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Neoadjuvant Trials in High-risk Melanoma

Panelists: Robert H.I. Andtbacka, MD, CM, Huntsman Cancer Institute; Michael A. Davies, MD, PhD, MD Anderson Cancer Center; Antoni Ribas, MD, PhD, University of California Los Angeles; Georgina Long, MD, Melanoma Institute of Australia; Michael Postow, MD, Memorial Sloan Kettering Cancer Center
Published: Wednesday, Feb 01, 2017


Transcript:

Robert H.I. Andtbacka, MD, CM:
If we did the initial staging for the patient and we found that the patient actually had not only the large lymph node in the superficial groin, but also had numerous lymph nodes along the external common iliac area and going up toward the bifurcation of the iliac and the aorta, for me, from a surgical perspective, could I resect that? It’s very possible it’s resectable, but it truly is borderline from the perspective that the risk of this patient recurring is very high. And we really, as surgeons, think about this as, “Surgically, I could take this out, but as soon as I move the patient from the operating room to the recovery room, they probably are already recurring.” I would say it would not be a meaningful surgical resection. In this setting then, I know that there are some ongoing neoadjuvant clinical trials right now. I know Mike, you have done some at MD Anderson, and Georgina, you’ve done some in Australia. Tell me a bit about those studies that you have conducted and some other ongoing studies that you have at the moment. So, Georgina, tell me.

Georgina Long, MD: Again, as a surgeon, you are still telling me this is resectable. It’s just extensive, and you know they’re going to recur quickly.

Robert H.I. Andtbacka, MD, CM: So, in surgery, nothing is black-and-white. I would tell you that, surgically, we could potentially take this out, but this is not a meaningful operation. This is due to the risk of recurrence, which would really fall under that category of “unresectable” because of the futility of the operation to render the patient free of disease for a reasonable amount of time.

Georgina Long, MD: It’s not black-and-white, and in our institution, something that can be chopped out is considered “resectable.” It would be considered “resectable” despite all the caveats about the fact that the patient almost has 100% chance of recurring. So, we would consider neoadjuvant trials; they’re eligible. In our institution, for our neoadjuvant trials, the surgeon has to be able to say, “We can remove this as is, leaving no melanoma behind, getting good margins.”

We’ve got several neoadjuvant trials. One is on targeted therapy for BRAF V600-mutant patients; it works very well. We’ve completed enrollment of that. We’ve done one look-see in the first 19 patients. It is very much a translational study, so it’s looking at biomarkers. And in that trial, we had 50% of patients have a complete pathological response, complete RECIST response, and complete metabolic response after 12 weeks of neoadjuvant dabrafenib and trametinib. The question of how much dabrafenib and trametinib you need, I don’t think you need 12 weeks. I think you could do it in 8 weeks, possibly even 6 weeks. I don’t know what the pathological response rate would be, but I think it would be near what we see at 12 weeks, given what we see in the metastatic setting.

The other study we have that’s about to open is on neoadjuvant combination nivolumab and ipilimumab. Again, this patient would be perfect for that. We have some early data from the Netherlands in that situation, where of the first 10 patients, 3 of them had a complete pathological response by week 6. So, that’s really compelling and interesting as well. There are also mouse data that suggest that if you have the tumor in situ and give immune therapy, you actually may induce a better immune response rather than chopping it out first and then giving it adjuvantly. Maybe the neoadjuvant approach is better, but we don’t know the answer to that.

The third trial we have, which I find to be a very interesting and important trial as well, is neoadjuvant. It has to be resectable. This time it’s for BRAF-mutant, but it’s looking at 3 arms. How do we combine targeted therapy and immunotherapy? It’s dabrafenib and trametinib followed by pembrolizumab for 12 weeks, all 3 together, or just anti-PD-1. It’s going to answer a whole heap of questions about sequencing, in terms of translational tissue endpoints. So, they’re the neoadjuvant trials we have open at the moment. We plan to continue to use this neoadjuvant platform. We’ve got a lot of work to do in that space, but it is only in a clinical trial. That’s the important point.

Robert H.I. Andtbacka, MD, CM: Mike, you led a neoadjuvant symposium, recently, talking about this, how we evaluate these patients. You’ve also done some studies at MD Anderson, very similar to what Georgina has, with BRAF/MEK combinations, as well as studies with immunotherapy for this. Tell me a little bit about those studies that you’ve done.

