Transcript:Jeffrey S. Weber, MD, PhD: The other difficult discussion is the stage IIIa patients. Vern, you obviously see a lot of patients who have stage IIIA disease, and the surgical maxim is that patients who had less than 1 mm of tumor in the sentinel node didn’t go on the adjuvant studies because they did pretty well. And it was the tumor burden volume in the sentinel node that was associated with outcome, so how comfortable do you feel referring a stage IIIA patient for adjuvant therapy with that terrific low risk of relapse?

Vernon K. Sondak, MD: Let’s unpack the question a little bit, because the first thing we need to recognize when we talk about the staging is that the staging system changed and the words we use now mean different things. Stage IIIA, as it was used in all the adjuvant therapy trials that have been reported, in the seventh edition of the American Joint Committee on Cancer (AJCC) staging system meant nonulcerated primary melanoma with 1 or 2 positive sentinel lymph nodes. And among all those nonulcerated melanomas with a positive sentinel node, the patient had to have at least a 1-mm tumor deposit in the sentinel node to get on to the trial.

They also had to have a node dissection, which we don’t do now since MSLT-II. Today stage IIIA switches to only the thinner melanomas—thinner and nonulcerated T1 or T2, with a positive sentinel node. In any size but for the purposes of adjuvant therapy trials, 1 mm was the cutoff. A stage III patient who is stage IIIA in the eighth edition has a better prognosis than we were used to. And most true, eighth edition stage IIIA patients have small tumor deposits. They don’t have larger tumor deposits.

But of all the stage IIIAs who were on the clinical trial, that’s only a small percentage. Today when I have a stage IIIa patient, meaning a thin primary and a positive sentinel node, if there’s a small tumor deposit and my cutoff is less than 0.2 mm, virtually all those patients we observe. If it’s greater than 1 or 2 mm, virtually all those patients we’d consider for adjuvant therapy. And between that is a gray zone where patients need to know [that] this is the favorable risk profile. We don’t have absolute information, but you ought to think about this in terms of your goals and in terms of, is it better to treat now or later? Stage IIIb, which now includes some of the old IIIAs, I don’t have any qualms referring virtually all those patients.

Jeffrey S. Weber, MD, PhD: Right. I think most of us will treat the b’s and the c’s. But Ryan, at your institution [Massachusetts General Hospital in Boston, Massachusetts], how do you feel about a stage IIIa patient? Do you have that slicing and dicing—0.2 mm or less you’ll observe; 0.2 to 1 mm, you’ll think about it; 1 mm and more, you’ll definitely treat?

Ryan J. Sullivan, MD: I think we obviously take it on a case-by-case basis. Certainly, if somebody has a thin primary but for some reason a significant bulk to the node 0.2, 0.3, 0.4, we’ll likely want to do adjuvant therapy. Whereas I think somebody who has 3 cells in their sentinel lymph node and a 1.1-mm-thick primary, we’re probably not going to offer that patient adjuvant therapy, because we’re thinking about the potential benefit. Even if you’re thinking that, what’s the benefit of immune therapy? Adjuvant immune therapy with PD-1 [programmed cell death protein 1] inhibitors is a very different adjuvant therapy [from] any other therapy because with most other care therapies—combination chemotherapy in breast cancer, chemotherapy in lung cancer, etc—the treatment that you get in the adjuvant setting is curative potentially, but it’s also potentially curative in the metastatic setting. I think the chance to “salvage somebody with immunotherapy” at relapse, particularly in somebody who’s had such low risk of relapse is there. The toxicity risking the 20% chance of thyroid toxicity, 2% chance of pituitary toxicity, 1% chance of type 1 diabetes, doesn’t seem to make as much sense in that type of patient.

Jeffrey S. Weber, MD, PhD: I would agree. Jason, would you consider a stage IIIa patient to be a better candidate for BRAF/MEK adjuvant therapy than immunotherapy?

Jason J. Luke, MD, FACP: I don’t necessarily think so. It’s interesting to note that in the trials, they focused on slightly different populations. If you looked in the clinical trial data, I would suggest that the data [are] more robust in that IIIa population—although by AJCC7, so again it’s not a 1-for-1 consideration. I think those IIIa’s are really the nuance population, and we really have to think about, similar to what Ryan had mentioned, what do I think the absolute risk reduction is for this patient?

How to put that in context. And often, for these very thin primary lesions, it’s around 5%. And when you think about the toxicity of immunotherapy, there’s about a 5% chance of an irreversible toxicity, slightly less. But you end up sort of as a wash there. And to me, those are the patients I really have a tough time advocating strongly that they take therapy because I worry that we have as much chance to do harm as we do good.

And then these people are going to do very well anyway, so I tend—in that population, that IIIa population by AJCC8—to back off a little bit. Now some patients will come in, and they’re knocking the door down and they’re like, “When are we starting?” So to each their own, and then you have that conversation. If they want to go forward, then that’s fine. But in these nuanced conversations, we like to take all this into account.

Hussein A. Tawbi, MD, PhD: I really like your point, Jason, about the magnitude of the benefit. And I think that, actually, it’s probably a time to highlight again. Remember, for those adjuvant therapies, it’s a 50% reduction and the risk of recurrence. And most of the time, although we don’t have the long-term survival for PD-1 yet, we expect the associated improvement of survival as well.

That’s a pretty steep decline in the risk of recurrence for death from melanoma. And I think from that perspective, that’s the conversation I have with my patients—what is the absolute benefit that you really want to see to subject yourself to the therapy? And it’s, actually, again, an opportunity to personalize based on patients’ preferences. And this is the situation where we would offer that treatment.

Transcript Edited for Clarity