New Treatment Paradigms for Advanced Melanoma - Episode 5

Initiating Adjuvant Therapy in Stage 3 Melanoma


Jeffrey S. Weber, MD, PhD: What do you think the 5-year relapse risk would be in a patient with a 1.2-mm primary nonulcerated case with 0.3 mm of tumor and 1-sentinel lymph node? What do you think—5-year relapse-free survival?

Robert Andtbacka, MD, CM: From the AJCC Eighth Edition Staging System, we have the overall survival for those patients. We don’t necessarily have the RFS. However, extrapolating from some retrospective data that have been done for this, it is going to be about 15% or so.

Jeffrey S. Weber, MD, PhD: That’s exactly what I would tell a patient. The question is, would you take a patient with a 15% risk of recurrence over 5 years, with way less than a 10% risk of death over 10 years, and put him or her on adjuvant treatment? Michael?

Michael A. Postow, MD: I think that’s a patient who you could safely observe. If they recur, there will, hopefully, be some type of treatment in the metastatic setting that could be helpful. With all of this enthusiasm that we have for these adjuvant trials, we’re really just talking about recurrence-free survival. We don’t have overall survival for any of these approaches yet. I would be surprised if these really low-risk patients do have an overall survival benefit with these adjuvant treatments now versus treating later. With that about 15% recurrence rate, hopefully, that wouldn’t even happen right away. It would be very difficult to see an overall survival benefit in these low-risk stage 3 patients, although we don’t have data, and so we don’t know about that yet.

Hussein Tawbi, MD, PhD: I will actually challenge that because the AJCC, again, for this stage 3a patient, was melanoma-specific survival. The melanoma-specific survival at 10 years is actually 88%, so there’s a 12% risk of dying in those patients. If you look at the pembrolizumab data, the hazard ratio in the stage 3a patients was actually 0.37. It was hugely impressive.

Robert Andtbacka, MD, CM: But you have to remember that there were very few patients in that group. And if you look at their confidence interval, it actually passed 1.

Hussein Tawbi, MD, PhD: Agreed, but at least it was on the better side of the overall hazard ratio for the entire population.

Jeffrey S. Weber, MD, PhD: You’re talking about stage 3a patients. I think we agree that in the stage 3a category, based on KEYNOTE-054 and COMBI-AD, you had to have a millimeter’s worth of tumor. The hypothetical patient that I mentioned to you was someone with less than 1 mm. So, the question comes down to, is there an 88% melanoma-specific survival at 10 years in a stage 3a patient with less than 1 mm? Or is it more?

Robert Andtbacka, MD, CM: We have to remember that all of those patients had a completion lymph node dissection.

Jeffrey S. Weber, MD, PhD: Right.

Robert Andtbacka, MD, CM: So, we first have to ask the question of, in the 0.3-mm thin or sort of intermediate thickness melanoma without ulceration, what’s the risk of having additional lymph nodes with melanoma in them? It’s going to be about 15% to 20%.

Jeffrey S. Weber, MD, PhD: Even with a minimal disease burden in the sentinel node itself?

Robert Andtbacka, MD, CM: Correct.

Jason J. Luke, MD, FACP: Which is why my answer to your question was probably going to be “unlikely.” But I would talk about it with the patient.

Jeffrey S. Weber, MD, PhD: Correct.

Jason J. Luke, MD, FACP: I have patients who come in. They want treatment. I have others who are much more cautious. I think that would be something I would discuss with them.

Omid Hamid, MD: This discussion that we’re having is completely different from the discussion that we’d have with a patient who comes in, who probably won’t understand half of the statistics and the background. We have a long discussion: “We’re not so sure if it will affect your long-term outcome yet, and there are trials that will tell us that. There are toxicities. There are newer trials with other combinations that may help you more in the future than they do now. That may mean that you may not be wasting an opportunity by taking early therapy, or you may have better chances of doing well compared to what the statistics tell you now.”

I always send the patient away to come back. Now we have time to look at and learn more about the tumor. “We know your BRAF status. Come back after you’ve thought about it.”

Jeffrey S. Weber, MD, PhD: Once you get the BRAF data, how do you decide who’s going to get adjuvant BRAF/MEK versus adjuvant nivolumab or, soon, pembrolizumab? How do you make that decision?

Omid Hamid, MD: Again, we have a discussion about those toxicities—how they would affect their life. We talk about how coming into the clinic would affect their lifestyle—whether it’s once every 2 weeks or once every 4 weeks. We discuss the toxicities that come with combination targeted agents. They’re not trivial. There are ocular toxicities. There are cardiac toxicities that are there. MEK inhibitors have other toxicities, although rare, that can be just as morbid. In addition, you’re clearly not in the office as much, but you’re tied to your physicians more when the toxicities come up. We talk about calling and coming in; about how we would then decrease and manage the dose. Those are longer discussions to have with the patient.

Transcript Edited for Clarity