Dr. Ribas: In the last three years, there have been approvals of several agents that have improved overall survival in patients with metastatic melanoma. Those have included ipilimumab, which is a CTLA-4–blocking antibody; it's an immunotherapeutic approach that is not restricted by the driver mutation of the cancer.6,7
And then the targeted agents vemurafenib and dabrafenib, which are two BRAF inhibitors, and trametinib, which is a MEK inhibitor, all of which are approved only in patients who have a BRAF-mutant melanoma.8-14 So the good thing is that in a short period of time, we have a series of agents that have been demonstrated to be active and improve survival in the majority of patients with BRAF-mutant melanoma.
The decision on which is the optimal first therapy may depend on several variables, but I think one of the main variables is the discussion between the physician and the patient about the pros and cons of each mode of therapy. The immunotherapeutic ipilimumab and also high-dose interleukin-2, which is also approved in the US for metastatic melanoma, are agents that give low frequency of responses, but those tend to be very durable responses and can last years. The problem is that this durable response rate is [observed in] between 5% and 10% of the patients, and the overall response rate is [observed in] between 10% and 15% of the patients.
That's very different from the benefit that's given by the targeted therapies that block oncogenic BRAF, which have a very high response rate. Between 50% and 60% of patients have an objective response by RECIST criteria; but those responses tend to have a limited duration, with a median of six to seven months—although some patients can have durable responses, and some are going on for four years from the phase 1 trial of vemurafenib.
We have to talk about the potential toxicities, with ipilimumab having the risk of occasional life-threatening autoimmune conditions like colitis with bowel perforation or hypophysitis or hepatitis. These are infrequent, but can really affect particular patients, as opposed to the BRAF inhibitors, which have less serious—but more common—toxicities that can alter the life of patients, like proliferative skin processes, joint pains, and the development of secondary squamous cell carcinomas.
The approvals of all of these agents were not based on a particular subset of BRAF-mutant melanoma, even though many melanoma oncologists consider that patients with a slow-growing melanoma with normal LDH and good characteristic features are better off starting with ipilimumab. Those patients are also the ones who derive the best and longest benefit with the BRAF inhibitors. And the other way around, if we have a patient with a fast-growing melanoma that can respond transiently to a BRAF inhibitor, if that patient was one of the few who responds to ipilimumab, then that patient could go from having a life-threatening disease to being alive long term.15
So my decision-making is not particularly based on growth kinetics or presentation features, but more of [a] discussion of the pros and cons of each mode of therapy to the patients. In practice, the majority of patients will get both ipilimumab and a BRAF inhibitor.
Should [the] BRAF inhibitor be given with a MEK inhibitor? The data so far in the clinic suggest that it's a very promising strategy,16 where we have higher, more durable response rates, because this combination addresses some main mechanisms of resistance to single-agent BRAF inhibitors. But also, it decreases the side effects, because BRAF inhibitors have a pharmacological property called paradoxical mitogen-activated protein [MAP] kinase pathway activation, which transactivates this pathway in cells that are wild-type for BRAF, and that leads to some of the toxicities of BRAF inhibitors. If we give a MEK inhibitor, it will block this phenomenon of paradoxical MAP kinase activation, and then there are less skin proliferative conditions and less joint pains and other side effects from BRAF inhibitors.
These combinations are in clinical trials,17,18 and we eagerly await the results, because I'm pretty sure that those clinical trials will demonstrate that there is a benefit for doing the combined therapy, and I would assume that's going to be what we'll be doing not too long from now as the standard of care.
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