General Discussions

Monotherapy Versus Combination Therapy Approaches in Melanoma

By Michael A. Postow, MD, and Michael B. Atkins, MD


Michael A. Postow, MD:
When we think about immune therapy for melanoma, our major initial decision is, do we give this patient a single PD-1 drug, like pembrolizumab or nivolumab, or do we give this patient a combination of immune therapy drugs, such as the combination of nivolumab with ipilimumab? That’s the major decision that we come across. So, what goes into our mind in thinking about these 2 approaches, both single-agent PD-1 drugs or the combination of ipilimumab and nivolumab? Single-agent PD-1 drugs are very, very effective in and of themselves and incredibly well tolerated. In terms of any single-agent approach, PD-1 drugs in the immune therapy class are incredibly effective and are always a reasonable choice for patients. However, when you combine immune therapy drugs like ipilimumab and nivolumab, you do have a higher response rate. So, that means more patients are having tumor shrinkage with the combination of ipilimumab and nivolumab compared to single-agent PD-1 drugs like pembrolizumab or nivolumab.

With ipilimumab in PD-1 combinations, you do get higher response rates. You do get a higher proportion of patients with tumor shrinkage. That is an important consideration. Unfortunately, we don’t have information yet on long-term survival rates of patients with the combination approach of ipilimumab and nivolumab compared to single-agent PD-1. We don’t really know long term how are we helping patients with combinations compared to giving single drugs one at a time. So, it’s really reasonable to think about, should I give this patient a combination of ipilimumab and nivolumab together or should I give this patient a single PD-1 drug, like pembrolizumab or nivolumab alone? And if that doesn’t work, do I then switch that patient to ipilimumab alone or ipilimumab and nivolumab in combination? It’s really an ongoing area of research.

One would say, “Well, if the combination has a higher degree of shrinkage of tumors in patients, a higher proportion of patients with shrinkage, we don’t know long term how beneficial that really is yet compared to the sequential approach. Why don’t we just give the combination to everyone?” The reason that we don’t is because there are more side effects with the combination, and that’s just no surprise. When you combine 2 drugs together, you get more side effects than when you just give PD-1 alone. Ipilimumab drives more of the side effects within the combination, so we know that with that combination, the toxicities are more driven by ipilimumab than PD-1 alone and it is incredibly well tolerated. But sometimes the combination really is justified and the higher frequency of side effects is worth it to ensure that that patient is going to have the best numeric chance of having a response, and trying to tease that out is a really complex question.

Michael B. Atkins, MD: We have a lot of experience with combination ipilimumab/nivolumab and also some experience with the combination of pembrolizumab and ipilimumab. We were involved in the initial clinical trials of both of those combinations and, therefore, have a lot of information as well on long-term follow-up. In our hands, with the combination of ipilimumab and nivolumab, we see 60% of our patients responding exactly as we’ve seen in the CheckMate-067 and CheckMate-069 clinical trials. We find that a lot of those responses are very durable with progression-free survival at 18 months, being 50% and being flat after that. Even when patients have only partial responses, we’ve been sampling their tumor and finding that there’s no viable tumor in those cases, allowing us to stop treatment. And in our patients, the cohort that we followed for 3 years, 70% of those are still alive, disease-free, and off treatment.

With monotherapy—with either nivolumab or pembrolizumab—we see a fair amount of activity and it’s certainly well tolerated. But the data seem to suggest that the plateau on the survival curves are going to be in the 30%-to-40% range. So, there’s a difference that’s as much as a 20% to 30% plateau on the survival curves. We look at that and say that that’s a real difference. That’s 2 to 3 out of 10 patients who are living disease-free and treatment-free from the combination compared to the single agents. And we think that even though the combination has considerably more toxicity, that difference in the potential cure rate is far worth that extra toxicity because every patient who’s not on that tail of that survival curve is dead. I think it’s much easier to treat toxicity from treatment than it is to treat melanoma that is unresponsive to therapy. And, as of yet, we have no data on whether we can actually salvage patients who start with anti-PD-1 therapy, with combination therapy administered afterwards.

Transcript Edited for Clarity
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