Malignant Melanoma: Contemporary Management - Episode 20

The Use of Dual Targeted Therapy in Metastatic Melanoma


The data for the COMBI studies are very interesting. COMBI-d was a study where dabrafenib and trametinib was compared with dabrafenib alone in patients with melanoma in the first line. And COMBI-v was a study where dabrafenib and trametinib was compared with vemurafenib, which is another BRAF inhibitor. And so these 2 COMBI studies were presented initially in 2014 and 2015, and what they showed is that there’s a marked benefit basically to the combination of dabrafenib and trametinib to either vemurafenib or to dabrafenib alone. Either way, there’s a marked benefit.

Now, what we have recently is a long-term analysis of progression-free survival and survival. And essentially what’s been shown in this combination study, which has over 950 patients, is that you can have extremely prolonged progression-free survival and overall survival basically beyond 3 years. The progression-free survival curve seems to flatten out, and patients who have not had progression at 3 years can expect to stay pretty much in the same status up to about 5 years. And that’s roughly a fifth of all patients. So roughly 20% of patients will have prolonged disease control on the dabrafenib-trametinib combination. And if you look at overall survival, that number looks even better.

COMBI progression-free survival data are interesting in another way. The progression-free survival was 49% in patients who had a complete response, or CR. And so that’s interesting that, in a sense, once you’ve had a CR on treatment with dabrafenib and trametinib, it’s very likely that those patients followed longitudinally will have no evidence of progression in 5 years. It’s just based on a number. So that’s another important thing to consider.

We usually know pretty quickly after starting treatment if somebody has had a complete response, a partial response, or no response. So for the folks who are having a CR on dabrafenib-trametinib therapy, the odds look really good over a longitudinal time period.

The overall survival in the COMBI studies is interesting as well. If you look at the overall survival in the COMBI studies for all patients on dabrafenib-trametinib, the overall survival was over 34% at 5 years. And what is interesting is that you now subcategorize that according to LDH [lactate dehydrogenase] and sites of disease.

For example, patients who have normal LDH and less than 3 sites of disease, have a 55% overall survival at 5 years. That’s a pretty amazing number. And then in the COMBI paper, they look at different categories of normal LDH or abnormal LDH, multiple types of disease, and you can see that many of these subsets over, over half of all patients are alive at 5 years.

Managing the adverse effects of dabrafenib-trametinib is something for which we’ve had a learning curve over the years. And at this point we have so much information about adverse effects that it’s become, in my mind, very easy to manage the adverse effects. The biggest adverse effects continue to be fevers and chills. I think patient education is the most important thing. Once you talk and sit down with a patient and say, “Hey, you know, it’s very likely that you will have fevers and chills within the first 4 to 6 weeks after you start treatment,” I think that reassures patients, and patients know that’s something that’s expected, that’s something that will happen.

We tell patients to stop treatment with both medicines as soon as they have that first episode of fever, and not to restart back until the fever is totally resolved—and only then do we start at the same dose as before. Some patients will have repeated episodes of fevers and chills. And if that happened, you might need to reduce doses, or you might need to space out treatment some more. But in the vast majority of patients you can basically just restart the same treatment after the fevers and chills have resolved, and at the same dose as before.

Another common adverse effect is skin rashes. And that appears to be linked to the MEK inhibitor, to the trametinib component, and they can sometimes be maculopapular, which are the measles-like rashes. They can sometimes be like acne on the face and head and shoulders, depending on what type of rash it is. A lot of times topical steroids can help. Sometimes antihistamines can help if it’s an itchy kind of rash. If it’s an acne kind of rash, our dermatologist will often recommend treatments that are helpful for those types of rashes.

Another common adverse effect with the BRAF and MEK inhibitor combinations is [ECG; electrocardiogram] abnormalities. We ask people to get an ECG every month on treatment. And then rare but serious adverse effects include eye adverse effects. The MEK inhibitors are known to cause some swelling at your optic disk. If that happens, usually you’ll have to just hold the MEK inhibitor, the trametinib, and then restart at a reduced dose, especially for patients who are having some visual abnormalities.

A second adverse effect from the MEK inhibitor that can be very serious is reduced heart function, reduced ejection function. And again, it’s reversible. It responds well to just stopping the MEK inhibitor and then restarting once your ejection fraction is up to normal.

And then what we’ve seen over the last few years among patients who have been on long-term treatment, is lung inflammation, or pneumonitis. Again, it appears to be related to the MEK inhibitor. Oftentimes it will respond to just reducing the dose of the MEK inhibitor. These 3 rare adverse effects of MEK inhibitors are worth monitoring carefully for and having patients seen by the ophthalmologist, and getting echocardiograms, and being aware of the possibility of having lung inflammation.

Transcript Edited for Clarity