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Melanoma: BRAF/MEK-Inhibitors as Adjuvant Therapy

Panelists: Jeffrey S. Weber, MD, PhD, Laura and Isaac Perlmutter Cancer Center; Robert Andtbacka, MD, CM, Huntsman Cancer Institute; Omid Hamid, MD, The Angeles Clinic and Research Institute ; Jason J. Luke, MD, FACP, University of Chicago; Michael A. Postow, MD, Memorial Sloan Kettering Cancer Center; Hussein Tawbi, MD, PhD, UT MD Anderson Cancer Center
Published: Tuesday, Aug 14, 2018



Transcript: 

Jeffrey S. Weber, MD, PhD: Jason, if you see pyrexia in a dabrafenib/trametinib-treated adjuvant patient, how do you try to minimize it, avoid it, or manage it? What do you do?

Jason J. Luke, MD, FACP: My experience, especially in the adjuvant patient setting, is that it’s quite prevalent, and so there’s the on-label and number that you see. But in my practice, it’s very common. I tell patients outright, right from the very beginning—from the first conversations—that if we go this route, it’s OK to take a break. If you get any symptoms that you think are consistent with a fever, whether it be fatigue, sweats, or so on and so forth, stop and give us a call. Let us know. Let it wash out.

What patients really need is that information to empower them. They don’t want to stop. But if you tell them it’s all right, then we keep going.

A lot of our patients do get the fever. We’ll give it a shot, take a break, and come back to it, maybe to give it another try. But in the adjuvant setting, we’re not going to belabor it over time. There is a rare group of patients who really just don’t seem to be able to get out of the first month without having continuous fevers. I think those patients self-select as not great adjuvant therapy candidates, at least with targeted therapy. But generally speaking, empowering the patients, letting them know it’s OK to take a break, allows them to kind of manage it themselves to get through.

Jeffrey S. Weber, MD, PhD: So de facto, you’re going to essentially do intermittent dosing?

Jason J. Luke, MD, FACP: Yes.

Jeffrey S. Weber, MD, PhD: Do others do that?

Hussein Tawbi, MD, PhD: The concept of intermittent dosing is a little different from that. There are the kind of proscribed breaks that are weeks long, and then you restart at the high dose again. For the dabrafenib/trametinib regimen in this setting, the interruptions can be very short. As long as a day or 2 is sometimes enough for patients to break their fevers, allowing them to be able to be retreated, and so I wouldn’t consider interrupted dosing, per se.

Omid Hamid, MD: I would agree with that. But remember, some of the paradigms we have in managing fever in metastatic disease do not hold in the adjuvant setting. I would never put a patient on low-dose prednisone for fever. The question for me becomes, if we’re beginning early and we’re seeing this toxicity, how will that affect switching to some other type of adjuvant therapy? We know that there can be even more toxicities.

Jeffrey S. Weber, MD, PhD: You mean that you’re going to take a break from it? If you go off dabrafenib/trametinib, you have to give them an interval off any therapy?

Omid Hamid, MD: Absolutely an interval.

Jason J. Luke, MD, FACP: This all goes to show that all of these studies—the 3 studies that we are talking about—are used to 1 year of treatment. But in reality, we don’t really know what the optimal duration of treatment is. From my perspective, it’s not an all-or-nothing, like you say, Jason. This is to try to decrease the risk of this coming back, but they also have to live life.

Jeffrey S. Weber, MD, PhD: Robert, do you have any concerns about the long-term use of nivolumab? It’s a year. That’s a fairly long time. In patients who come back to you, who have been on adjuvant therapy, when you check them, are you seeing long-term side effects that you didn’t expect?

Robert Andtbacka, MD, CM: We have had patients who have had type 1 diabetes come back. You are 32 years old and now you have type 1 diabetes. I think that occurs in about 3% of patients who get on these studies. That is concerning to me. What is the long-term effect of that, especially if you have a patient who had an earlier-stage disease, such as one of those stage 3b patients who was on that and had relatively lower risk of recurrence than others? What’s the long-term effect in terms of end organ toxicities and so on? We don’t know yet. To Michael’s point, as you pointed out, and also as Hussein pointed out, these are long-term toxicities that we don’t know the effects of yet. Even in the metastatic setting, we don’t truly know what the long-term effects are for some of these therapies.

Jeffrey S. Weber, MD, PhD: To close the loop on the adjuvant choices, is there any role left for high-dose ipilimumab, which was approved in the United States at the end of 2015? That was a little over 2 years ago, but it has not been approved in the EU, Australia, or Canada, and probably never will be. Is there a role for that, Hussein?

