Long-term follow up for adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma: Final results of the COMBI-AD study

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COMBI-AD (NCT01682083) evaluated dabrafenib plus trametinib for patients with BRAF-mutated AJCC-stage III melanoma, and here the final results for RFS, distant-metastasis-free survival and overall survival are presented.

Long-Term Follow up for Adjuvant Dabrafenib Plus Trametinib in Stage III BRAF-Mutated Melanoma: Final Results of the COMBI-AD Study

 Phase 3 study (PIVOTAL) of neoadjuvant intralesional daromun vs. immediate surgery in fully resectable melanoma with regional skin and/or nodal metastases

PIVOTAL (NCT02938299) is an open label, randomized, multicenter, phase 3 trial evaluating Daromun as a neoadjuvant intralesional therapy for resectable, locally advanced Stage III melanoma.

 Phase 3 Study (PIVOTAL) of Neoadjuvant Intralesional Daromun vs. Immediate Surgery in Fully Resectable Melanoma With Regional Skin and/or Nodal Metastases

 Dirk, at the end, we want to discuss the recent releases from ASCO [the American Society of Clinical Oncology annual meeting] 2020. There was a release on lifileucel, an LN-122, adoptive T-cell transfer…dealing with tumor-infiltrating lymphocytes [TILs]. It had a promising response rate of 38%, but I know that at least, in part, you would disagree, in patients who were heavily pretreated with 1 to 9 lines of previous treatment. What is your expectation on the further development of lifileucel?

 It is an interesting concept that had been proposed nearly 30 years ago by Steven Rosenberg, MD, PhD already.

It was in 1985 in The New England Journal of Medicine.

You see? It has been 35 years now. The concept of using T cells, and we know from the IOs [immune-oncology] that T cells are the critical component of the immune system to control the disease. To infuse TILs in principle, is a good starting point. 

On the other hand, one has to say that taking such a mass of tumor out of the body is already a selection. A patient who has survived 7 lines of treatment needs to have a certain biology of the disease to make it to this line of treatment.

There are certain selection biases that drive this response rate. Nevertheless, for those patients who are achieving a complete response that is long lasting, hopefully for years, that is a benefit. Whether this is something that would shift the standard of care, I am still a bit doubtful.

Dirk, these are excellent responses. My last question is this: what is your expectation for the next positive, statistically significant positive phase 3 clinical trial in the year 2021 or may I say 2021 and 2022? Which drug can make it to the market? Which is the most promising one?

After the lesson that it is not so easy to combine different modes of action to improve outcome of our patients, we need to rethink our strategy. That is my personal belief. To think that we have chosen the wrong drug and that we just must take another drug and combine it with PD-1 or whatever will lead to the next breakthrough, I am not very hopeful.

In that sense, I am a bit skeptical about the breakthroughs in 2021 and 2022. We are expecting 2 clinical trial results over the next 2 years. The first is the MASTERKEY-265 trial, which is pembrolizumab plus or minus TVEC [talimogene laherparepvec]. It is whether an injectable is producing a systemic immune response that is even better than what we get with PD-1 monotherapy. It is an interesting question.

The second similar avenue is the bempegaldesleukin study, which is a combination with nivolumab that is in clinical phase 3 testing, which is liposomal encapsulated IL-2 [interleukin-2], which is also a revival introduced by Steven Rosenberg over 30 years-plus back.

 Dirk, I would like to thank you very much, and I will sum up now. The adjuvant treatment of melanoma has completely changed in the last 3 years. We now have very effective anti–PD-1 antibodies in dabrafenib and trametinib as a targeted therapy available for our patients, but all of them are leading to a 50% improvement of relapse-free survival.

Hopefully, all of them will one day show an overall survival improvement as well. This has been shown for dabrafenib/trametinib alone now. For stage IV disease, we heard that there are already some failures, although in the last 10 years, most of the trials have been positive.

