Adjuvant Therapy Options in Melanoma Treatment


Sanjiv S. Agarwala, MD: Let’s talk about something now that is available to us: adjuvant therapy. It’s the other side of the spectrum. A lot of data have come out recently. I think I’ll start with you, Dr Robert.

Caroline Robert, MD, PhD: Explosion of clinical trials.

Sanjiv S. Agarwala, MD: Exactly. Let me turn to you for discussion regarding the usual trials: KEYNOTE-054 with pembrolizumab, CheckMate 238 with nivolumab, and then COMBI-AD. These are all well-known trials, [with] good data, and available. What are your thoughts of adjuvant therapy? How do you pick? Let’s start with you.

Caroline Robert, MD, PhD: Just to summarize, we have shown that initially ipilimumab at 10 mg is more effective adjuvant treatment than anti—PD-1 [programmed cell death protein 1], and nivolumab versus the same dose of ipilimumab is more effective. And now we have this trial with pembrolizumab versus placebo, the EORTC [European Organisation for Research and Treatment of Cancer] trial, which Alex can give us a lot of detail on. We have anti–PD-1, which is demonstrated as having an acceptable ratio between the benefit and the risk, which we think ipilimumab at 10 mg did not have. Although it was effective, it was associated with a lot of adverse events. Anti-PD-1 is a treatment that’s acceptable that we use and that we are happy to be able to propose to our patients regardless of BRAF-mutation status. On the other side we have the BRAF/MEK combination that also has been shown to be very effective.

Sanjiv S. Agarwala, MD: Great, someone has a vision?

Caroline Robert, MD, PhD: Yes. And we have a longer follow-up, so we have the significance in terms of overall survival, but it’s going to be really statistically significant. Although the curves at the end are of a slightly different profile. As we see with the immunotherapy, they tend to get closer together but remain different and significantly different. Right now we have our patients, and when they have a BRAF mutation, we can offer them either anti—PD-1 or anti-BRAF, anti-MEK.

Clearly, I don’t think we can say that today 1 is better than the other. But we can discuss depending on, of course, the patient’s choice and the patient capability of coming to the hospital; and patient acceptance to potentially have permanent adverse events. We have to really explain the spectrum of toxicity, and they are very different between BRAF/MEK therapy and immunotherapy. And although the tumor is low, we know that it might be different also.

In fact, it’s not so easy to really say that patient with a macroscopic disease should benefit more from 1 than the other, but we can discuss around that. Today, honestly, I think we need to take a lot of time to explain to the patient the possibility, and I don’t think we should really because we did it more or less in something. It’s not a question of ability; it’s a question of seeing the data. And I think right now there is really a choice.

Sanjiv S. Agarwala, MD: We’ll come back to that again because I do want to delve deeper into the choices. But before we do, Alex, I’d like to ask you about 1 other trial that was at ASCO [the American Society of Clinical Oncology Annual Meeting] this year, ECOG 1609, which looked at the control arm of high-dose interferon. Do you think that trial is relevant at all anymore? What is it going to teach us, if anything?

Alexander Eggermont, MD, PhD: Basically, what it teaches us is that 3 mg of ipilimumab is less toxic than 10 mg of ipilimumab. That 10 mg of ipilimumab is not acceptable in the adjuvant setting—in spite of a long-lasting overall survival benefit, which we did report at ASCO—in an absolute difference of 10% at the 5, 6, 7, 8 years. We know, and the good news is, that with an immune checkpoint inhibitor, you do get long-lasting sustained effect. That’s point 1.

Is ipilimumab still relevant as an adjuvant drug? No, not really, because the curves for the anti—PD-1s are superior to the ipilimumab. And where 50% of patients discontinue treatment because of immune-related adverse events, only 14% discontinue treatment with anti–PD-1 regimens, whether it’s nivolumab or pembrolizumab. And then in the COMBI-AD—so dabrafenib-trametinib combination—26% of patients discontinue treatment because of adverse effects.

The least-adverse effects are actually being observed with anti—PD-1, with pembrolizumab and the nivolumab; however, they can be chronic. What’s good is that the majority of these effects are actually thyroiditis, and then sliding into hypothyroidism, which is mainly laboratory abnormalities that often does not need treatment. Not even substitution, but it may need that.

This is the major part of the adverse-effect profile of the anti—PD-1s, and therefore it seems like a very reasonable proposal. The important thing is that with COMBI-AD, which is limited to only BRAF mutant melanoma patients, nobody relapses basically in the first year. Only 12% of patients do. Whereas with anti—PD-1, you have the traditional 25% of patients who don’t care at all about anti–PD-1. And therefore you see a relapse rate, both in the nivolumab arm or in the pembrolizumab arm in these trials, of around 22% in the first year. That’s where the difference is.

And then with anti—PD-1, you’re already at 1½ years, and you slide into a plateau. And so at 2 years you have similar efficacy numbers. What’s going to happen is just like what happened with advanced disease. It crosses over with the BRAF-MEK combos.

Dirk Schadendorf, MD, PhD: I disagree.

Alexander Eggermont, MD, PhD: And the anti—PD-1s. And the anti–PD-1s already at 3 years have superior overall survival in advanced disease. And at 5 years the immunotherapy regimens have superior numbers. This is what I expect for the adjuvant setting to happen, and this is now the picture that is going to unfold over the coming 2 years. We’ll see what happens.

Transcript Edited for Clarity

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