Neoadjuvant Melanoma Therapy: Patient Selection

Brian Gastman, MD: When do we think about neoadjuvant treatment? Neoadjuvant treatment is important in the era of COVID-19 [coronavirus disease 2019] because we may not be able to get a patient in anyway, so the fact that there is a concept of neoadjuvant treatment is important. I was part of the NCCN [National Comprehensive Cancer Network] ad hoc guidelines for what to do with melanoma during COVID-19, and we were talking about delaying sentinel node biopsy, getting the tumor out, and palliating to deal with the cell node biopsy later. 

The thought of being able to palliate or at least treat a resectable but macroscopic lesion with neoadjuvant therapy is highly palatable and more attractive. Giving a patient 1 dose gives you a lot of opportunities: No. 1, it’s unlikely, based on the data, that the patient with 1 dose will become unresectable, and No. 2, if the patient has an obvious meaningful reduction in tumor size, you can probably feel good that giving them the same therapy postoperatively is the right thing to do. 

We are not quite there, but if someone has no change in their tumor status with at least 1 dose of anti–PD-1 therapy, there might be a thought to treating them with ipilimumab-nivolumab postoperatively or switching them over even if they are BRAF positive. We’re not doing that, but in theory, that’s the kind of information that this may drive. A lot of these are still ongoing questions. In terms of the impact of neoadjuvant therapy, you also have to look at how big the tumor is. 

In theory, some of these tumors are difficult to get out. I wouldn’t say it’s that often that I have to, for example, resect the axillary vein, but once in a blue moon, when I have to, I also sometimes have to dissect out the various brachial plexus branches. Some of those patients can wake up with poor motor function even if it’s temporary.

This is the idea of being able to shrink the tumor to begin with, especially when you are dealing with other cancers; you are hoping to get true negative margins because it’s the surgery with maybe a little radiation and chemotherapy that will salvage, save, or cure that patient. It is not so in melanoma. In melanoma, if we can salvage and save major blood vessels or nerves even though we might leave a bit of tumor behind, we know that the surgery is helping the immunotherapy, not the immunotherapy helping the surgery. 

What about PD-L1 and BRAF testing? Absolutely. With the BRAF testing, you need to know, No. 1, do you have that as an option? You need to be able to offer your patient that option if it’s available. An exception might be, for example, if it’s a foot melanoma or an acral lentiginous melanoma because the chances of the patient being BRAF positive are extremely small. The question is then about what type of BRAF testing you can do. If the patient is rapidly progressing, and you want to do BRAF-based neoadjuvant therapy, you can do immunochemistry, which is quick. These are usually relegated more for the patients with fast-growing, stage IV disease, but we’ll usually do a PCR [polymerase chain reaction] hot spot type of analysis. 

For PD-L1, the honest truth is that we don’t use it. It’s still a research tool. There are probably some data that, if you’re PD-L1 low, then adding ipilimumab is beneficial, certainly in a stage IV setting. If you look at CheckMate 067, it went back and forth. At the current point, we’re not using it routinely, but it is an important research tool. If you want to go back retrospectively and see what your data are in the real world, it may be that, if you live in a certain part of the country with a certain socioeconomic class of patients, certain insurance coverage, and a certain amount of compliance, you might see differences that you wouldn’t see in a clinical trial. For example, we [at the Cleveland Clinic] published the data looking mainly at the national cancer database. Those are real-world patient data. That’s not highly regulated ECOG status 0 and 1 clinical trials, and there were some differences. For example, there was a meta-analysis of multiple trials—it was more lung cancer than melanoma—but it showed that women did poorer than men with a checkpoint-based immunotherapy. We didn’t see that, for example. The real-world data, especially regionally or locally might differ, and having those PD-L1 data might be useful for your practice. It’s worth having, especially if we are even considering adding ipilimumab to a patient with stage IV disease.

The next rendition in all this in terms of trials is a SWOG trial comparing pembrolizumab with interferon and ipilimumab. I’m not sure that’s going to change practice much, but there may be some interesting information there; it’s certainly confirmatory. The other trial, which has not been published, but you can google it, is CheckMate 915, which is the BMS [Bristol-Myers Squib] trial of ipilimumab-nivolumab vs nivolumab. It confirmed the power of nivolumab, but it showed that adding ipilimumab to ipilimumab-nivolumab didn’t make a difference. What’s interesting is that it’s the first trial that I know about that is a major phase 3 trial that did not require completion lymphadenectomy. 

Nobody knows how many patients did or did not have completion lymphadenectomy; it depends. The trial spanned from when we did it to the time we didn’t do completion lymphadenectomy. We didn’t participate in it, but this has been brought up. It wasn’t powered to ask the question, so even if it was fifty-fifty with half who did and half who didn’t have completion lymphadenectomy—I doubt it’s that ratio—it wasn’t powered to ask that question.

It is interesting to note that this trial, which didn’t show ipilimumab-nivolumab benefit over nivolumab, may have had a lot of patients who didn’t have completion lymphadenectomy. Nobody knows if that affected the trial’s outcome because we haven’t seen the data, and they may not have been able to have the power to answer that. This raises the question about MSLT-II and whether there is a role for completion lymphadenectomy, not because of completion of lymphadenectomy by itself but because the role of surgery here is to help the immune checkpoint inhibitors, not the other way around.

Transcript edited for clarity.