Professor Schadendorf was pointing out that he is still hopeful for at least some drugs, and we need to go back to the laboratory if I understand him correctly. We must go back to the bench to find the right concept, not only for combination treatments but eventually for intelligent sequential treatment as well. 

With this, I would like to thank you very much for your attention. It was a great pleasure that we could discuss the recent developments in adjuvant and stage IV melanoma treatment with you. I wish all the best for you.

Future Directions in Metastatic Melanoma 

Dirk, can you briefly explain the differences so far in the efficacy and tolerability of the 3 approved regimens for BRAF/MEK inhibitors? At least in Europe and in the United States, we have 3 different opportunities that are approved and reimbursed. In some other countries, they are approved but not reimbursed so far. Encorafenib/binimetinib is the latest development.

 Yes. If one looks at the clinical trials, cross-trial comparisons are always difficult. In all the clinical trials, vemurafenib was a comparator, so you have a certain indirect way of comparing that. If one looks at the 2-year, 3-year PFS [progression-free survival] and also overall survival rates, it’s clear that all 3 combinations are quite effective and similar in controlling the disease over time. The major difference is the safety profile of the different combinations. 

 Yes. It’s dabrafenib/trametinib. If you would count 1 adverse event that is very obvious, it’s fever and chills. For the Roche combination of cobimetinib/vemurafenib, it is sun sensitivity and direct reactions to the skin, typically. There are no particular adverse events with encorafenib/binimetinib, but the treatment discontinuation rates for all the 3 are almost the same. This is what is most important for me. Therefore, I can only say that I believe the efficacy might be slightly different. There is difference in the tolerability, and this might also drive our decisions. 

Dirk, I was personally very disappointed in the year 2020 because the triplets didn’t show the results I expected. When I talk about triplets, it’s BRAF plus MEK inhibitors plus or minus PD-1 or PD-L1 antibody.

The atezolizumab trial from Roche showed 4.5 months of an absolute difference in PFS and 4.2 months for the COMBI-I trial from Novartis, which looks very much the same. The Roche trial made it to FDA approval, and the Novartis trial failed because it was not statistically significant. What about your expectations of these clinical trials? Would you share my opinion that this was a disappointing year for the triplets?

 Absolutely. The hope we’ve had and what we have played for the last 5 years was that we have different modes of action, and if you would combine them, it would make deep and quick responses from targeted therapy now very durable. That didn’t turn out. The response rates are the same if we compare targeted therapy to the triplet therapy. The PFS curves were completely overlapping in the first 6 to 8 months. Whether this has a long lasting or as much benefit at the end is quite questionable. The toxicity is also quite increased.

 I don’t really see a new standard of care using triplets.

Looking at Approved Agents in Metastatic Melanoma 

 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?

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?

 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.

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.

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?

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.

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?

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.

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?

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.

Metastatic Melanoma Treatment Decisions 

Dirk, we want to discuss metastatic melanoma, stage IV now. I have just one question, and I hope you can shortly repeat what you are doing in your center University Hospital of Essen. Are you doing another molecular testing as a routine, or is it just an experimental setting in your translational research program to go for another molecular test once a patient has progressive disease?

 If we have BRAF testing available, that is sufficient. Nevertheless, we have a large translational program taking blood and doing molecular profiling of these patients as part of the work-up. This has no clinical consequence if we have a known BRAF mutational status.

 I am sure you have a so-called molecular tumor board in your center.

 If the molecular tumor board finds added mutations, are they directing to a kind of treatment that is off label? Are you applying with the insurance companies for these patients?

 We have various clinical studies that are open, for example, the NRAS-mutated melanomas and some other mutational variants. That is what we do, yes, but we are not applying for rare tumor mutations to insurance companies. That is not what we do.

OK, good. The question now is on the distinction of BRAF-directed treatment in stage IV and treatment with immune checkpoint inhibitors. Will you tell us, in the first place, what is the German guideline for first-line treatment? Is there a clear preference?