Hussein Tawbi, MD, PhD: The first time I had to consider that after the approval of adjuvant nivolumab was a couple of weeks ago. One of my patients on adjuvant nivolumab progressed with a resectable disease. This patient has declared that he’s very high risk. And now, even on PD-1, which we don’t fully understand the biology of, it’s clear that he would require adjuvant treatment after resection. Obviously, again, this is a population that’s never been studied, because all of the patients who were treated with adjuvant ipilimumab were basically patients who had never received immunotherapy or PD-1 in the past. But that’s where I see a potential role—when I feel that this patient has a high risk of recurrence after surgical resection of a recurrent disease. I will offer adjuvant ipilimumab.

Omid Hamid, MD: Remember, also, that this is a 10-mg dose in someone who is at very high risk of metastatic disease, who has clearly failed PD-1 therapy. In the metastatic setting, we know that this dose had better long-term 5-year survivals. I just can’t turn my back to that. In a setting where they’re metastatic and their risk is so high, once they are deemed as “clearly metastatic,” you’re going to give them a dose that’s inferior at 3 mg.

Jeffrey S. Weber, MD, PhD: That’s what I will do. I acknowledge that there is a modest augmentation in response rate and survival—10 versus 3 in the metastatic mode. But it’s a tough sales pitch to have a 33% rate of stopping from toxicity in a 41% rate of grade 3/4 side effects in a stage 3 patient. I’ve had a handful of patients who have had BRAF wild-type disease, who have relapsed after adjuvant nivolumab, and have been re-resected and then put on ipilimumab.

Jason J. Luke, MD, FACP: I’m sure that Robert’s going to make the same point that I’m about to make here. The recurrence matters a little bit in terms of what we’re talking about here. If they had 1 node that was positive, and it turns out that they had a recurrence in 1 node, I think I would be pretty cautious about exposing that patient to potential long-term toxicity. If it’s a substantive recurrence that can be resected and then they’re free of disease, then I think these arguments are much longer.

Robert Andtbacka, MD, CM: Yes. From a surgical perspective, this is really important. The site of recurrence is important.

Additionally, the kinetics of that recurrence is also very important. Is the patient currently receiving treatment in an adjuvant setting, experiencing a recurrence, and sort of breaking through that? From my perspective, those are really the same as those who progress for metastatic disease, who are on treatment.

Transcript Edited for Clarity 

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Transcript: 

Jeffrey S. Weber, MD, PhD: Jason, if you see pyrexia in a dabrafenib/trametinib-treated adjuvant patient, how do you try to minimize it, avoid it, or manage it? What do you do?

Jason J. Luke, MD, FACP: My experience, especially in the adjuvant patient setting, is that it’s quite prevalent, and so there’s the on-label and number that you see. But in my practice, it’s very common. I tell patients outright, right from the very beginning—from the first conversations—that if we go this route, it’s OK to take a break. If you get any symptoms that you think are consistent with a fever, whether it be fatigue, sweats, or so on and so forth, stop and give us a call. Let us know. Let it wash out.

What patients really need is that information to empower them. They don’t want to stop. But if you tell them it’s all right, then we keep going.

A lot of our patients do get the fever. We’ll give it a shot, take a break, and come back to it, maybe to give it another try. But in the adjuvant setting, we’re not going to belabor it over time. There is a rare group of patients who really just don’t seem to be able to get out of the first month without having continuous fevers. I think those patients self-select as not great adjuvant therapy candidates, at least with targeted therapy. But generally speaking, empowering the patients, letting them know it’s OK to take a break, allows them to kind of manage it themselves to get through.

Jeffrey S. Weber, MD, PhD: So de facto, you’re going to essentially do intermittent dosing?

Jason J. Luke, MD, FACP: Yes.

Jeffrey S. Weber, MD, PhD: Do others do that?

Hussein Tawbi, MD, PhD: The concept of intermittent dosing is a little different from that. There are the kind of proscribed breaks that are weeks long, and then you restart at the high dose again. For the dabrafenib/trametinib regimen in this setting, the interruptions can be very short. As long as a day or 2 is sometimes enough for patients to break their fevers, allowing them to be able to be retreated, and so I wouldn’t consider interrupted dosing, per se.

