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Stage III Melanoma: Neoadjuvant Therapy

Panelists: Jeffrey S. Weber, MD, PhD, Laura and Isaac Perlmutter Cancer Center; Jason J. Luke, MD, FACP, UPMC Hillman Cancer Center; Vernon K. Sondak, MD, Moffitt Cancer Center; Ryan J. Sullivan, MD, Massachusetts General Hospital; Hussein A. Tawbi, MD, PhD
Published: Thursday, Jul 18, 2019



Transcript:

Jeffrey S. Weber, MD, PhD:
Talking about personalizing, which is sort of the hot topic in melanoma, locoregional treatment is the issue of neoadjuvant therapy. Vern, can you tell me a little bit about the REDUCTOR trial, which again is an ASCO [American Society of Clinical Oncology Annual Meeting] abstract that I think will be discussed this afternoon. It’s basically BRAF/MEK neoadjuvant therapy, which I think has had at least 1 very nice publication and could be a practice-changing discovery. What can you tell us?

Vernon K. Sondak, MD: First of all, as we just heard, adjuvant therapy is helping patients. Adjuvant therapy is helping patients with high-risk melanoma to delay or even prevent recurrence. And it clearly helps prevent local and regional recurrence, as well as distant recurrence. So all the advantages of adjuvant therapy are there. Some patients can benefit by neoadjuvant therapy, getting the drugs before surgery, in that they also have an easier operation. We can shrink large tumors down, make the surgery potentially easier, perhaps not need postoperative radiation or other treatments. But we also get another very important advantage of neoadjuvant therapy, and that is we see whether it works.

You’ve all talked about the risk-benefit discussions you’re having with the patient—treat now, treat later. Give these people a year of adjuvant therapy, and you have no idea whether it did anything—whether they were cured, whether they were resistant. You don’t know until it’s too late.

Neoadjuvant therapy gives us a window into what is happening, and then we’re going to hear how important that window can be. But neoadjuvant therapy can be used in several different situations, and the REDUCTOR trial is important to understand in that context.

Originally we, and many others, started with patients who had unresectable disease, very advanced disease, in the nodal basin. We knew, not that we couldn’t operate but that we couldn’t get all the disease out. We’d be leaving microscopic or even macroscopic disease at the margins.

The availability of BRAF/MEK inhibitors let us shrink those patients down with a high level of reliability. And the REDUCTOR trial is a prospective study, not randomized but prospective, that shows that, in most cases, patients will respond and surgery can be done on patients who used to have no surgical option. And now the real focus is on less advanced cases, still locally advanced, a large lymph node or multiple lymph nodes, and even into the resectable, measurable tumors. For any tumor at least 1.5 cm in size in the lymph nodes, I think we should be thinking about, should we do treatment before surgery?

And for the surgeons out there, one very practical point. Make a diagnosis with a needle biopsy. Leave the tumor alone until we are sure we know what we’re going to do. Get a needle biopsy. Get a BRAF test, and bring that to multidisciplinary evaluation so these neoadjuvant approaches have a chance to be utilized.

Jeffrey S. Weber, MD, PhD: OK, and then there have been a couple of abstracts recently; interestingly, they’re all published in Nature Medicine, it turns out, a very high-level publication. And there was recently an article from investigators at the University of Pennsylvania who did a single dose of neoadjuvant pembrolizumab, which to me is a bit interesting. You wouldn’t think that it would be much of an effect, and I believe it started out as essentially a study to understand biomarkers and mechanism of action with pembrolizumab.

But clinically it turned out that I think they treated something like 27 patients with 1 dose of pembrolizumab, and they had a pathologic complete response in 20% of the patients. And they had an additional 15%, 20% of the patients who had a 90% partial response. So a very good partial response. Which, when you think about it, is pretty darn surprising—1 dose would have such an affect? And of those who had a PCR, pathologic complete response—almost none of them relapsed with moderate follow-up in the range of a year. And they had lots of correlative marker studies associated with this, but I was quite impressed that you could have such a high PCR rate. And then there have been other trials looking at BRAF/MEK. Ryan, …looking at ipilimumab and nivolumab with either higher PCR rates, tell us about the ipilimumab-nivolumab study.

Ryan J. Sullivan, MD: The first ipilimumab-nivolumab study was actually a randomized trial performed at Dr Tawbi’s institution, The University of Texas MD Anderson Cancer Center in Houston, Texas, in which the patients received either nivolumab or ipilimumab and nivolumab. And they received the ipilimumab and nivolumab; 3 mg of ipilimumab and 1 mg of nivolumab. And they showed that they had much better pathologic complete responses with ipilimumab and nivolumab than with nivolumab alone, and that they were able to operate on patients. That toxicity may have delayed operations from time to time, but it didn’t get in the way of the operative plan. Interestingly though, these were 2 small cohorts. Three of the patients in the nivolumab arm ended up having—2 had widely metastatic disease, and the other patient was unable to have surgery, or had a more complicated surgery and a greater progression of the tumor.

