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Medscape
08-07-2025
- Health
- Medscape
Real-World Data: Adjuvant Therapy for BRAF-Mutated Melanoma
This transcript has been edited for clarity. Hello, everybody. My name is Teresa Amaral. Welcome back to this Medscape Oncology series on melanoma. Today, we'll finalize a discussion about real-world data on adjuvant therapy in patients with BRAF -mutated melanoma. We discussed the visual comparison between immunotherapy and targeted therapy using real-world data. We also discussed the benefit in terms of relapse-free survival and distant metastasis-free survival in this adjuvant setting when we compared the two therapies, showing that visual comparison seems to show a better benefit for patients receiving targeted therapy compared to immunotherapy. We looked into the differences in terms of quality of life and the toxicity profile for both therapies. Now, we will look into the last aspect that we need to discuss with our patients, which is what we do when the patients have a relapse. Obviously, it is different whether the patients have a relapse under adjuvant therapy or off adjuvant therapy. Patients who have a recurrence under adjuvant targeted therapy seem to benefit from programmed cell death protein 1 (PD-1) therapy afterward in a similar way as patients who had PD-1 monotherapy in stage IV and were treatment naive. Patients with recurrence under adjuvant PD-1 therapy do not seem to benefit from continuing PD-1 therapy, but they might benefit from other immunotherapies, such as ipilimumab or the combination of ipilimumab plus PD-1. We have other real-world data, which we've discussed in the episodes before, on where to go in terms of immunotherapy judgment setting. Even if we have a prolongation in terms of relapse-free survival or metastasis-free survival, when we look into overall survival data from real-world studies, we don't see a benefit in either of the two cohorts, one before introducing adjuvant therapy and another after introducing adjuvant therapy. This is also something that we need to discuss with our patients when we propose adjuvant therapy. The paper I mentioned before is an indirect comparison, and of course, it needs to be read as so. There are real-world data that have been analyzed, but obviously, we cannot change the data and how they were analyzed. When we look into the relapse-free survival events, we need to consider that these events are dependent on the timing when the imaging evaluation was performed. If you have an imaging evaluation that was performed a little bit earlier, you might detect relapse-free survival earlier as compared to an imaging evaluation that was performed later. The criteria for including these studies in this analysis was the same, but inclusion criteria may vary in the different trials, which might lead to a bias. Another aspect that is important to retain from this analysis is that we included both patients with BRAF wild-type and BRAF -mutated melanoma, because we could not separate these as we didn't have access to raw data. We also included all patients despite the BRAF mutation subtype. We didn't know if the patients were BRAF V600E or K, although the majority were reported as having BRAF V600E. We also were not able to analyze the data based on the substage — so stage IIIA to IIID. We included all the patients as stage III, but not the substage. Although the median follow-up time is long, it might not be long enough to capture all the events in the adjuvant setting. We probably need an update of this work in the near future. We were unable to exclude a couple of patients that were stage IV with no evidence of disease that were included in the different publications because we didn't have access to the raw data. We didn't perform any statistical comparison because of the differences in terms of the publications that we selected. The comparison was visually performed based on the formula that I mentioned in the first episode of this series. We have some advantages from this analysis. One is the number of patients, where more than 3600 patients were included. We included analyses that started around 2018, which means that, for the majority of the patients, they would have had access to PD-1 therapies or PD-1-based therapies as in the modern era if they had progressive disease or a recurrence. We don't know if this is the case for all the patients included in the analysis. Finally, grouping all the analyses and doing this digitalization using this visual comparison is obviously, I would say, an advantage. Another advantage is the fact that we used weighted average calculations to produce these Kaplan-Meier curves, showing that there is a concordance among the different works that we selected for this analysis. In conclusion, I would say that, based on this real-world analysis, targeted therapy seems to have a better outcome when we look into relapse-free survival and distant metastasis-free survival in stage III. Targeted therapy has a different profile from immunotherapy, and this needs to be discussed with the patients, especially when we look into long-term toxicity. Also, the impact in terms of quality of life between these two therapies seems to be different, and this needs to be taken into consideration when we discuss this with our patients. With that, I'll finish this three-episode series. I look forward to your comments and to our next series together. Enjoy your day.