Michael A. Davies, MD, PhD: Our first trial was for patients with a BRAF V600 mutation. This was actually a clinical trial where one-third of the patients got randomized in a 2:1 fashion to standard-of-care surgery and were offered standard adjuvant therapy. And then, two-thirds of the patients were randomized to neoadjuvant treatment with dabrafenib and trametinib for 8 weeks followed by surgery. After surgery, they had an additional 44 weeks of adjuvant treatment to complete 1 year of therapy. This trial was actually stopped early by our DSMB (Data and Safety Monitoring Board) because of the marked difference in relapse-free survival we saw between these 2 arms, which made it unethical to continue to randomize patients to standard-of-care surgery.

These data are actually going to be presented in full in just 2 days and will certainly then be available to the public. That trial is then going to reopen to be very similar to Georgina’s trial: to not have randomization to the standard-of-care, but to neoadjuvant therapy for 8 weeks for each patient who has this BRAF mutation. We actually, again, with this 8 weeks of therapy, had a very similar pathologic CR rate of almost 60% that was seen in the Australian study, suggesting that 2 to 3 months may not be that different, at least in terms of how much therapy it takes to see a pathologic CR.

We have another trial open in which patients are randomized to neoadjuvant treatment with single-agent nivolumab or combined treatment with ipilimumab and nivolumab. That trial is really too early to have any reportable results, but it does reflect this hypothesis that neoadjuvant therapy may have significant clinical benefit. And certainly, again, as we try to understand why some patients respond better than others, why resistance happens, it’s a very powerful opportunity for us to hopefully understand resistance and develop the next generation of therapies.

Certainly, one of the ultimate questions is whether this becomes a standard approach, as it’s used in diseases like breast cancer, where neoadjuvant therapies are actually a way that new therapies can gain regulatory approval. This was one of the things that was discussed at that workshop that you mentioned, and it is something that is only now feasible because of the marked developments we’ve made with much more effective targeted and immune therapies. Again, just to reinforce: this is something that really should only be done in the setting of a clinical trial.

Transcript Edited for Clarity
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Transcript:

Robert H.I. Andtbacka, MD, CM:
If we did the initial staging for the patient and we found that the patient actually had not only the large lymph node in the superficial groin, but also had numerous lymph nodes along the external common iliac area and going up toward the bifurcation of the iliac and the aorta, for me, from a surgical perspective, could I resect that? It’s very possible it’s resectable, but it truly is borderline from the perspective that the risk of this patient recurring is very high. And we really, as surgeons, think about this as, “Surgically, I could take this out, but as soon as I move the patient from the operating room to the recovery room, they probably are already recurring.” I would say it would not be a meaningful surgical resection. In this setting then, I know that there are some ongoing neoadjuvant clinical trials right now. I know Mike, you have done some at MD Anderson, and Georgina, you’ve done some in Australia. Tell me a bit about those studies that you have conducted and some other ongoing studies that you have at the moment. So, Georgina, tell me.

Georgina Long, MD: Again, as a surgeon, you are still telling me this is resectable. It’s just extensive, and you know they’re going to recur quickly.

Robert H.I. Andtbacka, MD, CM: So, in surgery, nothing is black-and-white. I would tell you that, surgically, we could potentially take this out, but this is not a meaningful operation. This is due to the risk of recurrence, which would really fall under that category of “unresectable” because of the futility of the operation to render the patient free of disease for a reasonable amount of time.

Georgina Long, MD: It’s not black-and-white, and in our institution, something that can be chopped out is considered “resectable.” It would be considered “resectable” despite all the caveats about the fact that the patient almost has 100% chance of recurring. So, we would consider neoadjuvant trials; they’re eligible. In our institution, for our neoadjuvant trials, the surgeon has to be able to say, “We can remove this as is, leaving no melanoma behind, getting good margins.”