I think based on that information and based on the fact that ipilimumab and nivolumab combinations then used more widely in the metastatic setting as a frontline agent, it became logical to think, “OK, let’s further study that combination in patients in the neoadjuvant setting.”

The biggest issue, of course, with ipilimumab and nivolumab is that they’re highly toxic. And that was seen certainly at the MD Anderson Cancer Center, and it’s been seen everywhere when we use 3 mg of ipilimumab and 1 mg of nivolumab. Based on alternative dosing regimens that had originally been used in other diseases and that has been compared in the CheckMate 511 study of 1 mg ipilimumab and 3 mg nivolumab versus 3 mg ipilimumab and 1 mg nivolumab, it was thought that we should look at—meaning the folks in the Netherlands—a couple of different combinations.

In the OpACIN study, or the  OpACIN-neo study, patients were randomized to either the standard ipilimumab-nivolumab dosing, times 2. So 3 mg ipilimumab and 1 mg nivolumab every 3 weeks, times 2 dosages and on to surgery at week 6. Or 1 mg ipilimumab and 3 mg nivolumab, and times 2 doses every 3 weeks and off to surgery; or some strange thing which was basically nivolumab 3 mg, nivolumab 3 mg, and off to surgery.

What was clear is that the standard and the flip dose did the best. Those patients had pathologic complete response rates over 50% and really good responses over 70%, actually over 75%. However, toxicity was a bigger issue with the ipilimumab 3 mg and nivolumab 1 mg than ipilimumab 1 mg and nivolumab 3 mg. And so that third arm was actually more toxic and not as effective. What was clear is that if you had to pick a winner to move forward with neoadjuvant ipilimumab-nivolumab, it was the flipped dose, 2 doses prior to receiving surgery. And I think it’s a really important study. It may help us really move the field forward in terms of what we think are going to be the standard treatments in the neoadjuvant setting if neoadjuvant therapy becomes the standard treatment.


Transcript Edited for Clarity

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Transcript:

Jeffrey S. Weber, MD, PhD:
Talking about personalizing, which is sort of the hot topic in melanoma, locoregional treatment is the issue of neoadjuvant therapy. Vern, can you tell me a little bit about the REDUCTOR trial, which again is an ASCO [American Society of Clinical Oncology Annual Meeting] abstract that I think will be discussed this afternoon. It’s basically BRAF/MEK neoadjuvant therapy, which I think has had at least 1 very nice publication and could be a practice-changing discovery. What can you tell us?

Vernon K. Sondak, MD: First of all, as we just heard, adjuvant therapy is helping patients. Adjuvant therapy is helping patients with high-risk melanoma to delay or even prevent recurrence. And it clearly helps prevent local and regional recurrence, as well as distant recurrence. So all the advantages of adjuvant therapy are there. Some patients can benefit by neoadjuvant therapy, getting the drugs before surgery, in that they also have an easier operation. We can shrink large tumors down, make the surgery potentially easier, perhaps not need postoperative radiation or other treatments. But we also get another very important advantage of neoadjuvant therapy, and that is we see whether it works.

You’ve all talked about the risk-benefit discussions you’re having with the patient—treat now, treat later. Give these people a year of adjuvant therapy, and you have no idea whether it did anything—whether they were cured, whether they were resistant. You don’t know until it’s too late.

Neoadjuvant therapy gives us a window into what is happening, and then we’re going to hear how important that window can be. But neoadjuvant therapy can be used in several different situations, and the REDUCTOR trial is important to understand in that context.

Originally we, and many others, started with patients who had unresectable disease, very advanced disease, in the nodal basin. We knew, not that we couldn’t operate but that we couldn’t get all the disease out. We’d be leaving microscopic or even macroscopic disease at the margins.

The availability of BRAF/MEK inhibitors let us shrink those patients down with a high level of reliability. And the REDUCTOR trial is a prospective study, not randomized but prospective, that shows that, in most cases, patients will respond and surgery can be done on patients who used to have no surgical option. And now the real focus is on less advanced cases, still locally advanced, a large lymph node or multiple lymph nodes, and even into the resectable, measurable tumors. For any tumor at least 1.5 cm in size in the lymph nodes, I think we should be thinking about, should we do treatment before surgery?

