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Adjuvant Therapy Options in Advanced 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 Online: Tuesday, Jan 24, 2017



Transcript:

Robert H.I. Andtbacka, MD, CM:
We had an informed discussion with the patient, went through all the risk, benefit, and alternatives. We did have a neoadjuvant study available, but the patient opted to undergo surgical resection, and we did that. Now, at this point in time, would we consider adjuvant therapy for this patient when we know she has already recurred and we know that the risk of having subsequent recurrences are exceedingly high? And, if so, outside of a clinical trial but currently available adjuvant therapies, what are the therapies that we could choose for her, Tony, if she came to UCLA?

Antoni Ribas, MD, PhD: This patient would be referred to medical oncology for adjuvant systemic therapy. We would be discussing, at this point, high-dose ipilimumab. Ipilimumab came in at 10 mg/kg, which, in the recent EORTC trial, has demonstrated improvement in overall survival significantly to the control arm, which was a no treatment control arm. We would also discuss high-dose interferon. The likelihood of a serious side effect from high-dose interferon would be lower than with ipilimumab, but the common toxicities would be higher with high-dose interferon. Those would be the 2 options.

Robert H.I. Andtbacka, MD, CM: What are the common toxicities, Tony, in high-dose interferon that would be different from the high-dose ipilimumab?

Antoni Ribas, MD, PhD: High-dose interferon will give toxicities in the majority of patients. It’s given intravenously for 5 days on, 2 days off for 1 month. And during that period of time, the majority of patients have fevers, chills, and malaise. Many times, treatment needs to be stopped because of pancytopenia or elevation of a liver function test. Then, the patients would continue with getting dosing subcutaneously 3 times a week for 1 year. Where the patients with continued dosing have a sensation of being really tired most of the time. At with time, they can develop depression, something that’s not only because they’re on treatment and they had melanoma surgery, but because interferon often can induce depression. It has been something that’s well recognized.

With high-dose ipilimumab, the majority of patients will have no adverse side effects. We forget about these when we talk about high-dose ipilimumab because all of us are worried about the ones who have side effects. And the ones who have side effects can have colitis that can be severe and that can be difficult to manage. We’re talking, with a first case, about treating with high doses of corticosteroids, not being able to taper rapidly, which becomes a bigger problem in patients where some of them may be cured from the surgery, and now we’ve induced toxicity and we have to deal with that toxicity. Some patients may develop hypophysitis, and may then require substitution therapy for life and having to watch their lifestyle because, at some point, their body would not react to that. That may be a problem. Thyroiditis and other “itis" can be seen with ipilimumab. So, those are things that come into big consideration in this case.

The other therapy that would be approved in the United States is pegylated interferon, which the side effects are similar to high-dose interferon. The data does support using it. There’s no overall survival advantage in the randomized trials. In patients with an ulcerated primary, there’s a hint that maybe pegylated interferon may have more activity, but that doesn’t mean that high-dose interferon would not.

Robert H.I. Andtbacka, MD, CM: Again, all of it really being on ad hoc analyses, not predefined analyses in this.

Antoni Ribas, MD, PhD: Yes.

Robert H.I. Andtbacka, MD, CM: So, with the EORTC 18071 trial—which just looked at high-dose ipilimumab, 10 mg/kg versus the placebo—that showed an improvement in recurrence-free survival and also, recently, in overall survival. I think it is important for us to recognize, though, that in this adjuvant study, there were 5 patients on the high-dose ipilimumab arm that actually died. I think it’s also important to recognize that many of these patients, as you indicated, may have been cured with surgery alone. So, I think that’s a very important discussion for us to have.

Antoni Ribas, MD, PhD: Absolutely.

Robert H.I. Andtbacka, MD, CM: Now, Tony, the other thing we’re also seeing in the community, we know that the approved dose that we use for patients with metastatic disease, oligometastatic disease, with ipilimumab is 3 mg/kg. And yet, the approved dose in the adjuvant setting is 10 mg/kg, and there definitely is more toxicity with that. In the community, we are seeing patients being treated with 3 mg/kg with really no data at all to support that. What is your take on this? I know there are some clinical trials that we have conducted that will look at this, but, at the moment, what is your take on this?

Antoni Ribas, MD, PhD: It’s a difficult question. I find myself tongue tied more than once whenever I’m talking to patients about the ipilimumab dose in the more serious condition, in metastatic disease. It’s one-third lower than in the adjuvant setting where some patients may be cured, but we would be more careful about side effects. The data so far suggest that there’s a dose response effect with ipilimumab. There was a presentation at this year’s ESMO meeting of ipilimumab at 3 mg/kg versus 10 mg/kg in patients with metastatic disease, showing that there’s improved outcomes on patients with 10 mg/kg versus 3 mg/kg. So, if we think about the therapeutic effect, it may be more beneficial to be on the high dose, on the 10 mg/kg. The problem is that it also brings a lot more toxicities, and we have to consider that. But, the data of adjuvant ipilimumab is with the 10 mg/kg, and we haven’t changed that. That’s a trial that took several years of planning, conduct, and readout, and we cannot change it right now. And my standard is giving the 10 mg/kg dose and hoping that the patient will tolerate it. The 3 mg/kg is being tested prospectively in the ECOG E1609 trial, which has 3 arms: high-dose interferon, ipilimumab at 10 mg/kg, or ipilimumab at 3 mg/kg. And that study, we hope will read out in the next year or so. Then, we’ll be able to see if it’s enough benefit in the adjuvant setting to be on the 10 mg/kg versus the 3 mg/kg and what are the differences in toxicities.

