Axel Hauschild, MD: Dabrafenib and trametinib are also entering this field. We need to cover one very important question. This is in BRAF-mutated patients. What are we going to do in the near future?

Caroline Robert, MD, PhD: Yes, that’s the question.

Axel Hauschild, MD: So we have the choice of either the PD-1 [programmed cell death protein 1] antibodies or dabrafenib and trametinib as BRAF-directed treatment. I would like to listen to your response to this difficult question. Caroline?

Caroline Robert, MD, PhD: This is going to be a real question, and it is based on approvals.

Axel Hauschild, MD: In Europe, we have approval.

Caroline Robert, MD, PhD: Recently, I had a young woman. She had Crohn’s disease. If you don’t have Crohn’s disease, you can really use either of the approaches: targeted therapy or immunotherapy. We don’t have the answer yet. Depending on things that are not evidence-based with a clinical trial, you can say that they might be wrong. Instinctively, we might think about using targeted therapy because we know about relapse in the metastatic setting. We know they relapse quite often in the brain. We know it’s difficult to rescue them afterwards.

Maybe some colleagues would be more inclined to use immunotherapy, but we don’t have the results. We don’t have head-to-head results. We don’t have the same metric clinical trials. We have very good results from the COMBI-AD study. So honestly, I don’t think we know. We really have to talk with our patients because of the differences that we see in toxicity. We see many adverse events when we start therapy, but almost none of them are permanent. Whereas you might have a thyroid dysfunction forever or some other serious disease.

Merrick I. Ross, MD: I’m taking care of 3 patients right now who received immunotherapy in the adjuvant setting. Two of them were pretty high risk, in terms of their risk of relapse. All 3 of them have severe insulin-dependent diabetes, probably for the rest of their lives.

Caroline Robert, MD, PhD: Oh, that’s a big problem.

Merrick I. Ross, MD: Right.

Axel Hauschild, MD: It’s the same with hypophysitis. There are also some other rare adverse events. Honestly, it’s just 1% of the patients.

Merrick I. Ross, MD: Right, it’s not a huge percentage of patients.

Axel Hauschild, MD: Eventually, a patient is dying. It’s 0.6%, regarding a recent review on adverse events from the immune-oncology field. But there is a small risk, and it’s not easy to identify the patients who are at risk. It would be great if we had biomarkers to identify these patients. A paper at this conference from Germany tells us about a panel of autoimmune biomarkers that can be evaluated before treatment initiation, which can at least give us an idea as to whether these patients are at risk for colitis and other autoimmune diseases. But this is not being done routinely right now.

Merrick I. Ross, MD: It’s interesting because most of my medical oncology colleagues, including you, Jason, would probably offer immunotherapy as a first-line option in the adjuvant setting. At our institution, that’s what most of my colleagues do. But given this new data with targeted therapy, you have to think twice. You have to be very thoughtful about these recommendations. That data is very impressive. I haven’t seen it published yet, but it’s so impressive, and I think it goes along with our paradigm about how targeted therapies work.

Maybe there are less-resistant clones when you treat the patient early. The fear is that in the stage IV setting, almost all patients will develop resistance. But maybe they don’t in this setting because they have les- resistant clones inherently since it’s earlier disease.

Caroline Robert, MD, PhD: We need to tell the patient that there are several options.

Michael A. Davies, MD, PhD: It’s important that we talk about how to pick among these therapies in stage III patients. As we looked at results of the data, one of the questions was whether there was a difference in benefit in stage IIIa, stage IIIb, and IIIc patients. In the COMBI-AD study, the hazard ratios in each group were essentially identical. It wasn’t clear whether it was better to use it in those patients with higher burden of stage III disease. The benefit was really equivalent across those groups. When looking at the adjuvant PD-1 data, my impression is that the results look relatively equivalent across the subgroups with stage III disease. We haven’t been able to separate out whether you would do something different for a stage IIIa patient versus a stage IIIc patient.

Axel Hauschild, MD: Most importantly, the PD-1 antibodies are working in both the BRAF—wild type and BRAF-mutated patients. A subgroup analysis showed equally effective results. They’re equally effective in both groups of patients. Therefore, it’s not helping us very much. Is oral versus intravenous [IV] treatment an issue for your patients, Jason?

Jason J. Luke, MD, FACP: The answer is yes, but I also want to hit on the practical point that we discussed before. Unfortunately, for many patients that come to see us, we don’t know if they have a BRAF mutation. There is sometimes a sense of urgency to start treatment in patients who are concerned. I’ve heard that it’s very reasonable not to rush into therapy, but not having information is a problem.

Axel Hauschild, MD: That’s a good point.

Jason J. Luke, MD, FACP: When we think about individual agents, there is a consideration between oral and IV infusions. Our experience is that patients do prefer pills, but they do seem to get pyrexia. That tends to turn them off from therapy. Their tolerance for any side effect is often very low. So in the adjuvant setting, as soon as they run into any problems, they don’t really want to do it any longer.

Axel Hauschild, MD: Out of the 26% of patients who had discontinued their treatment with the COMBI-AD trial, 13% had either fever or chills. I believe it’s the same group of flu-like symptoms. Even in the light of 26% treatment discontinuation, the results are good. They are surprisingly good for many of us. We don’t know if these patients are doing as good as the ones who continued for 1 full year. Eventually you don’t need to treat for 1 full year, but just for the occurrence of adverse events—3 or 6 months. We have no idea.

I want to emphasize something. We have very effective adjuvant treatment modalities. Roughly half of the patients who have a locoregional relapse have lymph node/skin metastases that are resectable. If you resect, there is another opportunity for a so-called second-line adjuvant treatment modality. Would you switch from dabrafenib/trametinib, in the light of a progressive disease, to a PD-1 antibody? Or, in the United States, would you switch to ipilimumab? Mike?

Michael A. Davies, MD, PhD: If we had a patient who received adjuvant targeted therapy or immunotherapy and relapsed and resected, to me it would make sense to switch over to the other treatment modality for sure. And again, if it was a patient who had progressed after receiving targeted therapy, I would certainly recommend adjuvant PD-1 therapy as opposed to adjuvant ipilimumab at this point.

Jason J. Luke, MD, FACP: I want to comment on the other scenario, which is the BRAF wild-type patient who gets up-front anti—PD-1 adjuvant therapy. If they have some sort of regional relapse or something similar, the question is whether or not you would give adjuvant ipilimumab. That’s a pretty tough call. With no data to really support that and because of the risk of toxicity, I would be very cautious about this. I want to emphasize that just because drugs are approved, it does not necessarily mean that they have to be used. As great as the NCCN [National Comprehensive Cancer Network] guidelines are, there is sometimes a lot of flexibility. We are starting to see some of these people come in, where it’s kind of like they just kept rolling with it. I think we need to be judicious about how we think about using some of these therapies.

Transcript Edited for Clarity