Metastatic Melanoma Treatment Decisions

Axel Hauschild, MD, PhD: In the distinction of using BRAF/MEK inhibitors vs immune checkpoint inhibition, what are the factors driving the decision? I would list here the speed of disease growth, which is metastatic growth. I would also list here the oral vs IV [intravenous] preference of patients. We can discuss brain metastasis. Brain metastasis is the clearest concern, so I would like to ask you if you agree that ipilimumab and nivolumab treatment for multiple brain metastases is the standard of care everywhere where the drugs are available and reimbursed?

Dirk Schadendorf, MD: Yes.

Axel Hauschild, MD, PhD: That is the clearest consensus. With mucosal melanomas, it’s the same, but for all the others, we know that low tumor load is leading to good results with all drugs. Higher tumor load is leading toward less good efficacy results. In general, what is making the decision at the end of the interdisciplinary tumor board?

Dirk Schadendorf, MD: Fit-for-toxicity is mainly of concern if you are considering IO [immune-oncology]. If you are asking about fit-for-toxicity as the question, it’s if the patient is able to get nivolumab/ipilimumab and is able to stand the toxicity of that. That is what is behind this fit-for-toxicity idea. This is warranted in poor prognostic patients in stage IV, which are patients with high LDH [lactate dehydrogenase] test levels and even significantly elevated LDH with difficult-to-treat metastases like in the brain, the bone, or the liver.

For mucosal melanoma, I completely agree. If one looks at the landmarks after 2, 3, or 4 years, there is a clear advantage in favor of nivolumab/ipilimumab in comparison to PD-1 monotherapy as well as targeted therapy.

Axel Hauschild, MD, PhD: Yes.

Dirk Schadendorf, MD: It’s also the speed of the response. If you look at the 1-year survival rates for nivolumab/ipilimumab vs targeted therapy or PD-1 monotherapy, there is no disadvantage for the combination. The story is different if we look at this good category of patients and the good category of patients in the metastatic setting. If we are then talking about the good category, then that setting is already unique. We hadn’t talked about that 10 years ago.

Axel Hauschild, MD, PhD: Give us an idea about the newest 5-year survival data for pembrolizumab/nivolumab and ipilimumab/nivolumab, and we can then compare that to the 5-year survival of dabrafenib/trametinib, for instance, because from Roche, there is vemurafenib/cobimetinib trial data out on 4 years, and for the COLUMBUS trial on encorafenib/binimetinib, it’s also 4-year survival. 

We can have an indirect cross-comparison. Honestly, Selma Ugurel, MD, wrote a nice overview on overall survival curves, Kaplan-Meier curves in the European Journal of Cancer earlier this year. Can you briefly summarize the findings? Where are we now?

Dirk Schadendorf, MD: Yes. For the PD-1 monotherapy and first-line studies, the 5-year rate is in the range of over 40%: 40% to 45%. This is consistent whether you’re looking for nivolumab or for pembrolizumab. For nivolumab/ipilimumab, it’s roughly 7% more: it’s 52% at 5 years. That’s across the entire population, and for the population of the combined analysis of COMBI-D and COMBI-V, it’s around 35% after 5 years.

There, if you look at the cohort of patients who are a good prognostic group, the patients with normal LDH and possibly only 1 or 2 organ sites, then the 5-year survival range is between 50% and 60%, which is comparable to the same cohort of patients for the PD-1 monotherapy, whether you’re looking for pembrolizumab or nivolumab monotherapy in the same category with normal LDH; it’s around 50% to 55% of the patients who are still alive.

Axel Hauschild, MD, PhD: Yes. For summarizing this, I could say that it’s a bit unfair to say that the BRAF and MEK inhibitors are good candidates for patients with high tumor volume and those who are symptomatic, because they are good for this. But they are not as good as for the patients with low tumor volume because these are the best patients where you can show your true profile, correct?

Dirk Schadendorf, MD: Yes. What we have learned over the last 5 years is clear: this is the patient cohort who benefits best from the new and innovative treatment modalities we have developed. The pity is that we have different modes of action with immune-oncology and targeted therapy, but it’s still the same group of patients who in the majority are benefiting.

Axel Hauschild, MD, PhD: Nowadays, it counts if you have long-term toxicities, and we’ve discussed the toxicities in the frame of the adjuvant treatment already, but we now have 5-year survival data that are so good. As you know, 37% to 52% of patients are alive after 5 years. We need to take into account that patients might live forever, and they might have sequela from certain treatment modalities. Just a brief comment on this?

Dirk Schadendorf, MD: No, I agree. After years of looking for 5-year survival data, we now have 5-year survival data, and we now need to think about survivorship programs in patients with skin cancer in order to detect latent and subclinical toxicities.

Transcript Edited for Clarity