Adjuvant Therapy in Stage IIIB/IIIC/IIID Melanoma

Brian Gastman, MD: In the world of stage III melanoma or resectable stage IV melanoma, the only molecular testing that we routinely do is BRAF with additives, because in most hospitals, there is usually a base hot spot analysis that they’ll throw in. Tumor mutational burden [TMB] is clearly associated with benefit. The issue is that melanoma usually has a high tumor mutational burden. It is sometimes like asking this question: “How yellow is the sun?” Almost all your melanomas have high tumor mutational burden: There’s high and there’s higher, but there’s not that much low in melanoma.

TMB is probably not going to make a difference, necessarily. That is probably also why PD-L1 is not that effective either, because many of our tumors are PD-L1 positive. The idea of a cold or desert tumor where PD-L1 is probably low and certain aspects of immunology like Th1 signaling and tumor-infiltrating lymphocytes are low occurs, and we may see it more in stage IV disease, but whether we see it depends on which part of the tumor you are looking at. It’s less of an issue in the early stage III diseases. Regardless, no study has formed the basis of ordering it as standard of care, so it does not impact our standard of care.

To answer the practical question for stage IIIB, IIIC, and IIID melanoma, there are a couple of things. First, there is a question about stage IIIA melanoma. The FDA approved stage IIIA, and the KEYNOTE-054 trial of pembrolizumab vs placebo included stage IIIA, as did the COMBI-AD trial. You could give stage IIIA, and the questions are why you would and why you wouldn’t. For why you would, you would also want to look at the amount of tumor in a lymph node. To be stage III, you have to have a thin tumor with a minimal number of lymph nodes involved. However, if a lymph node has significant disease, you could still be a patient in stage IIIA, and you might consider doing adjuvant therapy. It’s important to point that out. I don’t want to negate that completely.

There may be some molecular prognostic testing that people might do to help them make the decision 1 way or the other. For stage IIIB, IIIC, and IIID melanoma, these run the gamut. To be a patient with stage IIID melanoma, if you look at the AJCC [American Joint Committee on Cancer] data, a rare number of patients who were stage IIID because they had to have a of number of positive nodes and trans-metastatic disease. Many of those patients may be unresectable, or if you are resecting them, then you are not getting resection with the confidence of negative margins or full-on resection that you would get otherwise, which is something the radiation people would call R1.

An R0 means there is nothing left in my path. An R2 means there is grossly visible disease left behind, and R1 is microscopic disease. In stage IIID melanoma, you may not be able to resect, or you might end up with R1 disease. That needs to be considered. The prognosis for stage IIID melanoma is similar to stage IV, so for that group, you might consider ipilimumab-nivolumab because they are such a high-risk group.

For stage IIIB and stage IIIC melanoma, there’s a bit of heterogeneity there. You can have macroscopic disease and be there, and you can have microscopic disease and be there. In general, for resected disease for stage IIIB through IIID melanoma, you are going to get your molecular testing. If you have a BRAF mutation, then you have 2 options: a BRAF/MEK inhibitor, and within that you have 3 options—some of it is about comfort, and some of it can be hospital negotiations with the companies. Among those 3 options, there are some people who like it so much that, if 1 option gives an adverse effect that the patient can’t stand, they might go to a different combination before going to immunotherapy. 

On the other side is immunotherapy. We are talking about anti–PD-1 immunotherapy: nivolumab or pembrolizumab. Why would you choose 1 agent over the other? Everybody has their own empirical experiences with them. At 1 point, it was nivolumab every 2 weeks and pembrolizumab every 3 weeks. If you want to see your patient more often, then you get it every 2 weeks. If you want to see them less often, then it’s every 3 weeks. Then nivolumab became every 4 weeks. Now with pembrolizumab you can do every 6 weeks.

You have to tailor it to your patient. You have to look at what your patient wants and what their knowledge base is. Some people come in having seen commercials about anti–PD-1 therapy for lung cancer and melanoma, and they are going to tell you, “That’s what I want.” Some patients are going to say, “No I don’t want the IV [intravenous] therapy. I want a pill.” Another question that still exists in the field is this: If you have both options, and it’s dealer’s choice, which do you give? If 1 fails, you are going to give the other when it fails, so maybe you should give the BRAF/MEK inhibitor first. Or should we give anti–PD-1 therapy first?

Like all things in melanoma, we usually ask those questions in the stage IV setting, and we then bring it to stage III melanoma. EA6134, which is about answering that question, is about 90% accrued, but it is still going to be years before we know the answer. It was a tough trial to recruit too, so I’m not sure there will be an appetite to even answer the question in stage III melanoma, but the results of that in the stage IV setting may drive what we do first. For 1 or the other, the bottom line is that you have to tailor to your patients: Do they want a pill, or do they want an IV? In my mind, I look at the data that pembrolizumab in the stage IV setting did better with less disease, and you are more likely to get a durable cure stage IV melanoma with anti–PD-1 therapy. There is no better time to have less disease than in the adjuvant setting. 

I tend to lean toward anti–PD-1 therapy, and I’ll throw in the fact that, although the adverse-effect peaks are lower with BRAF/MEK inhibitor, the chances of having some annoying adverse effects are much more common with the BRAF/MEK inhibitors. Even though you get lifestyle improvement with a pill, you might get lifestyle reduction with some of those chronic annoying problems. This harks back to the days of interferon, which weren’t that long ago, where patients had no other choice: they did it, and it was an annoying thing to be on because they were always feeling sick all the time. You have to tailor it, and you’ll sometimes do 1 option, and they can’t handle it, so you do the other option because they couldn’t handle the first therapy.

Evan J. Lipson, MD: CheckMate 915 is an important study. It looked at adjuvant ipilimumab plus nivolumab. This is mostly important because we know that, in some patients, combination therapy of ipilimumab plus nivolumab is highly effective in the stage IV setting. The question that CheckMate 915 asked was about whether you could extrapolate and perhaps say that ipilimumab plus nivolumab would be beneficial in the adjuvant setting.

This was a randomized phase 3 study that evaluated ipilimumab plus nivolumab vs nivolumab alone for patients who had undergone a complete surgical resection as stage IIIB, IIIC, IIID, or IV melanoma according to AJCC Cancer Staging Manual, 8th edition. To some people’s surprise, adding the 2 drugs, ipilimumab plus nivolumab, did not result in a statistically significant improvement in recurrence-free survival in the intent-to-treat population compared with nivolumab by itself.

For some patients in the stage IV setting, ipilimumab plus nivolumab is a good way to go. It does not appear that, in the adjuvant setting, there is a benefit in using dual therapy, at least in CheckMate 915.

A question that sometimes comes up is about whether there’s a role for ipilimumab in the adjuvant setting. Given the studies that we’ve talked about and given the benefits of using anti–PD-1 or BRAF/MEK therapy in the adjuvant setting, there’s a limited role for ipilimumab in the adjuvant setting. In some patients who have received anti–PD-1 therapy in the adjuvant setting and then progressed, they would like to do something additional now that they have been rendered free of disease after surgery. In those cases, if BRAF/MEK therapy is not an option and they’ve already progressed to anti–PD-1 treatment in the adjuvant setting, then ipilimumab can be considered there. The same is true in a patient with BRAF-mutant melanoma who has progressed through anti–PD-1 treatment and BRAF/MEK inhibition adjuvantly. In the right patient who’s enthusiastic about pursuing a third adjuvant treatment, ipilimumab can be considered in that setting. We do not consider ipilimumab as first-line adjuvant therapy for anybody.

Transcript edited for clarity.