Yes. As you know, Axel, since you are part of the panel, it is clear that in the first-line setting, the patient should get either targeted therapy if they are BRAF-mutated or a checkpoint blockade. The checkpoint blockade could be PD-1 monotherapy or a combination with ipilimumab. There is no preference among these 3 different options, but there is a clear statement that they should get one of these 3 innovative treatments, and clinical studies should be considered.

 Yesterday, I was talking in a seminar about the new ESMO [European Society for Medical Oncology] clinical practice guidelines, and I was really surprised. There is a paragraph saying that it is difficult to draw an algorithm for stage IV first-, second-, and third-line treatment in the absence of direct comparisons of targeted therapies and immune checkpoint inhibitors. But then found the algorithm that is clearly saying that BRAF-directed treatment should only be given if patients are not fit for toxicity for immune checkpoint inhibitors. The clear preference is immune checkpoint inhibition over BRAF/MEK inhibitors. 

Do you think it is worthwhile to change all the German guidelines now that the ESMO clinical practice guidelines are out?

 One must have in mind how guidelines evolve or how they are generated. For example, the Australian and the German guidelines are clearly evidence-based and are considering all the evidence, like clinical studies that have been published and peer reviewed, and they have drawn conclusions from that. They are not considering personal opinions on the abstracts, for example. This guideline process also includes, like the multidisciplinary tumor boards, different perspectives, including radiation, oncology, surgeons, and so on. It is not a mix of a selected small number of people who have personal opinions that are given. The NCCN [National Comprehensive Cancer Network] is criticized a bit in that direction, but the ESMO guidelines are also driven by a few figures in the same direction, yes.

 OK. What you are saying to us in a few words is that it is more eminence- than evidence-based guidelines, correct?

Molecular Testing in Metastatic Melanoma 

Let’s switch to a brief discussion at the end of the adjuvant section of our discussion on COVID-19 [coronavirus disease 2019].

What has changed in your center the University Hospital of Essen? Keep in mind that the NCCN [National Comprehensive Cancer Network] guidelines were recommending the use of more of the BRAF-directed treatments because of the comorbidities going along with new checkpoint inhibition that may require immunosuppressive treatment or eventually, in rare cases, immune checkpoint inhibitors may stimulate a cytokine storm syndrome.

Did you switch your BRAF-mutated patients more to dabrafenib/trametinib rather than the PD-1 antibodies?

 This recommendation reflects some of the insecurities, especially in early 2020 in the first wave of COVID-19. At that time, a lot of clinical trials stopped recruitment because there was no clear idea whether there would be any interference with that.

The numbers are now much higher than they were in spring and early summer. There is now a certain routine now at all the centers. We have to protect ourselves. We have to protect our patients. That’s true, but it’s also important to keep this in mind because there was also some recommendation to postpone tumor surgery. There was also some reluctance to start adjuvant treatment. This is definitely not warranted. Cancer is a deadly disease, much more deadly than COVID-19 in most settings.

The concern is that the patient with cancer, who is potentially immunosuppressed or has other comorbidities, is getting COVID-19 on top. That is obviously an important educational point for the patient to take care of. You have to make sure. It may be part of the reflection about bringing patients back to the hospital, for traveling and all of that.

If it is possible to prevent that, an oral drug could be a better choice, for example. That’s a good thing, but the cytokine storm and all of that, that’s not relevant in most of the cases.

 That’s good. We have a publication in process on immune checkpoint inhibitors, particularly in melanoma, which showed no clear increase in the death rate when they were used. We also have prolonged the intervals for the application of immune checkpoint inhibitors because different intervals are approved, so we can go for the long intervals.

The Role of COVID-19 in Adjuvant Treatment Decisions in Melanoma 

 Dirk, you were one of the coauthors for the cure-rate model paper, which has been released in the Journal of Clinical Oncology. There is a report on a 17% improvement of cure. Are you touching the “C” word with your patients if you treat in the adjuvant setting? Is your goal to cure the patient, or just to prolong the relapse-free survival? This is a major difference in the discussions with patients.

