Jeffrey S. Weber, MD, PhD: Su, how do you talk to patients about the toxicity issues? Jason just started to get into that. Maybe you could continue. In other words, in front of you is the stage IIIA patient with some minimal amount of disease in the lymph nodes, and they don’t have ulceration in primary. I just saw such a patient yesterday as a new patient. It’s a tough discussion. How do you handle explaining the relative toxicities to them?

Sunandana Chandra, MD: First of all, I do go over the data somewhat with the patient. For example, if they have less than 1-mm focus of tumor in their lymph node, then based on the trials, they probably don’t even need therapy, right? That’s something worth considering if they truly are eligible for adjuvant therapy based on the trials we have.

It’s really a balance between the 2 paradigms of therapy, 1 being targeted, and 1 being immunotherapy. By balance, with targeted therapy, you can certainly see adverse effects. They can be pretty life-impactful in the sense that you could have pyrexia, for example, with a particular combination of BRAF and MEK inhibition. You can see transaminitis. There are certainly adverse effects that can be impactful for the patient, impactful for whether we can continue treatment. As opposed to immunotherapy, where there are certainly also adverse effects, these adverse effects may actually, in some cases, be permanent. They may lead to endocrinopathies requiring lifelong supplementation. They can sometimes be life-threatening adverse effects, albeit very rarely.

I just have a frank discussion with our patient population in terms of this is what we can expect. They both have rigorous data. We have overall survival benefit now that has been shown specifically with the combination approach. Together, we come to a decision. The nice thing is that they’re both very valuable and efficacious options. It’s just a matter of going through the nitty-gritty and trying to figure out what kind of toxicities are acceptable to the patient and their family, as well as us.

Jason J. Luke, MD, FACP: Jeff, can I follow on that really quick, just because I’ve thought about this toxicity question? It’s important to note, and none of us has alluded to it yet, that escalation of cancer therapy has been associated with improved benefit in general. We’ll talk about the metastatic—the data where ipilimumab and nivolumab together really do appear to have the best long-term overall survival advantage. In the adjuvant setting, we already have a study now, the CheckMate 915 study, that actually does not seem to suggest that we have an added benefit by adding double I/O [immuno-oncology] therapy.

The reason I bring that up, to dovetail into what Su just said, was that the toxicity associated with ipilimumab and nivolumab is not insignificant in the metastatic setting, let alone in the adjuvant setting. That’s a really important consideration when you think about choosing adjuvant therapy. The toxicities that we would tolerate, potentially in the metastatic setting, are not the same toxicities that we would tolerate in the adjuvant setting. Being very aggressive up front to educate patients—to let us know so we can interrupt therapy, we can intervene very quickly, whether it’s I/O or targeted therapy—is truly an important part of the care of adjuvant patients.

Jeffrey S. Weber, MD, PhD: It’s going to be even more important. I was about to turn to you, Jason. I know you’re the PI [principal investigator] of the KEYNOTE-716 trial. It’s going to be even more important because now we’re treating stage IIB and IIC patients. If that’s a positive study, which I assume it will be, you’d better bet that there will be a lot of stage IIA patients who get treated in the community. Your point about having a different threshold for stopping and a different threshold for choosing based on toxicity will become even more important because if those studies, the KEYNOTE-716 and the BMS [Bristol-Myers Squibb Co] CheckMate76K trials, I’m assuming they’ll be positive. Assuming they are, that opens a lot of patients to adjuvant therapy. It’s like, 20,000 patients in addition a year.

Jason J. Luke, MD, FACP: The number of patients with stage II melanoma who would be amenable if the approval comes through would be approximately the same as the stage III population. We would essentially be doubling the number of adjuvant patients. But again, as we talked about in the beginning, the risk of those patients for relapse is actually as high as for the ones we already treat. It makes sense to potentially extend that to those patients, but yes, it will be many more. Being cognizant of that toxicity is important.

Transcript Edited for Clarity