And for the surgeons out there, one very practical point. Make a diagnosis with a needle biopsy. Leave the tumor alone until we are sure we know what we’re going to do. Get a needle biopsy. Get a BRAF test, and bring that to multidisciplinary evaluation so these neoadjuvant approaches have a chance to be utilized.

Jeffrey S. Weber, MD, PhD: OK, and then there have been a couple of abstracts recently; interestingly, they’re all published in Nature Medicine, it turns out, a very high-level publication. And there was recently an article from investigators at the University of Pennsylvania who did a single dose of neoadjuvant pembrolizumab, which to me is a bit interesting. You wouldn’t think that it would be much of an effect, and I believe it started out as essentially a study to understand biomarkers and mechanism of action with pembrolizumab.

But clinically it turned out that I think they treated something like 27 patients with 1 dose of pembrolizumab, and they had a pathologic complete response in 20% of the patients. And they had an additional 15%, 20% of the patients who had a 90% partial response. So a very good partial response. Which, when you think about it, is pretty darn surprising—1 dose would have such an affect? And of those who had a PCR, pathologic complete response—almost none of them relapsed with moderate follow-up in the range of a year. And they had lots of correlative marker studies associated with this, but I was quite impressed that you could have such a high PCR rate. And then there have been other trials looking at BRAF/MEK. Ryan, …looking at ipilimumab and nivolumab with either higher PCR rates, tell us about the ipilimumab-nivolumab study.

Ryan J. Sullivan, MD: The first ipilimumab-nivolumab study was actually a randomized trial performed at Dr Tawbi’s institution, The University of Texas MD Anderson Cancer Center in Houston, Texas, in which the patients received either nivolumab or ipilimumab and nivolumab. And they received the ipilimumab and nivolumab; 3 mg of ipilimumab and 1 mg of nivolumab. And they showed that they had much better pathologic complete responses with ipilimumab and nivolumab than with nivolumab alone, and that they were able to operate on patients. That toxicity may have delayed operations from time to time, but it didn’t get in the way of the operative plan. Interestingly though, these were 2 small cohorts. Three of the patients in the nivolumab arm ended up having—2 had widely metastatic disease, and the other patient was unable to have surgery, or had a more complicated surgery and a greater progression of the tumor.

I think based on that information and based on the fact that ipilimumab and nivolumab combinations then used more widely in the metastatic setting as a frontline agent, it became logical to think, “OK, let’s further study that combination in patients in the neoadjuvant setting.”

The biggest issue, of course, with ipilimumab and nivolumab is that they’re highly toxic. And that was seen certainly at the MD Anderson Cancer Center, and it’s been seen everywhere when we use 3 mg of ipilimumab and 1 mg of nivolumab. Based on alternative dosing regimens that had originally been used in other diseases and that has been compared in the CheckMate 511 study of 1 mg ipilimumab and 3 mg nivolumab versus 3 mg ipilimumab and 1 mg nivolumab, it was thought that we should look at—meaning the folks in the Netherlands—a couple of different combinations.

In the OpACIN study, or the  OpACIN-neo study, patients were randomized to either the standard ipilimumab-nivolumab dosing, times 2. So 3 mg ipilimumab and 1 mg nivolumab every 3 weeks, times 2 dosages and on to surgery at week 6. Or 1 mg ipilimumab and 3 mg nivolumab, and times 2 doses every 3 weeks and off to surgery; or some strange thing which was basically nivolumab 3 mg, nivolumab 3 mg, and off to surgery.

What was clear is that the standard and the flip dose did the best. Those patients had pathologic complete response rates over 50% and really good responses over 70%, actually over 75%. However, toxicity was a bigger issue with the ipilimumab 3 mg and nivolumab 1 mg than ipilimumab 1 mg and nivolumab 3 mg. And so that third arm was actually more toxic and not as effective. What was clear is that if you had to pick a winner to move forward with neoadjuvant ipilimumab-nivolumab, it was the flipped dose, 2 doses prior to receiving surgery. And I think it’s a really important study. It may help us really move the field forward in terms of what we think are going to be the standard treatments in the neoadjuvant setting if neoadjuvant therapy becomes the standard treatment.


Transcript Edited for Clarity
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Online CME Activities
TitleExpiration DateCME Credits
Advances in™ Melanoma: Exploring BRAF/MEK in Adjuvant and Neoadjuvant SettingsSep 28, 20191.5
Medical Crossfire®: What Does Data Tell Us About How to Optimize Checkpoint Inhibitor Strategies Across Lines of Care for Patients with Melanoma?Nov 30, 20191.5
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