in fact, the only events that occurred in more than 10 percent of patients, were asymptomatic laboratory abnormalities, which sometimes resolved by themselves. In addition, a very important take away message is that the combination of nivolumab and ipilimumab, at its maximal tolerated dose, led to objective responses in 53 percent of the treated patients and, in those responding patients, all of them showed a greater than 80 percent reduction in the baseline tumor burden by the time of the first set of radiographic imaging.”



But can we say that this combination is better than either agent used alone? 


Wolchock-3: “So while the results show that the combination has a manageable safety profile and signs of very impressive efficacy, we don’t know yet whether it’s truly better than either ipilimumab or nivolumab alone –that is actually the next step: to perform a phase 3 clinical trial, which establishes that as a fact. And that phase 3 clinical trial is now open to recruit globally, where patients will be randomized to either to the concurrent combination of nivolumab + ipilimumab, or nivolumab or ipilimumab alone.”



Do you think this combination is edging us closer towards a –dare I say –“cure” for melanoma?


Wolchock-4: “So I think this combination establishes a new level of activity for immunotherapy against melanoma. I think “cure” is always a tricky word to use because we don’t really know what it means. We don’t know when we can start using it. I think what this combination shows is that durable disease control can be obtained in a significant number of patients using this combination immunotherapy.



And what about combining immunotherapy with targeted therapies --this is another important area for investigation I think...


Wolchock-5: “I think we’ve heard some continued reports of how challenging this could be because of safety interactions of these two approaches, but there are still ongoing trials using BRAF inhibitors and ipilimumab and certainly now a lot of discussion about using BRAF and MEK inhibitors and PD1 blocking antibodies together. I think it’s very important not to come to a conclusion about the use of targeted therapies with immunotherapy yet –it could provide even more benefit and the safety signals that have been generated thus far are just in small numbers of patients using concurrent therapy –there may be a lot of area for further investigation using sequenced approaches as well.”



So what should practitioners make of all this?


Wolchock-6: “I think the practicing community should take away that there are multiple active agents in clinical development for patients with metastatic melanoma. A very important message is that patients should be referred for clinical trials whenever possible so that we can get those answers, which we need, about the value of the combination versus to the single approved agents as quickly as possible.”




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