Medscape
03-07-2025
- Health
- Medscape
Evolving Approaches in Melanoma Treatment
This transcript has been edited for clarity. Hello, everybody. I am Teresa Amaral, head of the Skin Cancer Clinical Trials Center at Tübingen University Hospital in Germany. I'm here directly from ASCO 2025 to discuss with you a couple of works that have been presented here and I think are important for you to know about and discuss. We are already in June, but last month was Melanoma and Skin Cancer Awareness Month. I think it's interesting that one of the posters and one of the works that was selected to be discussed here was associated with strategies and interventions to prevent melanoma and other skin cancers — namely, works and interventions that have been done in kids and young adults in order to prevent ultraviolet exposure. This is something that you don't see often. It's talked about frequently, but these kinds of interventions are not very common. It's very interesting to see that this has been selected to be discussed here. Well, that was part of the prevention, and now we go to early-stage melanoma. As you can imagine, and as you probably know, the majority of the patients that are diagnosed with melanoma are actually diagnosed at an early stage. This means stage I and stage II. Being the majority of the population that is diagnosed with melanoma, it's also the population for which we don't have any approved therapy, especially until stage IIA. What can we do for these patients? There have been a couple of works presented here at ASCO using artificial intelligence to look at slides from patients and from primary tumors of patients diagnosed with early-stage melanoma. Actually, these have been pretty promising for predicting the risk for recurrence of these early-stage patients. In this transcript to accompany the video, we've linked the posters and you can get more information if you want to look into more detail at the data that have been presented. Another work that I would like to call your attention to, for which I definitely have some bias because it's the poster that I presented here, is a gene expression profile also using the primary tumor of patients diagnosed with early-stage melanoma — so stage I and stage II. The majority of the patients had stage IA disease. We looked into the primary tumors and tried to identify the patients that are at higher risk of developing a recurrence without having the information of the sentinel lymph node biopsy. Looking into those who have high risk is one of the ways to look into this population, but also looking into those who have low risk and can safely forgo other evaluations or other interventions such as further follow-up, skin checks, ultrasounds, blood tests, and so on. Then moving into the adjuvant setting, where we already have some therapy that is reimbursed. For stage II, we have immunotherapy. For stage III, we have immunotherapy and targeted therapy for the patients with BRAF mutation. Some of the data that has been presented here are looking into different ways of not only clinical data, but also gene expression profile, next-generation sequencing, and other assays such as circulating tumor DNA, and combining all this information to try to understand who are the patients that will have a recurrence, and if we can see it from the very beginning in those patients who received adjuvant therapy. There were a couple of posters looking into this, showing that in principle, and based on these data, we might not have only one biomarker that can tell us which patients are those who, despite therapy, will recur, or which patients who, under therapy, will have a benefit. Interestingly enough, we also have other trials being presented on Tuesday, and we'll have another session looking into detail at trial data on targeted therapy in the adjuvant setting — the COLUMBUS-AD study— and also a negative trial, the Bristol Myers Squibb trial RELATIVITY-098, which looked into programmed cell death protein 1 (PD-1) vs PD-1 plus lymphocyte activation gene 3 in patients in stage III. I think this is a very important trial, and it's important that these negative trials are also presented and are discussed so that we can understand which patients really don't benefit and what we can use from these trials to move the investigation forward. Another interesting poster that was presented here is looking into patients receiving adjuvant therapy with immunotherapy or targeted therapy if they have a BRAF mutation. Why is this poster interesting? I would say that there are some conflicting data on what type of therapy you should use in the adjuvant setting if the patients have a BRAF mutation. There are some retrospective data showing that targeted therapy upfront might be better. The poster presented here shows that immunotherapy actually seems to do better, although the majority of the patients were indeed treated with immunotherapy, not targeted therapy. I think real-world data and retrospective data are more important every day because I don't expect to have any trial in the future looking into adjuvant targeted therapy or immunotherapy for patients with stage III melanoma. Besides the BRAF mutation, we will definitely need other biomarkers that will help to guide our decisions for patients who have BRAF -mutated stage III melanoma. Moving into the advanced setting, the most important questions that we want to get answered are not what we should use in first-line therapy because this is, I would say, pretty clear for the majority of patients. We have data from the SECOMBIT trial. We have data from the DREAMseq trial saying that patients will probably benefit more from immunotherapy upfront, even when they have a BRAF mutation. Very particular patients will be candidates for having targeted therapy upfront, as the majority of them will receive immunotherapy. This is exactly what is going to be presented on Tuesday from the DREAMseq study. The data will show that after 5 years, there is almost twice as high overall survival rate in patients that started with immunotherapy and three times better progression-free survival for patients that started with immunotherapy as compared to targeted therapy alone. There are some nuances from this trial because not all the patients that started with immunotherapy or targeted therapy did the crossover; many had brain metastases, which was one of the exclusion criteria for the crossover. Still, it shows that for the majority of the patients, you should