Jeffrey S. Weber, MD, PhD: Michael, tell me about the toxicities of adjuvant treatment. It did seem like there were differences. It did seem like the proportion of patients who had to stop from toxicity was different between PD-1 trials and dabrafenib/trametinib. Is there a threshold, or is there an issue with you treating a really low-risk stage 3a patient, in terms of toxicity? Does that play into your decision making?

Michael A. Postow, MD: There is always a risk and benefit decision that you have with a patient. If their risk is lower in general, if they’re having toxicity, I’m more likely to discontinue them early. I can’t say that we need this treatment that badly, because I’m not sure what that relative benefit of ongoing treatment is in that case.

If I have a really high-risk stage 3c patient who is on adjuvant treatment with some mild or moderate toxicity, I may be more inclined to try to get them through the toxicity and continue treatment longer. If it’s really an early-risk stage 3a case, if I was on the fence about even treating them at all, if they’re having very mild to moderate toxicity, I might be more inclined to discontinue early. So, I think that it’s a threshold that you have with each individual patient—about how much you really feel they need that benefit from adjuvant treatment and what their side effects are. There are totally different side effects with dabrafenib/trametinib versus immunotherapy.

I think that’s also a really important issue to talk with patients about. In the adjuvant setting, we have to think about toxicities differently than we do in the metastatic setting. Many of these patients are cured with surgery. We know there’s a high risk, and, of course, that’s why we’re even thinking about adjuvant therapy. But these are patients who are not sick with cancer. They’ve had all of their cancer resected. They’re healthy people who are getting treatment that might be making them sick. And so, you really need to try to understand what their experiences are and how the toxicities are affecting their quality of life. You really have to work through that.

Jeffrey S. Weber, MD, PhD: Do you think the toxicity is different in the adjuvant mode versus the metastatic mode?

Michael A. Postow, MD: There’s always a notion that there’s greater toxicities, at least with immunotherapy. There have been discussions in the adjuvant setting, perhaps because there’s less tumor burden creating some immunosuppressive environment that mitigates toxicities in the metastatic setting. I think there may be this sense of higher toxicities with some combinations of immunotherapy, particularly in the adjuvant setting. I don’t think it’s totally clear as to which one is better or worse.

We do know that the toxicities are generally similar, in terms of the kinds of side effects that you have in the metastatic setting versus in the adjuvant setting, but there might be more long-term implications in the adjuvant setting. If you have young patients who have a new endocrinopathies with a PD-1 monotherapy, for the rest of their life, they’ll have hypothyroidism or secondary adrenal insufficiency. That may have different implications 20 or 30 years down the line versus for a patient with metastatic disease. That’s an important thing to think about—the permanency of some of these immunotherapy side effects.

Jeffrey S. Weber, MD, PhD: Hussein?

Hussein Tawbi, MD, PhD: I definitely agree with you. In the adjuvant setting, we really have to have a much lower threshold for stopping for toxicity, and we have to really think about the impact on patients who are otherwise surgically cured—in terms of the long-lasting toxicities. That’s actually one of the reasons why the discussion around PD-1 versus BRAF is really important. With BRAF-targeted therapy for BRAF-mutant patients, the toxicity rate appears to be higher. Patients develop fevers. And to your point, there are observations, especially in the neoadjuvant setting, that the toxicity rate seems to be higher in patients who don’t have active disease.

In those patients—with dabrafenib/trametinib, for instance—the toxicity rate is higher. But when you stop using the pills, the toxicity goes away, and the patient can move on with his or her life. With anti—PD-1 therapy, the rate of toxicity is a lot lower, but there is definite concern that some of the toxicities are long-lasting. And so, for every patient that we discuss adjuvant therapy with, endocrinopathy is very important.

In melanoma, we have some patient populations who are really young. Fertility is an issue in young females and even in young males. Patients are going to live for the rest of their lives with the potential outcomes of the adjuvant therapy, so I think it’s very important to discuss those issues with those patients. You should consider a much lower threshold to stop therapy and, again, make sure that the patient agrees with proceeding with therapy.

In general, from the stage 3a perspective, can you extrapolate the data from the 3b, 3c, and 1a to 3a patients? The hazard ratios are impressive enough that it’s not much of a stretch to say that the biology seems pretty consistent across all of these subgroups. Patients are expected to respond in a similar manner.

Robert Andtbacka, MD, CM: From a surgical perspective, this is a discussion that I initially have with patients when they come in, before we involve our medical oncologists, because they now have a positive sentinel lymph node and are classified as a stage 3a patient. We know that with targeted therapy with dabrafenib and trametinib, if we look at that and reanalyze this according to the AJCC Eighth Edition Melanoma Staging System, we have the true new stage 3a patients, and the hazard ratio is maintained there. This is quite impressive.

I think we have to recognize that the stage 3a patients who were a part of these studies still had a fair amount of tumor. Overall, in the United States, they actually represent the minority of patients. The majority of patients that we see in the United States have less disease in their sentinel lymph nodes. We haven’t really studied that, so we don’t really know the true impact in those patients. So, I think that there are still more things that we need to do.

Transcript Edited for Clarity