That’s an interesting point, Axel, because when I’m giving presentations on adjuvant therapy, I always like to start in my introduction and discuss this with my audience of colleagues: “What is the treatment goal I want to reach?” This is so that I’m clear, and when I’m clear, I’m able to talk to my patient.

The treatment goal might be quite different if I’m talking to a person who is, let’s say 35 years old, or a patient who is 75. I think that, if I’m able to control the disease for 10 years in the patient who is 75, the patient might die from other disease without having a relapse, and that is often fine for them and their family.

If the patient is 35, and I’m gaining 10 years, that’s also a good result, but it’s obviously not sufficient because I want to have more. I want to have control for decades in order to achieve a cure.

I think about aggressiveness and willingness to accept toxicity, and what you want to achieve might be quite different in terms of age as well as comorbidities, preferences, and characteristics the patient might have.

 This leads us to the next important question: the selection criteria. If you have a BRAF-mutated patient, let’s say it’s 60-year-old male, and you have the choice of a BRAF-directed treated with dabrafenib/trametinib, or you can give one of the 2 PD-1 antibodies that are approved in this setting. What would you recommend to the 60-year-old patient without significant comorbidities?

 It’s very much dependent on additional tumor characteristics, for example. Would the patient fall into the IIIA category more, or according to the new specifications, would the patient fall more into the IIIC or IIID categories, which gives us a certain likelihood on the chances that this patient will relapse and how quickly this relapse would occur.

In patients who are more in stage IIIC or IIID, I would definitely have a tendency to use and recommend targeted therapy. In stage IIIA, the patient has more options. 

That’s one thing in terms of tumor control while on treatment, but there are other options that are playing into this discussion. This is the adverse effect profile of the drugs. We have learned that in the COMBI-AD study, the discontinuation rate was quite high for dabrafenib/trametinib, 25%, which is surprisingly high. We see the algorithms and the discontinuation rates in the metastatic setting, which is roughly 50% of that.

With the results now of the high clinical efficacy and the good management algorithms for using dabrafenib/trametinib in our setting, the patient is experiencing these adverse effects, but it’s manageable. It’s usually pyrexia, which you can easily control by pausing for a day or two, and you can educate your patient on that. Most of the adverse effects with targeted therapy are reversible, and that’s one of the messages one has to give to the patient. 

That’s slightly different with a checkpoint blockade. The toxicity profile, the acute toxicity, is usually much safer. This is also reflected by the discontinuation rate, which is in the range between 10% and 15% for checkpoint blockade. On the other hand, there are some rare adverse effects that are irreversible, and odds are that these could have a strong effect on the patient’s quality of life, and these include endocrine toxicities, including rare cases of diabetes, autoimmune and neurological complications, and impacts on cardiac functionalities.

Here again, we are back to young patients, old patients, and patients with comorbidities. If you consider treating a patient who is in their 30s, and you are creating these irreversible adverse effects, then that’s a problem. And I think there’s another argument. 

If you look at the studies, particularly the placebo-controlled studies like COMBI-AD and KEYNOTE-054, these are perfect examples, now that we have the long-term follow-up of these clinical trials. We see that even in stage III, roughly one-third of the patients would not need adjuvant treatment at all. After 5 years, there is no relapse, so surgery would be sufficient. But we are not able to identify these patients early enough, so we are overtreating at least one-third of the patients. 

If we would induce toxicity in these patients that is irreversible, that’s very difficult to justify. You have to have a risk-benefit discussion with the patient on that.

 Dirk, we need to discuss this another time because gene expression profiling of primary tumors could eventually lead to the selection of good and less-good patients, and there are other markers under discussion, but all of this is experimental at this point. 

Treatment Goals and Patient Decisions in Melanoma 

 In the following, we particularly want to discuss the KEYNOTE-054 and the COMBI-AD studies because they have quite comparable eligibility criteria, and therefore they are not equally mature, but they might have the chance to compare, indirectly at least, the data. Would you like to give us a brief update on KEYNOTE-054 and COMBI-AD?

