Jeffrey S. Weber, MD, PhD: Let’s take another turn, and let’s go back to Jason. Jason, let’s talk about treating our patients with the higher risk—the stage IIIB, the IIIC, and the IIID by the AJCC [American Joint Committee on Cancer]. Those are really the bad actors, because frankly those with stage IIIa, by the current AJCC ratings, do pretty well. They have only a 20% risk of death at 10 years. It’s those with stage IIIB, IIIC, and IIID who do badly. How do you decide I/O [immuno-oncology] versus BRAF-adjuvant therapy? What’s the deal? Even add IIIA if you want.

Jason J. Luke, MD, FACP: It’s an important thing to think through. You mentioned earlier, do you test for BRAF in neoadjuvant? It becomes the same question. Do you test for BRAF in adjuvant? When you think about trying to make these decisions, you have to have that data to make such a decision. It’s very common that we get the patients referred to us through the usual referral channels, and they haven’t had the test. That actually often limits our ability to make that discrimination between therapies, and sometimes you need to delay that conversation.

I would emphasize that for anybody viewing, because that’s a really important need, that test. That should almost be reflexively routed by the pathology department at this point. If you have that data, then you can set up this question about which therapy you want to choose. It comes down to patients’ perspectives as well as doctors’ perspectives. Ryan Sullivan, MD, was just alluding to some people who use BRAF, some people use I/O. The data, as you just mentioned, look pretty similar going out. There are some caveats that I would just note. One of them, around the BRAF-mutated patients, is that 1 slide from KEYNOTE-054 was interesting to look at the disproportionate improvement in the hazard for relapse in the BRAF population, specifically relative to the total. Pembrolizumab in the adjuvant setting worked better in BRAF-mutant patients than it did in the total population.

I don’t want to exaggerate that more than anything else, except to say that it definitely works in BRAF-mutant patients as well. You can see that in some other I/O trials also. In terms of which stages to treat, for all of us here, there would be no question that we would try to get a patient who’s stage IIIC or IIID melanoma to take adjuvant therapy. In stage IIIB patients, most of us probably would say that. The stage IIIA population, as you alluded to, that’s the tough one. Their absolute benefit from adjuvant therapy, while it could be improved by 50%, ends up being single-digit improvement and absolute improvement.

When you think about the toxicity spectrum of these drugs, that’s a consideration, because there are long-term irreversible endocrinopathies that develop on I/O therapies—the thyroid, diabetes, etc—and I have difficulty with that population, stage IIIA especially, for using immunotherapy in the adjuvant setting. In those patients, I tend to defer, which I think you were alluding to in general. If they want adjuvant therapy, that’s where I would definitely tend to go for BRAF inhibition.

The data from COMBI-AD really highly support that. The data look really good in the stage IIIA setting as well. In that consideration point, you have to put it in front of the patient and think about what’s meaningful to them: coming for an infusion every 4 to 6 weeks or taking the targeted therapies each day?

I’d also summarize by noting that these—I won’t call it extreme benefits that we’ve seen with these hazards for improvement in the stage III setting—are likely going to be extended into other disease settings as well over the relatively near term. Due to idiosyncrasies in our staging system, all of you are aware that stage IIB and IIC melanoma is, in fact, higher-risk than stage IIIA. That really goes to the biology of the disease we treat, which is that the primary depth of the melanoma is actually more important than the involvement of single lymph nodes.

Because of that, we have this oddity where we have the on-label ability to treat that stage IIIa population that I just said I wouldn’t usually treat with immunotherapy, yet we do not have on-label usage of the drugs for a higher-risk population of stage II with deep primaries. Two trials are being investigated in that space, the KEYNOTE-716 study with pembrolizumab and the CheckMate76K study with nivolumab. The former study, KEYNOTE-716, is likely to read out much earlier. We’re really hopeful that we’ll be able to extend this benefit of adjuvant therapy into earlier stages of melanoma.

When you marry that to our previous discussion around neoadjuvant, we’re starting to get to a place where medical management of melanoma over the next 5 to 10 years may come forward as the primary modality for managing patients. That’s really interesting to think about. It would have been heretical to say that 10 years ago, but these data really do support that, as the field has brought all these data forward, moving into different disease settings. It’s really exciting.

Transcript Edited for Clarity