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Anti-PD-1 Adjuvant Therapy in Melanoma

Panelists: Axel Hauschild, MD, University Hospital Schleswig-Holstein; Michael A. Davies, MD, PhD UT MD Anderson Cancer Center; Jason J. Luke, MD, FACP, University of Chicago; Caroline Robert, MD, PhD Gustave-Roussy; Merrick I. Ross, MD UT MD Anderson Cancer Center
Published: Thursday, Dec 06, 2018



Transcript:

Axel Hauschild, MD: There’s also competition in the field. Two other treatments have been approved, at least in the United States. The approval for pembrolizumab in Europe is expected to happen over the next few weeks because of the positive CALGB [Cancer and Leukemia Broup B] opinion that is already out there for the drug. Likewise, nivolumab is approved in Europe. So we have the choice of either targeted therapies or PD-1 [programmed cell death protein 1]–driven therapies. But what are your impressions based on CheckMate 238? The data were presented for the first time a year ago at the ESMO [European Society for Medical Oncology] congress in Madrid. Do you see any differences versus KEYNOTE-054 on pembrolizumab, which has been presented on this year? Are there any differences between the PD-1 antibodies? What is your first choice for BRAF-mutated patients.

Michael A. Davies, MD, PhD: The design of the 2 studies was quite different. The Checkmate 238 study compared adjuvant nivolumab for a year versus adjuvant ipilimumab. And so, this had a control arm of an active therapy. The KEYNOTE-054 study compared adjuvant pembrolizumab versus placebo. And so, we have a different comparator. The second difference is that the Checkmate 238 study didn’t include patients with stage IIIa disease. This looked at stage IIIb, stage IIIc, and stage IV NED [no evidence of disease] patients. KEYNOTE-054 did include stage IIIa patients who had at least 1 millimeter of lymph node burden, as well as stage IIIb and stage IIIc patients. But it did not look at stage IV disease.

So again, there was a difference in the designs of the trials, both in terms of the patient populations and the comparators. Both trials showed that adjuvant PD-1 therapy is very safe and very effective. CheckMate 238 immediately replaced adjuvant ipilimumab as a therapy option with adjuvant PD-1. Again, we use it quite routinely in the United States. We do not use adjuvant pembrolizumab. This is not approved at this point in the United States, but probably will be in the near future.

Axel Hauschild, MD: Adjuvant ipilimumab as high-dose treatment for 3 years was never approved in Europe. It was not even submitted to the agencies. Therefore, it’s not an option in Europe, just to clarify the difference between the therapies in the United States and Europe at this point in time.

Jason J. Luke, MD, FACP: Another wrinkle to throw in there is the supplemental biologics license agreement that Bristol-Myers Squibb put in place around the dosing schedule of nivolumab. This was slightly different. In the study, they gave nivolumab every 2 weeks. Now we can give it every 4 weeks. I think that actually has some impact on which option gets used in clinical practice. Pembrolizumab is given every 3 weeks. Some of these practical issues with targeted therapy and immunotherapy start to become pressing for patients. When you’re engaging a patient, what do they want to do, in terms of what’s most convenient and has the best effects on their quality of life?

Axel Hauschild, MD: The observation period between the 2 trials of the PD-1 antibodies is different. There is a long observation for nivolumab compared to pembrolizumab, which was released very early in the New England Journal of Medicine. Do you see any differences or do you envision any differences in the activity and toxicity of these drugs?

Jason J. Luke, MD, FACP: I don’t see any big differences between these drugs. The minor differences that we see around hazard ratios are the usual variants that you’re going to get within a clinical trial, also taking into account that the populations were very slightly different. I think that may make a difference. I think we can consider using PD-1 antibodies as a standard of care either way.

Michael A. Davies, MD, PhD: The other challenge when comparing the hazard ratios is that they were compared to different controls. That really makes it virtually impossible to compare the hazard ratios. One of the things that we’re waiting to see is the overall survival data from these studies. The powerful thing with the COMBI-AD trial is that we have been able to see overall survival data. Again, knowing that dabrafenib/trametinib can extend survival in patients who develop stage IV disease is a really important result. Its use in the adjuvant setting appears to be impacting long-term overall survival. That’s one of the key questions we still have to address with the use of adjuvant PD-1 therapy: to actually see overall survival data.

Axel Hauschild, MD: You mentioned a very important point. These have different study designs. B Olivier Michielin from Luzern, Switzerland, was doing this. He estimated this with a very simple mathematic model, which was also done in Germany. The hazard ratio for nivolumab compared to placebo. This was nivolumab compared to high-dose ipilimumab, and there was the EORTC [European Organisation for Research and Treatment of Cancer] study comparing high-dose ipilimumab to placebo. It’s very simple. You simply need to multiply the hazard ratios, which comes to 0.49. So it’s very much the same.

Merrick I. Ross, MD: It’s the same as pembrolizumab.

