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Anti PD-1 Therapy in Metastatic Melanoma

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: Monday, Aug 27, 2018



Transcript: 

Jeffrey S. Weber, MD, PhD: Michael, no one would probably know better than you. How do you decide the usual conundrum: combination therapy versus single-agent PD-1 blockade?

Michael A. Postow, MD: I’ll give you a hypothetical example. A patient has a BRAF wild-type tumor, has metastatic disease, and has had no prior adjuvant therapy. Do we go with the PD-1 single agent or ipilimumab/nivolumab? That’s a tough decision. From the CheckMate-067 study, I think that we learned that at 3 years, the survival looks relatively similar. There’s a higher number compared to the nivolumab-alone arm in that study. That was not statistically significant, so you can’t really hang your hat on that as a reason to give patients combination therapy. I definitely do not think combination therapy is appropriate for all patients.

What do I use to make a decision in the clinic? We do know that the combination has a response rate that’s about 14%, 15% higher than single-agent PD-1. Is that important? In some patients, I think it is. If they have a tumor that I think is going to cause a problem if it doesn’t respond, I’m more likely to give that patient the combination regimen. If they’re sick with a pleural effusion, if they have a tumor in the bones that is getting close to the spinal cord and it’s not something you can irradiate, if there’s a tumor that’s about to cause a problem if it doesn’t respond, or if their whole tumor burden is such that it’s going to cause a problem if it doesn’t respond to that first-line systemic treatment, that’s a patient I’ll think more about using combination immunotherapy in. I came up with this kind of cheesy mnemonic, 3 Rs, for who I choose for PD-1 plus ipilimumab.

Jeffrey S. Weber, MD, PhD: The 3 Rs?

Michael A. Postow, MD: Yes. Response: If someone doesn’t respond, it’s going to be a problem. In those patients, I go with the combination. The second R is resilient, meaning I want to make sure that if they have a toxicity, this patient will be resilient enough from another medical comorbidity standpoint or other kind of family support scenario to handle the toxicities that could ensue with ipilimumab/nivolumab. And then, the third thing is reliability. I want to make sure that these patients are reliable. If you’re having toxicities with ipilimumab/nivolumab, it’s really important to communicate with your treatment team. Call if you’re having issues. Follow instructions on prednisone tapers. Follow instructions to come into the clinic to get infliximab. A lot of those issues are intangible. In many cases, I think this is more important in making a decision of combination therapy versus the single-agent option versus splicing through all of the numbers, PD-L1, and all of this kind of stuff you can try to rationalize in your head. The science is not that clear that you should do this or you should do that, in my opinion. In many cases, of course, brain metastases would favor ipilimumab/nivolumab. A lot of patients don’t fit into that “Must do ipilimumab/nivolumab” or “Must do PD-1” category. And so, it’s this clinical gestalt that you have to go with.

Jeffrey S. Weber, MD, PhD: So, in the nation’s No. 1-ranked cancer center, in the year 2018, we’re still using seat-of-the-pants assessment? I’m not criticizing it. I’m saying that I agree with you. But I think this is one of the ironies of our field; that in this era, at that place and in many other places, we’re still using seat-of-the-pants assessment to decide what to treat patients with.

Michael A. Postow, MD: We need better biomarkers. I think that’s the bottom line. In patients without brain metastases, who have these good characteristics, you could make a rationale for going either way. Once you start that discussion with the patient, a lot of it is in trying to get a sense of what’s important for them—what their family and support structure looks like. I think that’s very important for successful treatment with ipilimumab/nivolumab. You could kind of make a decision before you see a patient as to what may be best from chart review, scans, and these kinds of thing. But you walk into the room and you get a whole different sense. I find that the interaction is what makes the difference, one way or the other. We can think, in our head, that there’s some science or clinical data that really make the decision, but it’s a gut check, in the end, between you and the patient.

Jeffrey S. Weber, MD, PhD: Are we still using a gut check on this side of the room?

Jason J. Luke, MD, FACP: I really love these 3 Rs. More simply than that, I’ve been using a very similar algorithm, actually, from the very beginning with ipilimumab/nivolumab. My default, and it’s biased, is to give monotherapy. But that’s due to the toxicity. My question really is, who needs it? Then it becomes a high LDH, bone metastases, brain metastases, and these social issues surrounding this. Could we do more harm than good by giving the combination?