 Yes. That’s quite important, Axel. The trial design for both studies was comparing pembrolizumab and dabrafenib/trametinib. Both used a placebo arm as a control, and both used a 1:1 randomization of patients who got included. These were patients truly in stage III, so their AJCC [American Joint Committee on Cancer staging system,] classification, 7th edition, was used, which included patients in stages IIIA, IIIB, and IIIC.

Patients in stage IIIA are the sentinel node positive patients. In the stage IIIA category, both studies decided not to include all IIIA patients but only a small subset of patients who had the sentinel nodes. The tumor deposit in the node needed to be more than 1 mm in order to be included.

It was dependent upon the different countries. For example, in Germany, this is less than 20% of the patients in the IIIA category, according to the 7th edition of the AJCC staging system. In other countries where the primary detection of the primary tumor is not so frequent, parts of Eastern Europe for example, the frequency of patients who are in that category of more than 1 mm of sentinel node burden is much higher.

This has consequences for the patient characteristics’ inclusion in that clinical trial. The interesting part is that the majority of the patients were in stages IIIB and IIIC. Looking at the relapse-free survival, it was quite interesting to see that both treatments were given for 1 year without any rationale, just 1 year.

If you look at the relapse kinetics, you see that, of the patients who got treated with pembrolizumab, which is also true also for nivolumab at the end, roughly 25% of the patients who are relapsing are relapsing while on treatment within this 1 year. That’s completely different to targeted therapy in the dabrafenib/trametinib arm, and in the COMBI-AD study, only a small fraction, 5% to 7%, of the patients progressed while on treatment. 

One has to say that, for patients who got controlled nicely for this 1 year of treatment with dabrafenib/trametinib, if they relapsed, they relapsed after stopping the targeted therapy at month 12. After roughly 30 months, the relapse rate between targeted therapy and checkpoint blockade was very comparable and very stable at that point. It stabilized, and it’s stabilizing over time now. 

 Dirk, we didn’t discuss the magnitude of the benefit or that the hazard ratio was 0.50, 0.47 in all of this. It’s around a 50% improvement of relapse-free survival, and it has the same benefit for distant metastasis-free survival. For COMBI-AD, we already have the first interim analysis available. The final will be done with a final evaluation of the entire study. All of them are showing a 0.50 hazard ratio for a benefit. Don’t you think this is a breakthrough?

 That’s definitely a major step forward. If you think about 20 years of discussion regarding interferon, the hazard ratios were in the range of 0.8, a little bit more or less. It’s a completely different ball game here. When we talk about the effects on distant-metastasis-free survival as well, the hazard ratios were shrinking from relapse-free survival to distant-metastasis-free survival. 

We see a constant effect in both clinical trials. The hazard ratio is also protecting against the occurrence of distant metastasis in the same magnitude, cut roughly by half. That’s an important message not just for the physicians; it’s also good news for the patients and families.

A Look at the KEYNOTE-054 and COMBI-AD Data 

 The crucial question for all of us in tumor boards is if you have a 

-mutated patient. We are only discussing patients once the 

 Yes, that’s correct. For some time, it has also been that the German guidelines have recommended to test the odds of patients who have no metastatic disease for 

 mutation, definitely in stage III. For example, for years now, this could have therapeutic consequences. If you have thick primary tumors or other risk criteria, it’s strongly recommended to do the 

 That’s very important to say because if you have a tiny micrometastasis on the sentinel node, you might not be able to test for 

 mutation, so you need to go back to the primary tumor. We are also expecting to have clinical trials in stage II. Mainly, there are 2 trials in Germany right now, or it was 2 trials that were open, and it is now only 1 trial open for recruitment.

There is also 1 clinical trial in progress in the planning phase for 2021 that is using BRAF and MEK inhibitors. Therefore, we eventually need to test from stage IIA onward. Do you think it’s difficult to make this a routine procedure in the German dermatologic oncology environment?