Axel Hauschild, MD: It’s the same range. Therefore, we don’t expect to see a difference. In stage IV disease, there is no difference. As you mentioned, the scheme is different, but there are no obvious differences in efficacy and tolerability.

Merrick I. Ross, MD: The NCCN [National Comprehensive Cancer Network] guidelines, which will be coming out very shortly in the United States, suggest that you can use pembrolizumab or durvalumab in the adjuvant setting. Even though pembrolizumab is not approved yet, it certainly will be.

Axel Hauschild, MD: It makes sense.

Michael A. Davies, MD, PhD: Merrick, maybe you can address this. Even the trials that included stage IIIa patients required at least 1 millimeter of tumor burden in the lymph node.

Merrick I. Ross, MD: The interesting thing is that the FDA approved both of these approaches, whether targeted therapy or immunotherapy, for any node-positive disease. It does not suggest that you have to have 1 millimeter of tumor, which is kind of interesting, because the trials were set up by stage but the approvals are based on node positivity, globally. So it’s interesting to see how the practices are going to be affected by the approvals. We certainly have to discuss risk-benefit ratios for adjuvant therapy. Even though these therapies are tolerated relatively well compared to previous adjuvant therapies, they’re not candy. There are long-term side effects that can be very serious.

Jason J. Luke, MD, FACP: This becomes a big issue because we’ve split out stage IIIa patients, who are now substantially less likely to have recurrence. And so, the same issue comes up in our practice. If someone comes in with a miniscule amount of tumor, they’re called to be node-positive. They really have a 10% risk of relapse. You’re going to offer them a therapy that may have an upside absolute benefit of 5%, and you look at the toxicity profile and you’ve got a 5% chance of doing something severely bad. That’s the kind of patient situation for which we have to pause and discuss things with them.

Axel Hauschild, MD: In due time, we will have at least 2, if not 3, adjuvant trials for stage IIb and stage IIc patients. We are even going lower in the threshold of treating patients in the adjuvant setting, at least in the clinical trials.

Merrick I. Ross, MD: But that’s completely appropriate. The stage IIc patients do worse than the stage IIIa patients. I think that’s driven by ulceration, which is a very important prognostic marker.

Jason J. Luke, MD, FACP: When we were designing KEYNOTE-716, which is the stage II pembrolizumab study, one of the things that we took into account was the discussion around the changing biology and anatomy. As we treat patients, they’re going to have a local or regional relapse. What does that mean? How does that impact our paradigm for whether or not we continue with therapy or change therapy? I think the study was smartly designed to capture that, so that we treat patients up front, readdress regional relapse, and address the question of using PD-1 therapy now or later. Over time, we can actually start to learn what this new biology of melanoma recurrence looks like.

Transcript Edited for Clarity

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Transcript:

Axel Hauschild, MD: There’s also competition in the field. Two other treatments have been approved, at least in the United States. The approval for pembrolizumab in Europe is expected to happen over the next few weeks because of the positive CALGB [Cancer and Leukemia Broup B] opinion that is already out there for the drug. Likewise, nivolumab is approved in Europe. So we have the choice of either targeted therapies or PD-1 [programmed cell death protein 1]–driven therapies. But what are your impressions based on CheckMate 238? The data were presented for the first time a year ago at the ESMO [European Society for Medical Oncology] congress in Madrid. Do you see any differences versus KEYNOTE-054 on pembrolizumab, which has been presented on this year? Are there any differences between the PD-1 antibodies? What is your first choice for BRAF-mutated patients.

Michael A. Davies, MD, PhD: The design of the 2 studies was quite different. The Checkmate 238 study compared adjuvant nivolumab for a year versus adjuvant ipilimumab. And so, this had a control arm of an active therapy. The KEYNOTE-054 study compared adjuvant pembrolizumab versus placebo. And so, we have a different comparator. The second difference is that the Checkmate 238 study didn’t include patients with stage IIIa disease. This looked at stage IIIb, stage IIIc, and stage IV NED [no evidence of disease] patients. KEYNOTE-054 did include stage IIIa patients who had at least 1 millimeter of lymph node burden, as well as stage IIIb and stage IIIc patients. But it did not look at stage IV disease.

So again, there was a difference in the designs of the trials, both in terms of the patient populations and the comparators. Both trials showed that adjuvant PD-1 therapy is very safe and very effective. CheckMate 238 immediately replaced adjuvant ipilimumab as a therapy option with adjuvant PD-1. Again, we use it quite routinely in the United States. We do not use adjuvant pembrolizumab. This is not approved at this point in the United States, but probably will be in the near future.

Axel Hauschild, MD: Adjuvant ipilimumab as high-dose treatment for 3 years was never approved in Europe. It was not even submitted to the agencies. Therefore, it’s not an option in Europe, just to clarify the difference between the therapies in the United States and Europe at this point in time.

