Making Sense of Melanoma Care Without OS Data

Medscape

09-06-2025

This transcript has been edited for clarity.
Welcome back, everybody. My name is Teresa Amaral, and it's a pleasure as always to have you here for this melanoma series on Medscape.
We will finalize this series on where we should go, and what's next in terms of immunotherapy in the adjuvant setting, by looking into the two other aspects that we need to consider when we discuss the factthat there is no overall survival benefit nor are there data on the overall survival benefit for patients treated with immunotherapy in the adjuvant setting.
We discussed the first one, which was the fact that there might be some discussions or some uncertainties in terms of the reimbursement because these data are not available yet and might only be available in 2028.
We also discussed the number of patients that are needed to treat to prevent a recurrence, especially when we are talking about stage II disease. As well as the fact that this might lead to some uncertainty, both from the treating physicians and the patients, when they need to decide whether they will receive adjuvant therapy or when they will offer adjuvant therapy to their patients.
The final point that I would like to bring to the discussion is that this uncertainty might lead to a potential shift to using targeted therapy instead of immunotherapy in patients that have a BRAF V600 mutation. Why is this the case? We have data provided by the COMBI-AD study that investigated targeted therapy, in this case, dabrafenib and trametinib, in patients with BRAF V600–mutated melanoma.
We saw that, similar to what we see in immunotherapy, there is a benefit in terms of relapse-free survival and distant metastasis-free survival. We also saw that there was no overall survival benefit for the whole population, but there was a higher benefit when we look numerically at 3, 5, and 7 years, especially for patients with BRAF V600E mutations.
It came as a surprise, I would say, that patients with BRAF V600K not only didn't benefit from targeted therapy in the long run in terms of overall survival, despite having a benefit in terms of relapse-free survival, but when the overall survival analysis was conducted, we actually saw a detrimental effectfor patients with BRAF V600K when we compared the treatment with placebo. For these patients, we should not provide adjuvant therapy with targeted therapy.
When we compare targeted therapy with immunotherapy in a real-world setting — and this will be the topic for our next series — we see that patients who had received target therapy might have a larger benefit when we look into relapse-free survival and distant metastasis-free survival compared with patients who received immunotherapy.Here, I'm only talking about patients who have a BRAF V600 mutation.
Finally, some patients may prefer targeted therapies and oral therapy compared with immunotherapy that is given intravenously in the hospital.
We see three points that might be associated with the absence of data on overall survival benefit for immunotherapy: the fact that there might be some reimbursement discussions that are associated with this aspect; the fact that in some cases, despite this therapy being recommended in the guidelines, there might be some uncertainty from the doctors and the patients onreceiving and on proposing this therapy; and a potential shift in the use of targeted therapy in favor of immunotherapy for patients with BRAF -mutated melanoma.
If we don't have an overall survival benefit, why are we recommending this therapy? What is the benefit of having a relapse-free survival and a distant metastasis-free survival benefit?
I would argue that for the patients, this is quite an important event. We have shown that diagnosis of recurrence is the aspect that most impacts the quality of life. When the patients are diagnosed with a recurrence, the quality of life decreases significantly.
These data were, for example, mentioned during the COMBI-AD quality of life analysis. Obviously, the fact that the patients live longer without disease might provide them access to new therapies currently being investigated that were not available at the time they were treated with the adjuvant therapy, but might be available for them if they live longer without recurrence.
In real-world data, we also see that approximately 50% of patients who are diagnosed with stage IIIB melanoma will be diagnosed with metastatic disease. Although in some cases we might be able to provide surgical resection, neoadjuvant therapy, or other local therapies, such as radiotherapy, for example, the fact is that some patients will have unresectable disease or will be diagnosed with metastatic and inoperable stage IV melanoma, which is quite important and in some cases is associated with a worse outcome.A longer time without evidence of recurrence is important and might lead to a better outcome in the long run.
In conclusion, from our discussion so far, we can say that trial data are eagerly awaited, and mature trial data are necessary. In the meantime, we might be able to use real-world data to compensate for that and to analyze and maybe inform the way that we use programmed cell death protein 1 (PD-1) in the real-world setting in our daily practice.
When we look into the absence of overall survival benefit, we also need to consider access in terms of therapies post-recurrence. When the patients recur, they might have access to all the approved therapies or not. This also highlights the importance of deciding the kind of control arm that we use when we design trials in the advancedsetting. Depending on the type of control arm and the access of patients to these types of clinical trials, we might influence the overall survival benefit in these cases.
There is currently a dual strategy for treating patients diagnosed with stage IIIB or higher melanoma.This might be neoadjuvant therapy if we have macroscopically diagnosed disease, or it can be adjuvant therapy if we have a patient who has microscopic disease and therefore is not a candidate for immunotherapy in the neoadjuvant setting. We expect these patients to be around 40%, but also there will be patients diagnosed with stage IIIA and patients with stage IIB and IIC that will be candidates for adjuvant therapy.
Finally, the absence of overall survival data, and also the presence of relapse-free survival and distant metastasis-free survival data associated with the toxicity profile of these therapies, are important to be discussed and are part of this shared decision in terms of the treatment that these patients can be offered at this timepoint that we're discussing.
With that, I thank you for your attention and I look forward to seeing you again in the near future. Thank you.