start, if possible, with immunotherapy in the first line. It will be interesting to understand what to do for patients for whom we don't have a benefit using PD-1 therapy. There come the second-line therapies and more, I would say, experimental data on other strategies that include cell therapy and tumor-infiltrating lymphocyte (TIL) therapy. There have been some data presented in a poster, showing that patients who received TIL therapy have a good long-term outcome 5 years after this therapy. This might be a therapy that could possibly be given to a specific subgroup of patients in a very selected population. Also interesting would be to look into the same strategy without using the lympho depletion that is normally associated with this type of therapy and the interleukin-2 that is also given because this is, first, one of the limitations to select the patients that will get this therapy, and second, these two therapies are responsible for the majority of the toxicity that we see with this therapy. These are really interesting data to see how we can bring this therapy to our patients, but also how we can do it with reducing toxicity. Finally, one of our other treatments that has been discussed here and will also probably come in our future discussions are treatment-directed therapies — so local therapies such as injection therapies and viral therapies. These have been coming on the scene again, with new data from a different type of viral therapy but also with a combination of PD-1 therapy, which I think is quite interesting because they are looking into patients that really didn't benefit from PD-1 therapy. For the future, these would be my two or three populations where I think we need more data and we should definitely invest more in future trials. First, for early-stage trials, and again, looking into trials that are biomarker-selected. I don't think we can go on doing adjuvant trials in all the populations of patients with stage II and stage III. Second, for patients who did not benefit from PD-1 therapy in the advanced setting, but also those who received PD-1 in the adjuvant setting and did not benefit from that. And third, for patients with brain metastasis, which is obviously a difficult-to-treat population for which we don't have many options. Finally, there were some posters also analyzing treatment for patients with acral melanoma and mucosal melanoma, which again are populations that normally are excluded. It's nice to see that some companies are still investing in that. Also, there are some retrospective data showing that, despite the fact that patients do not benefit as much as those with normal cutaneous melanoma, there is still plenty of space to investigate new treatment avenues for this population that normally is excluded from clinical trials. This was my summary from what we know so far from ASCO 2025. I'll get back to you with a second take on this interesting meeting when we have the late-breaking abstracts presented in the rapid oral communications, and also in the oral communications, which I think might also come in handy when you want to decide what to do with your patients in the clinics next week. I hope you enjoyed the meeting, and I'm looking forward to seeing you again soon. Thank you.
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.
Medscape
28-05-2025
- Business
- Medscape
Understanding Gaps in OS Data for Melanoma Adjuvant Therapy
This transcript has been edited for clarity. Welcome back, everybody. My name is Teresa Amaral, and it's a real pleasure to have you here for this melanoma series on Medscape. We have talked in the last two episodes about the current status of adjuvant therapy and its benefit in patients with stage III melanoma, and in the last episode we discussed the absence of overall survival (OS) benefit. You may question why it is important to have this discussion in terms of the absence of OS benefit or the absence of data on the OS benefit. This absence of data might have three consequences, and I'm going to go through them with you. The first one is associated with reimbursement. The fact that we will need to wait until 2028, most likely, to evaluate the OS benefit from adjuvant therapy compared to placebo in stage III might lead to some discussions in terms of the reimbursement and might lead some agencies to consider whether they would like to continue reimbursing this therapy or not in this setting. Second, in some countries, the absence of OS data is leading to discussions on whether they will fund this therapy or not until there is clear proof that there is an OS benefit. The third point is related to the fact that we don't knowthe patient's individual benefit. We also know that, depending on the stage, we might need to treat more patients to actually have one patient to prevent a recurrence. For example, we know that in patients in stage IIB, we will have to treat between five and nine patients in stage IIB to prevent a recurrence. In patients with stage IIC, we need to treat between four and seven patients to prevent a recurrence. All of these cost-effectiveness analyses are being done by the healthcare agencies, and this obviously needs to be taken into consideration when we are discussing these types of therapiesthat have a benefit in terms of relapse-free survival and distant metastasis-free survival but lack data in terms of OS benefit. Another point is that, despite the fact that all the guidelines have been supporting the use of this therapy in stage III and stage IV — namely the ESMO guidelines and the ASCO guidelines— there is some uncertainty in terms of the OS benefit. This may lead to some difficult discussions and a lack of clear direction in terms of whatpatients should do when they need to make a decision on receiving adjuvant therapy or not. The patients and their treating physicians may struggle with treatment choices due to this uncertainty and the fact that they don't know if there will be a long-term survival impact for this particular patient or not. Here, we come to the first discussion that we had a couple of sessions before, which is the absence of prognostic and predictive biomarkers in this setting. Besides that, we really don't know the impact of these adjuvant treatments in terms of long-term benefitwhen we talk about OS, which might lead to reduced use of these therapies in stage III and stage II. This decline in terms of use of these adjuvant therapies has already been seen in some countries, like in Denmark.
