"What is the Optimal Treatment of Advanced Melanoma?"

A Conversation with Mario Sznol, MD
By Caroline Helwick. Sept 15, 2013. ASCO post.

Mutation testing:

"Although we consider immune therapy first in almost all patients, we send a tumor sample for mutation testing....(BRAF, NRAS, cKIT)... If the patient does not have a BRAF V600E mutation, we consider that he or she could have other mutations or alterations in BRAF that are not picked up on the conventional test and that could respond to a BRAF or MEK inhibitor, so we may send tissue for a more sophisticated molecular sequencing.  Patients with the unusual mutations or alterations are a vanishingly small population, but that's what personalized medicine is about..."

Treatment initiation:

"The targeted agents are...lower on our list...while some patients can have durable responses to BRAF inhibitors, so far we don't know if these responses are maintained once you stop the drug, unlike with immunotherapy.  If a BRAF inhibitor is indicated, the best recent data indicate it should be used in combination with the MEK inhibitor...  Even when we start targeted therapy first, our goal is to reach a level of response where we might stop the targeted therapy and start ipilimumab.  We also have the option of going back to targeted therapy if there is no response to the immune therapy.... For ipi, it's important to understand that some patients slowly build an immune antitumor response over 3-6 months, but once they respond they often have durable remissions - they just need time to get there...."

Novel Immunotherapeutic Agents:

"We are very excited about these immunotherapeutic agents, currently nivolumab and lambrolizumab, which block PD-1 but also the antibodies that block PD-L1.  About 30% of patients will respond to these agents by objective criteria, and conservatively, about half of this group may achieve very durable responses.  The median response duration to nivolumab is 2 years - the longest we have seen in advanced melanoma.  Even better responses are observed when we combine nivolumab with ipi. We see overall response rates of 40-50%, with about 30% of patients demonstrating at least an 80% tumor regression. This can occur even in patients with very large tumors that are progressing rapidly.  The responses happen quickly and are very deep."

"With anti-PD1, you can tell your patient that he or she will have a 30% chance of responding, and if a response occurs, there is a 50% chance that it will be durable, with almost no toxicity in most patients; toxicity, however, will be greater when PD-1 blockade is combined with ipi.  It's a no-brainer that we will probably offer some form of PD-1 blockade first, alone, or in combination."

"Perhaps we may change this view when we see long-term data from the dabrafenib/trametinib or other BRAF/MEK targeted agent combinations....I still don't know with 100% certainty if nivolumab/ipi is better than nivolumab alone, or better than lambrolizumab alone, or if one anti-PD1/PD-L1 agent is better than another....  We believe that having these new drugs will make some of the current treatment algorithms obsolete..."

Hmmmm....lots yet to learn, indeed.  Best to you all. - c