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Medscape
25-06-2025
- Health
- Medscape
Targeted- vs Immunotherapy in BRAF+ Stage III Melanoma
This transcript has been edited for clarity. Hello, everybody. My name is Teresa Amaral. Welcome back to this Medscape melanoma series. In the past four episodes, we talked a bit about adjuvant therapy in melanoma — what we have in terms of immunotherapy, the aspects that we need to consider, relapse-free survival data, distant metastasis-free survival data, and the absence of overall survival data. Today I'm going to discuss a little bit of the controversy that is ongoing in terms of what is the best therapy for patients who have a stage III melanoma and BRAF mutation. What kind of therapy in the adjuvant setting should we give to these patients? To address this question, we have recently published a review in terms of real-world data comparing these two therapies. Why did we do that? First, because these two therapies are approved for patients who have a BRAF mutation and there are no head-to-head comparisons that have been performed in clinical trials. Most likely, they will not be performed in the future because both therapies are approved in stage III; therefore, there is not really a big interest from the companies to perform this comparison in a head-to-head study. Because of that, we used a previous analysis based on a mathematical form where we visually compared the survival curves that have been published in real-world cohorts. This type of visual comparison has been published before to analyze stage IV systemic therapy, specifically immunotherapy and targeted therapy. The first publication was in 2017 in the European Journal of Cancer and the second was published in 2018 in the same journal. Basically, we used this strategy to also visually compare the different curves for immunotherapy and targeted therapy in stage III for patients with BRAF -mutated melanoma. We searched PubMed and other databases for articles that have published real-world data in this setting. We were able to include more than 3000 patients with a median follow-up that goes between 11 and 33 months. Approximately half of the patients, 57%, had a BRAF mutation. From these, approximately half of the patients had received treatment with a BRAF/MEK inhibitor, which gives us, at least from my point of view, a very good overview of the outcome of these patients treated with targeted- and immunotherapy. In total, we were able to retrieve 20 plus 32 publications. After the first review, we had 29 publications, excluding the duplicates. With further selection, we were able to have a total of eight studies that were included in this real-world analysis. We performed, as I said, a visual comparison between the two types of therapies, so immunotherapy and targeted therapy. The first analysis we performed was in terms of relapse-free survival. Here, we included nine publications in total. We see the relapse-free survival curves after 2 and 3 years, but from the very beginning, after 1 year, a difference that is visually better for targeted therapy. In this real-world data analysis, we saw that patients treated with targeted therapy seem to have a better benefit that is maintained, at least at 3 years, which is the last time that we performed this visual comparison. We also looked into the survival curves for immunotherapy and for targeted therapy in the different studies to make sure that patients treated with either therapy did not have a significantly different survival outcome. The curves are presented in the publication, and you can see that there is a significant overlap between the survival curves, showing that the patients treated in the different studies had a similar outcome. This is true both for targeted therapy and for immunotherapy. Why is this relapse-free survival analysis so important and why did we do this comparison? Both therapies were initially approved based on the relapse-free survival benefit that they showed for immunotherapy, and as we discussed in the previous episodes, there is still no overall survival benefit available. For targeted therapy we have overall survival benefit, but approval was based on relapse-free survival benefit. When we looked into the distant metastasis-free survival, we also saw that for patients treated with targeted therapy, the benefit was higher than for patients treated with immunotherapy. Here, we only had data from two publications; therefore, we cannot really have sound conclusions on what is better in terms of treatment for patients with BRAF -mutated stage III melanoma. Then we tried to do the analysis also for overall survival, but here again, we only had data from three publications; therefore, the comparisons cannot really be considered because the number of patients is quite low. Still, there is an overlap here, and the difference that we saw before in terms of benefit for distant metastasis-free survival and relapse-free survival favoring targeted therapy was not seen in this overall survival comparison.
Medscape
09-06-2025
- Health
- Medscape
Making Sense of Melanoma Care Without OS Data
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 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 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.