Transcript Edited for Clarity 

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Transcript: 

Jeffrey S. Weber, MD, PhD: Michael, no one would probably know better than you. How do you decide the usual conundrum: combination therapy versus single-agent PD-1 blockade?

Michael A. Postow, MD: I’ll give you a hypothetical example. A patient has a BRAF wild-type tumor, has metastatic disease, and has had no prior adjuvant therapy. Do we go with the PD-1 single agent or ipilimumab/nivolumab? That’s a tough decision. From the CheckMate-067 study, I think that we learned that at 3 years, the survival looks relatively similar. There’s a higher number compared to the nivolumab-alone arm in that study. That was not statistically significant, so you can’t really hang your hat on that as a reason to give patients combination therapy. I definitely do not think combination therapy is appropriate for all patients.

What do I use to make a decision in the clinic? We do know that the combination has a response rate that’s about 14%, 15% higher than single-agent PD-1. Is that important? In some patients, I think it is. If they have a tumor that I think is going to cause a problem if it doesn’t respond, I’m more likely to give that patient the combination regimen. If they’re sick with a pleural effusion, if they have a tumor in the bones that is getting close to the spinal cord and it’s not something you can irradiate, if there’s a tumor that’s about to cause a problem if it doesn’t respond, or if their whole tumor burden is such that it’s going to cause a problem if it doesn’t respond to that first-line systemic treatment, that’s a patient I’ll think more about using combination immunotherapy in. I came up with this kind of cheesy mnemonic, 3 Rs, for who I choose for PD-1 plus ipilimumab.

Jeffrey S. Weber, MD, PhD: The 3 Rs?

Michael A. Postow, MD: Yes. Response: If someone doesn’t respond, it’s going to be a problem. In those patients, I go with the combination. The second R is resilient, meaning I want to make sure that if they have a toxicity, this patient will be resilient enough from another medical comorbidity standpoint or other kind of family support scenario to handle the toxicities that could ensue with ipilimumab/nivolumab. And then, the third thing is reliability. I want to make sure that these patients are reliable. If you’re having toxicities with ipilimumab/nivolumab, it’s really important to communicate with your treatment team. Call if you’re having issues. Follow instructions on prednisone tapers. Follow instructions to come into the clinic to get infliximab. A lot of those issues are intangible. In many cases, I think this is more important in making a decision of combination therapy versus the single-agent option versus splicing through all of the numbers, PD-L1, and all of this kind of stuff you can try to rationalize in your head. The science is not that clear that you should do this or you should do that, in my opinion. In many cases, of course, brain metastases would favor ipilimumab/nivolumab. A lot of patients don’t fit into that “Must do ipilimumab/nivolumab” or “Must do PD-1” category. And so, it’s this clinical gestalt that you have to go with.

Jeffrey S. Weber, MD, PhD: So, in the nation’s No. 1-ranked cancer center, in the year 2018, we’re still using seat-of-the-pants assessment? I’m not criticizing it. I’m saying that I agree with you. But I think this is one of the ironies of our field; that in this era, at that place and in many other places, we’re still using seat-of-the-pants assessment to decide what to treat patients with.

Michael A. Postow, MD: We need better biomarkers. I think that’s the bottom line. In patients without brain metastases, who have these good characteristics, you could make a rationale for going either way. Once you start that discussion with the patient, a lot of it is in trying to get a sense of what’s important for them—what their family and support structure looks like. I think that’s very important for successful treatment with ipilimumab/nivolumab. You could kind of make a decision before you see a patient as to what may be best from chart review, scans, and these kinds of thing. But you walk into the room and you get a whole different sense. I find that the interaction is what makes the difference, one way or the other. We can think, in our head, that there’s some science or clinical data that really make the decision, but it’s a gut check, in the end, between you and the patient.

Jeffrey S. Weber, MD, PhD: Are we still using a gut check on this side of the room?

Jason J. Luke, MD, FACP: I really love these 3 Rs. More simply than that, I’ve been using a very similar algorithm, actually, from the very beginning with ipilimumab/nivolumab. My default, and it’s biased, is to give monotherapy. But that’s due to the toxicity. My question really is, who needs it? Then it becomes a high LDH, bone metastases, brain metastases, and these social issues surrounding this. Could we do more harm than good by giving the combination?

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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