 Testing thin tumors is challenging not only in Germany, it’s also challenging across the board, because testing for 

 mutation is also dependent on the amount of tumor in your sample in your primary tumor. If you have thin tumors, 1 mm or a little bit more than 1 mm, enriching for tumor cells is not trivial because all the molecular methodology is dependent on a certain percentage of tumor cells in your sample in order to be correctly positive or negative. The chance that you have false negative results is obviously a risk in very thin tumors.

 Can you give a brief comment to us about whether immunohistochemistry would be an alternative, yes or no? Which test is used as a PCR [polymerase chain reaction] test to detect V600 mutations in your center?

 Yes. For stage III and stage IV disease, most of the larger centers use NGS [next-generation sequencing] gene panels, which are larger panels that include not just the 

 NGS standing for next-generation sequencing.

 Yes, it’s next-generation sequencing. For 

 testing only, PCR technology is sufficient, and it’s the cheapest way to do it. We then have immunohistochemistry techniques available, which are based on antibodies that are usually specific for V600E mutations of the 

You have some countries and some centers that are doing that, a prescreen with immunohistology and the antibody. If this is negative, only in that case, subsequent molecular testing is done.

One also has to keep in mind that there are some specified molecular tests, like the Cobas test for example, which is detecting only a certain fraction of 

 V600 mutations. The high-specificity V600E and V600K are a percentage, but other, less frequent mutations like V600M, V600D, and so on are not detected. For that, you need molecular techniques.

Testing and BRAF Mutations in Melanoma

Hello. This is Axel Hauschild from the University Hospital Schleswig-Holstein in Kiel in northern Germany. I’m a professor of dermatology and head of the Skin Cancer Center, and I’d like to welcome you to our discussion with Professor Dirk Schadendorf, who is the head of dermatology at the University Hospital of Essen in western Germany.

Dirk, it’s a great pleasure to chat with you about the latest news on adjuvant and stage IV melanoma treatment. Hello.

We want to start with a description of the multidisciplinary team setting at your center. How are the decisions made in melanoma treatment in general?

Our patients who are entering the center will be seen by specialists who have certain training, and all the cases will be discussed in multidisciplinary tumor rounds on a regular basis. This obviously includes all advanced melanoma cases: stages III, stage IV, as well as other advanced skin cancer cases since we are a dedicated skin cancer center here in Essen.

Dirk, give me an idea about the number of cases you are discussing. Is it once per week or twice per week?

 We are doing it once per week, and we are usually discussing between 30 to 40 cases a week. It’s always on Wednesdays, and we will usually take roughly 90 to 120 minutes.

I need to say that Professor Schadendorf’s center is the largest center in Germany, and it is certainly one of the largest in the world. Professor Schadendorf is a key opinion leader, so it’s not surprising that it’s 30 to 40 cases. In our center, it’s 15 to 20, and this shows the difference in the magnitude of the patients.

Dirk, what are therecommended guidelines for the adjuvant treatment in stage III, not only in your center but also in Germany, because you were a crucial part of the German Malignant Melanoma S3-Guidelines?

 Yes. We have treated patients in stage II and stage III for quite some time with interferon, which is based on the long history of high-dose, intermediate-dose, and low-dose interferon within different time periods. This time has gone. For 3 years, we have had registration data on dabrafenib and trametinib, the COMBI-AD study, as well as 2 checkpoint inhibitors given as monotherapy: pembrolizumab and nivolumab.

On these data we have now 3 to 5 years of follow-up, and we have a clear idea of the clinical effects on relapse-free survival, distant metastases-free survival, and also first overall-survival data are available for these agents.

The tradition of interferon treatment in Germany is now gone, and all the centers are using these 3 treatment options, which are not only approved in Europe and therefore approved in Germany, but they are also fully reimbursed for every patient. It is totally independent of any insurance.

Axel Hauschild, MD, PhD, University Hospital Schleswig-Holstein

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