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Immunotherapy in Melanoma: Managing Toxicities

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: Thursday, Dec 29, 2016


Transcript:

Robert H.I. Andtbacka, MD, CM:
Tony, if you use monotherapy, anti-PD-1 therapy, how often do you have to stop those therapies in patients because of the side effects?

Antoni Ribas, MD, PhD: It’s actually very low. I forgot the exact number, but it’s less than 5% that patients on single-agent nivolumab or single-agent pembrolizumab would stop therapy because of side effects. The majority of side effects are manageable with these single agents. There are these low-frequency, serious side effects, as Georgina described. And, we have to be vigilant and we have to have patients informed. Our routine management of these patients is before we get the new infusion, we see the patient, we ask about potential side effects. We have full blood tests, including CBC and chemistry panels, and we look for any hint of inflammation in the liver or in the kidneys. And then, we try to have the patient informed, from the start, to say there are certain things that you really need to get back to us. I think diarrhea would be on the top of the list when we use ipilimumab alone or in combination. And from anti-PD-1 alone, nivolumab, or pembrolizumab, I do ask them to inform us if there’s pneumonitis, if there’s any evidence of shortness of breath that appears new. Then anything that goes out of the norm, that persists, is a reason to contact us, or come to see us in the clinic.

Robert H.I. Andtbacka, MD, CM: How often do you have to use steroids for these patients on monotherapy, anti-PD-1 therapy?

Antoni Ribas, MD, PhD: The steroid use is also very low. It’s less than 5% of the patients. The reasons for using steroids would be most frequently hypophysitis, pneumonitis, hepatitis, and nephritis in my experience. There are occasional neurological syndromes. If we treat enough patients, we do see encephalitis and meningitis-type syndromes, which obviously would require treating with corticosteroids. The majority of patients would improve with these therapies, especially when using anti-PD-1 antibodies alone.

Robert H.I. Andtbacka, MD, CM: What about in the combination therapies we have, such as using nivolumab with ipilimumab, how often do you have to use steroids in those patients?

Antoni Ribas, MD, PhD: There, we have a lot higher frequency of grade 3 to 4 toxicities. The frequency is over 50% of the patients have clinically significant side effects. Not only the frequency, but the magnitude of them seem to be higher, so we go over all of these itis in any part of the body that we describe. They are going to be more frequent. They are going to be more serious.

Robert H.I. Andtbacka, MD, CM: How long do you use the steroids in patients? How long do you keep them on steroids, and do you have a certain method of starting the steroids and tapering the steroids for the patients?

Antoni Ribas, MD, PhD: In general, I try to avoid using steroids unless I really need to. In the case of the combination therapy, there’s a significant number of patients that really need it. I will not use corticosteroids for a skin rash that’s not life threatening. We’re trying to turn on the immune system to fight the cancer. We should not try to dial it down at the minimal side effect. With diarrhea, I do the same. If a patient has loose bowel movements, but nothing else, I advise to change diet and hydration as opposed to start taking corticosteroids. Whenever we get toxicities that are grade 3 to 4, meaning that it warrants an intervention, then I don’t hesitate to start with corticosteroids at 1 mg/kg dosing if it’s a toxicity that I consider that’s really impacting the patient, and may be detrimental. Some toxicities, I’m more worried about with the combination therapy. Hepatitis and colitis, I tend to use high doses of corticosteroids and taper very slowly. I’ve seen reappearance of the toxicity even if a week later the symptoms have improved or the biochemical changes have improved, tapering at that time, sometimes has been a requiescence of the syndrome. So, I tend to go slow on the tapering. Some patients we’ve had to add the second drug for colitis, most frequently infliximab. For hepatitis, it would be mycophenolate. Infliximab would be counterindicated in a patient with elevated transaminases. But, obviously, it has to be personalized and has to be addressed in a way that we are adapting the treatment to how the patient is presenting and behaving.

Michael A. Davies, MD, PhD: I think one of the points about that is, again, for most of those toxicities, we are able to generally taper the patients off of the steroids, probably with the exception of the hypophysitis. If they develop that hormonal insufficiency, patients usually are staying on steroid replacement therapy, as far as we know, for the rest of their life.

Robert H.I. Andtbacka, MD, CM: For all of you, how do you decide when to admit these patients for their toxicities in this setting? Do you have certain standards that you use for that?

Michael A. Postow, MD: This falls into the category where we do have algorithms that can help, and these algorithms are available online. Doctors or nurses that are taking care of these patients can search for these algorithms and find them. But, at the end of the day, it comes to just clinical gestalt. And you know when your patient is not doing well with your initial first-line immunosuppression, such as first-line oral prednisone that you can give them, which is very easily available. If that’s not working, that’s when I start to think about whether or not this patient needs to come to the hospital—because, if they’re having colitis that’s refractory to steroids, I’m worried about its ability to be absorbed, and I’m worried about dehydration, hypokalemia, and other problems of ongoing diarrhea in that context. So, that’s a threshold for hospitalization. And, then, other types of side effects that are rarer, such as some of the neurologic side effects like the pneumonitis, I think more about hospitalization just because I want to ensure that these patients are in a monitored environment. If they don’t improve with their initial immunosuppression, we can continue to monitor them, support term, and then add additional immunosuppression as needed.

Georgina Long, MD: The only other factor, if I can add, is the comorbidity. So, for example, a little bit of diarrhea in a 40-year-old, who’s well supported and close by, is very different to diarrhea in a 75-year-old who has a bit of heart failure and some other things going on. That’s the other thing, so I have a lower threshold for people with a lot of comorbidities, which we all do.