Jason J. Luke, MD, FACP: Another wrinkle to throw in there is the supplemental biologics license agreement that Bristol-Myers Squibb put in place around the dosing schedule of nivolumab. This was slightly different. In the study, they gave nivolumab every 2 weeks. Now we can give it every 4 weeks. I think that actually has some impact on which option gets used in clinical practice. Pembrolizumab is given every 3 weeks. Some of these practical issues with targeted therapy and immunotherapy start to become pressing for patients. When you’re engaging a patient, what do they want to do, in terms of what’s most convenient and has the best effects on their quality of life?

Axel Hauschild, MD: The observation period between the 2 trials of the PD-1 antibodies is different. There is a long observation for nivolumab compared to pembrolizumab, which was released very early in the New England Journal of Medicine. Do you see any differences or do you envision any differences in the activity and toxicity of these drugs?

Jason J. Luke, MD, FACP: I don’t see any big differences between these drugs. The minor differences that we see around hazard ratios are the usual variants that you’re going to get within a clinical trial, also taking into account that the populations were very slightly different. I think that may make a difference. I think we can consider using PD-1 antibodies as a standard of care either way.

Michael A. Davies, MD, PhD: The other challenge when comparing the hazard ratios is that they were compared to different controls. That really makes it virtually impossible to compare the hazard ratios. One of the things that we’re waiting to see is the overall survival data from these studies. The powerful thing with the COMBI-AD trial is that we have been able to see overall survival data. Again, knowing that dabrafenib/trametinib can extend survival in patients who develop stage IV disease is a really important result. Its use in the adjuvant setting appears to be impacting long-term overall survival. That’s one of the key questions we still have to address with the use of adjuvant PD-1 therapy: to actually see overall survival data.

Axel Hauschild, MD: You mentioned a very important point. These have different study designs. B Olivier Michielin from Luzern, Switzerland, was doing this. He estimated this with a very simple mathematic model, which was also done in Germany. The hazard ratio for nivolumab compared to placebo. This was nivolumab compared to high-dose ipilimumab, and there was the EORTC [European Organisation for Research and Treatment of Cancer] study comparing high-dose ipilimumab to placebo. It’s very simple. You simply need to multiply the hazard ratios, which comes to 0.49. So it’s very much the same.

Merrick I. Ross, MD: It’s the same as pembrolizumab.

Axel Hauschild, MD: It’s the same range. Therefore, we don’t expect to see a difference. In stage IV disease, there is no difference. As you mentioned, the scheme is different, but there are no obvious differences in efficacy and tolerability.

Merrick I. Ross, MD: The NCCN [National Comprehensive Cancer Network] guidelines, which will be coming out very shortly in the United States, suggest that you can use pembrolizumab or durvalumab in the adjuvant setting. Even though pembrolizumab is not approved yet, it certainly will be.

Axel Hauschild, MD: It makes sense.

Michael A. Davies, MD, PhD: Merrick, maybe you can address this. Even the trials that included stage IIIa patients required at least 1 millimeter of tumor burden in the lymph node.

Merrick I. Ross, MD: The interesting thing is that the FDA approved both of these approaches, whether targeted therapy or immunotherapy, for any node-positive disease. It does not suggest that you have to have 1 millimeter of tumor, which is kind of interesting, because the trials were set up by stage but the approvals are based on node positivity, globally. So it’s interesting to see how the practices are going to be affected by the approvals. We certainly have to discuss risk-benefit ratios for adjuvant therapy. Even though these therapies are tolerated relatively well compared to previous adjuvant therapies, they’re not candy. There are long-term side effects that can be very serious.

Jason J. Luke, MD, FACP: This becomes a big issue because we’ve split out stage IIIa patients, who are now substantially less likely to have recurrence. And so, the same issue comes up in our practice. If someone comes in with a miniscule amount of tumor, they’re called to be node-positive. They really have a 10% risk of relapse. You’re going to offer them a therapy that may have an upside absolute benefit of 5%, and you look at the toxicity profile and you’ve got a 5% chance of doing something severely bad. That’s the kind of patient situation for which we have to pause and discuss things with them.

Axel Hauschild, MD: In due time, we will have at least 2, if not 3, adjuvant trials for stage IIb and stage IIc patients. We are even going lower in the threshold of treating patients in the adjuvant setting, at least in the clinical trials.

Merrick I. Ross, MD: But that’s completely appropriate. The stage IIc patients do worse than the stage IIIa patients. I think that’s driven by ulceration, which is a very important prognostic marker.

Jason J. Luke, MD, FACP: When we were designing KEYNOTE-716, which is the stage II pembrolizumab study, one of the things that we took into account was the discussion around the changing biology and anatomy. As we treat patients, they’re going to have a local or regional relapse. What does that mean? How does that impact our paradigm for whether or not we continue with therapy or change therapy? I think the study was smartly designed to capture that, so that we treat patients up front, readdress regional relapse, and address the question of using PD-1 therapy now or later. Over time, we can actually start to learn what this new biology of melanoma recurrence looks like.

Transcript Edited for Clarity
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