Transcript Edited for Clarity

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Transcript:

Robert H.I. Andtbacka, MD, CM:
We had an informed discussion with the patient, went through all the risk, benefit, and alternatives. We did have a neoadjuvant study available, but the patient opted to undergo surgical resection, and we did that. Now, at this point in time, would we consider adjuvant therapy for this patient when we know she has already recurred and we know that the risk of having subsequent recurrences are exceedingly high? And, if so, outside of a clinical trial but currently available adjuvant therapies, what are the therapies that we could choose for her, Tony, if she came to UCLA?

Antoni Ribas, MD, PhD: This patient would be referred to medical oncology for adjuvant systemic therapy. We would be discussing, at this point, high-dose ipilimumab. Ipilimumab came in at 10 mg/kg, which, in the recent EORTC trial, has demonstrated improvement in overall survival significantly to the control arm, which was a no treatment control arm. We would also discuss high-dose interferon. The likelihood of a serious side effect from high-dose interferon would be lower than with ipilimumab, but the common toxicities would be higher with high-dose interferon. Those would be the 2 options.

Robert H.I. Andtbacka, MD, CM: What are the common toxicities, Tony, in high-dose interferon that would be different from the high-dose ipilimumab?

Antoni Ribas, MD, PhD: High-dose interferon will give toxicities in the majority of patients. It’s given intravenously for 5 days on, 2 days off for 1 month. And during that period of time, the majority of patients have fevers, chills, and malaise. Many times, treatment needs to be stopped because of pancytopenia or elevation of a liver function test. Then, the patients would continue with getting dosing subcutaneously 3 times a week for 1 year. Where the patients with continued dosing have a sensation of being really tired most of the time. At with time, they can develop depression, something that’s not only because they’re on treatment and they had melanoma surgery, but because interferon often can induce depression. It has been something that’s well recognized.

With high-dose ipilimumab, the majority of patients will have no adverse side effects. We forget about these when we talk about high-dose ipilimumab because all of us are worried about the ones who have side effects. And the ones who have side effects can have colitis that can be severe and that can be difficult to manage. We’re talking, with a first case, about treating with high doses of corticosteroids, not being able to taper rapidly, which becomes a bigger problem in patients where some of them may be cured from the surgery, and now we’ve induced toxicity and we have to deal with that toxicity. Some patients may develop hypophysitis, and may then require substitution therapy for life and having to watch their lifestyle because, at some point, their body would not react to that. That may be a problem. Thyroiditis and other “itis" can be seen with ipilimumab. So, those are things that come into big consideration in this case.

The other therapy that would be approved in the United States is pegylated interferon, which the side effects are similar to high-dose interferon. The data does support using it. There’s no overall survival advantage in the randomized trials. In patients with an ulcerated primary, there’s a hint that maybe pegylated interferon may have more activity, but that doesn’t mean that high-dose interferon would not.

Robert H.I. Andtbacka, MD, CM: Again, all of it really being on ad hoc analyses, not predefined analyses in this.

Antoni Ribas, MD, PhD: Yes.

Robert H.I. Andtbacka, MD, CM: So, with the EORTC 18071 trial—which just looked at high-dose ipilimumab, 10 mg/kg versus the placebo—that showed an improvement in recurrence-free survival and also, recently, in overall survival. I think it is important for us to recognize, though, that in this adjuvant study, there were 5 patients on the high-dose ipilimumab arm that actually died. I think it’s also important to recognize that many of these patients, as you indicated, may have been cured with surgery alone. So, I think that’s a very important discussion for us to have.

Antoni Ribas, MD, PhD: Absolutely.

Robert H.I. Andtbacka, MD, CM: Now, Tony, the other thing we’re also seeing in the community, we know that the approved dose that we use for patients with metastatic disease, oligometastatic disease, with ipilimumab is 3 mg/kg. And yet, the approved dose in the adjuvant setting is 10 mg/kg, and there definitely is more toxicity with that. In the community, we are seeing patients being treated with 3 mg/kg with really no data at all to support that. What is your take on this? I know there are some clinical trials that we have conducted that will look at this, but, at the moment, what is your take on this?

Antoni Ribas, MD, PhD: It’s a difficult question. I find myself tongue tied more than once whenever I’m talking to patients about the ipilimumab dose in the more serious condition, in metastatic disease. It’s one-third lower than in the adjuvant setting where some patients may be cured, but we would be more careful about side effects. The data so far suggest that there’s a dose response effect with ipilimumab. There was a presentation at this year’s ESMO meeting of ipilimumab at 3 mg/kg versus 10 mg/kg in patients with metastatic disease, showing that there’s improved outcomes on patients with 10 mg/kg versus 3 mg/kg. So, if we think about the therapeutic effect, it may be more beneficial to be on the high dose, on the 10 mg/kg. The problem is that it also brings a lot more toxicities, and we have to consider that. But, the data of adjuvant ipilimumab is with the 10 mg/kg, and we haven’t changed that. That’s a trial that took several years of planning, conduct, and readout, and we cannot change it right now. And my standard is giving the 10 mg/kg dose and hoping that the patient will tolerate it. The 3 mg/kg is being tested prospectively in the ECOG E1609 trial, which has 3 arms: high-dose interferon, ipilimumab at 10 mg/kg, or ipilimumab at 3 mg/kg. And that study, we hope will read out in the next year or so. Then, we’ll be able to see if it’s enough benefit in the adjuvant setting to be on the 10 mg/kg versus the 3 mg/kg and what are the differences in toxicities.

Transcript Edited for Clarity
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