Adjuvant Therapy for Locally Advanced Melanoma

Transcript:

Sanjiv S. Agarwala, MD: In terms of adjuvant therapy, we’ve talked a lot about the stage III patients. I want to just delve a little bit into the stage IIIa population, which has evolved recently, right? There’s a small, very small amount of melanoma in 1 lymph-node positive, no...mapping done anymore. Dr Schadendorf, let’s start with you. What is your cutoff, if any, for that lymph node that’s positive for a IIIa patient. AJCC8 [American Joint Committee on Cancer Cancer Staging Manual 8^th edition] gives them a 90% survival at 10 years. It’s a very high number.

Dirk Schadendorf, MD, PhD: I believe that the AJCC survival curves we are seeing, not the correct numbers. I mean, there are several centers actually that have reanalyzed their databases, including our database. We analyze 2000 patients, and the 10-year survival is in stage IIIa patients without any kind of 75%. With a 75% chance to die within 10 years, I think it’s a good reason to offer these patients treatment.

Caroline Robert, MD, PhD: 25%.

Dirk Schadendorf, MD, PhD: Twenty-five percent death rate. At 12%, I would be more reluctant, and age and other factors would also play into that decision-making process. Another, so we would treat a patient with stage IIIa independent on any tumor load in the sentinel node.

Sanjiv S. Agarwala, MD: What stage IIIa patients do you treat? Regardless of 1 melanoma cell in the lymph nodes?

Caroline Robert, MD, PhD: Less than 1 mm?

Dirk Schadendorf, MD, PhD: Um hmm.

Sanjiv S. Agarwala, MD: Yes, that was the question, 1 mm.

Caroline Robert, MD, PhD: Less than 1 mm?

Dirk Schadendorf, MD, PhD: Yes, we would offer that.

Alexander Eggermont, MD, PhD: The point is, nobody is going to measure this in practice, and that’s why it’s been approved for all of stage III. Because the FDA knows that nobody is going to do this type of precision work. You have to be practical. But everybody knows that the more you look, the more you will find, and there is no absolute cutoff. It’s a sliding scale into sentinel-node negativity. And that sentinel-node negativity is defined by the number of sections you take. It’s all a very flux concept. You just need to look at the curves and need to see that there will be a 30% overlap relapse at 5 years. And that 30% relapse rate, or 35% relapse rate—I’m not talking about survivals—is that risk big enough to propose adjuvant therapy? And I would say yes if the patient is 20 years old.

Sanjiv S. Agarwala, MD: Independent of age?

Alexander Eggermont, MD, PhD: Twenty years old, yes. If the patient is 88 years old, well I’ll give it a thought.

Dirk Schadendorf, MD, PhD: Wait and see.

Alexander Eggermont, MD, PhD: Yeah, yeah. It’s a risk-benefit type of discussion with patients who bring all these different things into the equation, because you’re sliding into sentinel-node negativity. And sentinel-node negativity also has a group of patients who are still at high risk.

Dirk Schadendorf, MD, PhD: Alex, tell me, would you think that whether you are more on the stage IIIa site would prompt you to give more immunotherapy? Or would that favor targeted therapy? On the other side, for stage IIIc and IIId patients, would they be patients you would give more checkpoint blockade or targeted therapy? We have the tendency to give patients at stage IIIc and IIId more targeted therapy, because of what Alex mentioned, that there is an early escape with check in order to have a better tumor control in these patients.

Caroline Robert, MD, PhD: But there are also the patients, they are very close to the M1a, and these are the ones who do very well with anti—PD-1 [programmed cell death protein 1] monotherapy.

Alexander Eggermont, MD, PhD: The point is that all patients at some point in time who will relapse will be managed in a manner that they will be secured to receive immunotherapy. This is the thing you must always secure, whether they’re BRAF mutant or not. If they’re not, it’s an easy thing to start with. But if they are BRAF mutant, you must assure that you don’t miss the opportunity to also expose them to immunotherapy. Because that, in the end, has a certain cure rate that the other treatments do not have to the same extent. In that type of management, you can say I want to make sure he doesn’t relapse in the first year. But if it’s a stage IIId patient, are you then not going to give him anti—PD-1? Or are you going to wait for the relapse? The only trial that has been designed to answer that question is the EORTC [European Organization for the Research and Treatment of Cancer] trial.

Sanjiv S. Agarwala, MD: The crossover?

Alexander Eggermont, MD, PhD: Yeah. It’s the pembrolizumab trial that we have fought for years to make it acceptable to do crossover. It answers the question, is anti—PD-1 actually so good that you don’t have to give it in the adjuvant setting, but you can actually give it immediately at the time of relapse?

Sanjiv S. Agarwala, MD: That’s a great question. And you know it’s going to get more complicated when we get results from CheckMate 915 which is combination ipilimumab-nivolumab.

Alexander Eggermont, MD, PhD: Yeah, yeah, sure.

Sanjiv S. Agarwala, MD: This debate is going to go on, and we have no data. But what about the stage II patients? What was it, KEYNOTE-715 or KEYNOTE-716 that I think is looking at that.

Transcript Edited for Clarity