We’ve got several neoadjuvant trials. One is on targeted therapy for BRAF V600-mutant patients; it works very well. We’ve completed enrollment of that. We’ve done one look-see in the first 19 patients. It is very much a translational study, so it’s looking at biomarkers. And in that trial, we had 50% of patients have a complete pathological response, complete RECIST response, and complete metabolic response after 12 weeks of neoadjuvant dabrafenib and trametinib. The question of how much dabrafenib and trametinib you need, I don’t think you need 12 weeks. I think you could do it in 8 weeks, possibly even 6 weeks. I don’t know what the pathological response rate would be, but I think it would be near what we see at 12 weeks, given what we see in the metastatic setting.

The other study we have that’s about to open is on neoadjuvant combination nivolumab and ipilimumab. Again, this patient would be perfect for that. We have some early data from the Netherlands in that situation, where of the first 10 patients, 3 of them had a complete pathological response by week 6. So, that’s really compelling and interesting as well. There are also mouse data that suggest that if you have the tumor in situ and give immune therapy, you actually may induce a better immune response rather than chopping it out first and then giving it adjuvantly. Maybe the neoadjuvant approach is better, but we don’t know the answer to that.

The third trial we have, which I find to be a very interesting and important trial as well, is neoadjuvant. It has to be resectable. This time it’s for BRAF-mutant, but it’s looking at 3 arms. How do we combine targeted therapy and immunotherapy? It’s dabrafenib and trametinib followed by pembrolizumab for 12 weeks, all 3 together, or just anti-PD-1. It’s going to answer a whole heap of questions about sequencing, in terms of translational tissue endpoints. So, they’re the neoadjuvant trials we have open at the moment. We plan to continue to use this neoadjuvant platform. We’ve got a lot of work to do in that space, but it is only in a clinical trial. That’s the important point.

Robert H.I. Andtbacka, MD, CM: Mike, you led a neoadjuvant symposium, recently, talking about this, how we evaluate these patients. You’ve also done some studies at MD Anderson, very similar to what Georgina has, with BRAF/MEK combinations, as well as studies with immunotherapy for this. Tell me a little bit about those studies that you’ve done.

Michael A. Davies, MD, PhD: Our first trial was for patients with a BRAF V600 mutation. This was actually a clinical trial where one-third of the patients got randomized in a 2:1 fashion to standard-of-care surgery and were offered standard adjuvant therapy. And then, two-thirds of the patients were randomized to neoadjuvant treatment with dabrafenib and trametinib for 8 weeks followed by surgery. After surgery, they had an additional 44 weeks of adjuvant treatment to complete 1 year of therapy. This trial was actually stopped early by our DSMB (Data and Safety Monitoring Board) because of the marked difference in relapse-free survival we saw between these 2 arms, which made it unethical to continue to randomize patients to standard-of-care surgery.

These data are actually going to be presented in full in just 2 days and will certainly then be available to the public. That trial is then going to reopen to be very similar to Georgina’s trial: to not have randomization to the standard-of-care, but to neoadjuvant therapy for 8 weeks for each patient who has this BRAF mutation. We actually, again, with this 8 weeks of therapy, had a very similar pathologic CR rate of almost 60% that was seen in the Australian study, suggesting that 2 to 3 months may not be that different, at least in terms of how much therapy it takes to see a pathologic CR.

We have another trial open in which patients are randomized to neoadjuvant treatment with single-agent nivolumab or combined treatment with ipilimumab and nivolumab. That trial is really too early to have any reportable results, but it does reflect this hypothesis that neoadjuvant therapy may have significant clinical benefit. And certainly, again, as we try to understand why some patients respond better than others, why resistance happens, it’s a very powerful opportunity for us to hopefully understand resistance and develop the next generation of therapies.

Certainly, one of the ultimate questions is whether this becomes a standard approach, as it’s used in diseases like breast cancer, where neoadjuvant therapies are actually a way that new therapies can gain regulatory approval. This was one of the things that was discussed at that workshop that you mentioned, and it is something that is only now feasible because of the marked developments we’ve made with much more effective targeted and immune therapies. Again, just to reinforce: this is something that really should only be done in the setting of a clinical trial.

Transcript Edited for Clarity
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Online CME Activities
TitleExpiration DateCME Credits
Medical Crossfire®: Evolving Roles for Targeted Melanoma Therapies: Assessing Rapid Progress in the Field and Looking Toward Future CombinationsFeb 28, 20191.5
Advances in™ Melanoma: Exploring BRAF/MEK in Adjuvant and Neoadjuvant SettingsSep 28, 20191.5
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