Transcript Edited for Clarity
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Transcript:

Robert H.I. Andtbacka, MD, CM:
Tony, if you use monotherapy, anti-PD-1 therapy, how often do you have to stop those therapies in patients because of the side effects?

Antoni Ribas, MD, PhD: It’s actually very low. I forgot the exact number, but it’s less than 5% that patients on single-agent nivolumab or single-agent pembrolizumab would stop therapy because of side effects. The majority of side effects are manageable with these single agents. There are these low-frequency, serious side effects, as Georgina described. And, we have to be vigilant and we have to have patients informed. Our routine management of these patients is before we get the new infusion, we see the patient, we ask about potential side effects. We have full blood tests, including CBC and chemistry panels, and we look for any hint of inflammation in the liver or in the kidneys. And then, we try to have the patient informed, from the start, to say there are certain things that you really need to get back to us. I think diarrhea would be on the top of the list when we use ipilimumab alone or in combination. And from anti-PD-1 alone, nivolumab, or pembrolizumab, I do ask them to inform us if there’s pneumonitis, if there’s any evidence of shortness of breath that appears new. Then anything that goes out of the norm, that persists, is a reason to contact us, or come to see us in the clinic.

Robert H.I. Andtbacka, MD, CM: How often do you have to use steroids for these patients on monotherapy, anti-PD-1 therapy?

Antoni Ribas, MD, PhD: The steroid use is also very low. It’s less than 5% of the patients. The reasons for using steroids would be most frequently hypophysitis, pneumonitis, hepatitis, and nephritis in my experience. There are occasional neurological syndromes. If we treat enough patients, we do see encephalitis and meningitis-type syndromes, which obviously would require treating with corticosteroids. The majority of patients would improve with these therapies, especially when using anti-PD-1 antibodies alone.

Robert H.I. Andtbacka, MD, CM: What about in the combination therapies we have, such as using nivolumab with ipilimumab, how often do you have to use steroids in those patients?

Antoni Ribas, MD, PhD: There, we have a lot higher frequency of grade 3 to 4 toxicities. The frequency is over 50% of the patients have clinically significant side effects. Not only the frequency, but the magnitude of them seem to be higher, so we go over all of these itis in any part of the body that we describe. They are going to be more frequent. They are going to be more serious.

Robert H.I. Andtbacka, MD, CM: How long do you use the steroids in patients? How long do you keep them on steroids, and do you have a certain method of starting the steroids and tapering the steroids for the patients?

Antoni Ribas, MD, PhD: In general, I try to avoid using steroids unless I really need to. In the case of the combination therapy, there’s a significant number of patients that really need it. I will not use corticosteroids for a skin rash that’s not life threatening. We’re trying to turn on the immune system to fight the cancer. We should not try to dial it down at the minimal side effect. With diarrhea, I do the same. If a patient has loose bowel movements, but nothing else, I advise to change diet and hydration as opposed to start taking corticosteroids. Whenever we get toxicities that are grade 3 to 4, meaning that it warrants an intervention, then I don’t hesitate to start with corticosteroids at 1 mg/kg dosing if it’s a toxicity that I consider that’s really impacting the patient, and may be detrimental. Some toxicities, I’m more worried about with the combination therapy. Hepatitis and colitis, I tend to use high doses of corticosteroids and taper very slowly. I’ve seen reappearance of the toxicity even if a week later the symptoms have improved or the biochemical changes have improved, tapering at that time, sometimes has been a requiescence of the syndrome. So, I tend to go slow on the tapering. Some patients we’ve had to add the second drug for colitis, most frequently infliximab. For hepatitis, it would be mycophenolate. Infliximab would be counterindicated in a patient with elevated transaminases. But, obviously, it has to be personalized and has to be addressed in a way that we are adapting the treatment to how the patient is presenting and behaving.

Michael A. Davies, MD, PhD: I think one of the points about that is, again, for most of those toxicities, we are able to generally taper the patients off of the steroids, probably with the exception of the hypophysitis. If they develop that hormonal insufficiency, patients usually are staying on steroid replacement therapy, as far as we know, for the rest of their life.

Robert H.I. Andtbacka, MD, CM: For all of you, how do you decide when to admit these patients for their toxicities in this setting? Do you have certain standards that you use for that?

Michael A. Postow, MD: This falls into the category where we do have algorithms that can help, and these algorithms are available online. Doctors or nurses that are taking care of these patients can search for these algorithms and find them. But, at the end of the day, it comes to just clinical gestalt. And you know when your patient is not doing well with your initial first-line immunosuppression, such as first-line oral prednisone that you can give them, which is very easily available. If that’s not working, that’s when I start to think about whether or not this patient needs to come to the hospital—because, if they’re having colitis that’s refractory to steroids, I’m worried about its ability to be absorbed, and I’m worried about dehydration, hypokalemia, and other problems of ongoing diarrhea in that context. So, that’s a threshold for hospitalization. And, then, other types of side effects that are rarer, such as some of the neurologic side effects like the pneumonitis, I think more about hospitalization just because I want to ensure that these patients are in a monitored environment. If they don’t improve with their initial immunosuppression, we can continue to monitor them, support term, and then add additional immunosuppression as needed.

Georgina Long, MD: The only other factor, if I can add, is the comorbidity. So, for example, a little bit of diarrhea in a 40-year-old, who’s well supported and close by, is very different to diarrhea in a 75-year-old who has a bit of heart failure and some other things going on. That’s the other thing, so I have a lower threshold for people with a lot of comorbidities, which we all do.

Transcript Edited for Clarity
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Medical Crossfire®: Evolving Roles for Targeted Melanoma Therapies: Assessing Rapid Progress in the Field and Looking Toward Future CombinationsFeb 28, 20191.5
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