Omid Hamid, MD: I would agree with that. But remember, some of the paradigms we have in managing fever in metastatic disease do not hold in the adjuvant setting. I would never put a patient on low-dose prednisone for fever. The question for me becomes, if we’re beginning early and we’re seeing this toxicity, how will that affect switching to some other type of adjuvant therapy? We know that there can be even more toxicities.

Jeffrey S. Weber, MD, PhD: You mean that you’re going to take a break from it? If you go off dabrafenib/trametinib, you have to give them an interval off any therapy?

Omid Hamid, MD: Absolutely an interval.

Jason J. Luke, MD, FACP: This all goes to show that all of these studies—the 3 studies that we are talking about—are used to 1 year of treatment. But in reality, we don’t really know what the optimal duration of treatment is. From my perspective, it’s not an all-or-nothing, like you say, Jason. This is to try to decrease the risk of this coming back, but they also have to live life.

Jeffrey S. Weber, MD, PhD: Robert, do you have any concerns about the long-term use of nivolumab? It’s a year. That’s a fairly long time. In patients who come back to you, who have been on adjuvant therapy, when you check them, are you seeing long-term side effects that you didn’t expect?

Robert Andtbacka, MD, CM: We have had patients who have had type 1 diabetes come back. You are 32 years old and now you have type 1 diabetes. I think that occurs in about 3% of patients who get on these studies. That is concerning to me. What is the long-term effect of that, especially if you have a patient who had an earlier-stage disease, such as one of those stage 3b patients who was on that and had relatively lower risk of recurrence than others? What’s the long-term effect in terms of end organ toxicities and so on? We don’t know yet. To Michael’s point, as you pointed out, and also as Hussein pointed out, these are long-term toxicities that we don’t know the effects of yet. Even in the metastatic setting, we don’t truly know what the long-term effects are for some of these therapies.

Jeffrey S. Weber, MD, PhD: To close the loop on the adjuvant choices, is there any role left for high-dose ipilimumab, which was approved in the United States at the end of 2015? That was a little over 2 years ago, but it has not been approved in the EU, Australia, or Canada, and probably never will be. Is there a role for that, Hussein?

Hussein Tawbi, MD, PhD: The first time I had to consider that after the approval of adjuvant nivolumab was a couple of weeks ago. One of my patients on adjuvant nivolumab progressed with a resectable disease. This patient has declared that he’s very high risk. And now, even on PD-1, which we don’t fully understand the biology of, it’s clear that he would require adjuvant treatment after resection. Obviously, again, this is a population that’s never been studied, because all of the patients who were treated with adjuvant ipilimumab were basically patients who had never received immunotherapy or PD-1 in the past. But that’s where I see a potential role—when I feel that this patient has a high risk of recurrence after surgical resection of a recurrent disease. I will offer adjuvant ipilimumab.

Omid Hamid, MD: Remember, also, that this is a 10-mg dose in someone who is at very high risk of metastatic disease, who has clearly failed PD-1 therapy. In the metastatic setting, we know that this dose had better long-term 5-year survivals. I just can’t turn my back to that. In a setting where they’re metastatic and their risk is so high, once they are deemed as “clearly metastatic,” you’re going to give them a dose that’s inferior at 3 mg.

Jeffrey S. Weber, MD, PhD: That’s what I will do. I acknowledge that there is a modest augmentation in response rate and survival—10 versus 3 in the metastatic mode. But it’s a tough sales pitch to have a 33% rate of stopping from toxicity in a 41% rate of grade 3/4 side effects in a stage 3 patient. I’ve had a handful of patients who have had BRAF wild-type disease, who have relapsed after adjuvant nivolumab, and have been re-resected and then put on ipilimumab.

Jason J. Luke, MD, FACP: I’m sure that Robert’s going to make the same point that I’m about to make here. The recurrence matters a little bit in terms of what we’re talking about here. If they had 1 node that was positive, and it turns out that they had a recurrence in 1 node, I think I would be pretty cautious about exposing that patient to potential long-term toxicity. If it’s a substantive recurrence that can be resected and then they’re free of disease, then I think these arguments are much longer.

Robert Andtbacka, MD, CM: Yes. From a surgical perspective, this is really important. The site of recurrence is important.

Additionally, the kinetics of that recurrence is also very important. Is the patient currently receiving treatment in an adjuvant setting, experiencing a recurrence, and sort of breaking through that? From my perspective, those are really the same as those who progress for metastatic disease, who are on treatment.

Transcript Edited for Clarity 
View Conference Coverage
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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