Key Considerations for Detecting and Targeting BRAF Mutations - Episode 5

Developments in the Management of Stage III Melanoma


Hussein A. Tawbi, MD, PhD: Patients with stage III melanoma are defined as patients who have nodal involvement from their disease. In the past, those patients used to be treated first with a wide local excision for the primary tumor on the skin. Then we would do a sentinel lymph node biopsy, and that’s how we actually identified nodal involvement. The next step for almost all those patients used to be a pretty extensive surgery to remove all the nodes that were in that nodal basin, called a completion lymph node dissection.

Then, after that was performed, their staging was complete, but they remained at high risk of recurrence. The risk used to range from around 40% all the way up to 70% or 80%, depending on how much nodal involvement was present. So they had to be subject to significant surgery. Then, with that high risk of recurrence, there were very few therapies that had the ability to decrease that risk. In fact, for many years, the only adjuvant therapy we had was high-dose interferon alpha, which used to be a medication that gave patients high rates of adverse effects—close to 90%, but not 100%. For an entirety of 1 year, it was useful in that it decreased the risk of recurrence appreciably in large randomized trials, but there was a question about its ability to actually cure patients because the overall survival benefit that was shown in some trials wasn’t confirmed in others. Patients with stage III disease had to deal with a lot—significant surgery and adjuvant therapy that was toxic and not very effective.

Thankfully, in the last couple of years, all that has changed dramatically. On the surgical side, we ended up having the results of MSLT-II, a trial that actually took patients who had sentinel lymph node—positive disease and randomized them to either go for the full completion dissection or just be observed until they recurred, and then they would go for the completion resection. The results of that trial showed that there is no survival benefit to the big surgery that left people with lymphedema and other things. That was the first improvement we have. Those patients are now most likely to be observed as opposed to having a completion lymph node dissection.

The second very important development is actually the approval of effective adjuvant therapy. Now we have 3 different drugs or drug combinations. We have 2 immunotherapy drugs—nivolumab as a single agent and pembrolizumab as a single agent—that are immunotherapy based and decrease the risk of recurrence by almost half. And we have targeted therapy, with dabrafenib and trametinib, that is also appropriate for patients with BRAF mutations and that also decreases the risk of relapse by about half.

All these drugs are actually relatively tolerable. They do have an adverse-effect profile, as most cancer drugs do, but their toxicities are generally manageable. With the magnitude of benefit, we really feel strongly that most patients with stage III disease would be appropriate for that treatment. And so to summarize the developments, less surgery and more effective adjuvant therapy. I think we’re in a place where we can cure more patients with stage III disease than we did in the past.

Transcript Edited for Clarity