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Continuing Anti PD-1 Therapy Beyond RECIST Progression

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: Friday, Sep 07, 2018


Transcript:
Jeffrey S. Weber, MD, PhD: Omid, there is a very interesting report. I believe it was actually an FDA report from a number of investigators at the FDA. They have the capacity to take data from multiple large randomized studies. Essentially, they have a meta-analysis, which wouldn’t be possible any other way. You or I, or a pharmaceutical company, would not have access to other companies’ data, but the FDA does. And, with permission, they can do a meta-analysis. For example, there’s a recent article in Lancet Oncology that looked at what happens when you continue PD-1 blockade beyond RECIST progression. Is that something that you would routinely do? Do you think the data would change practice?

Omid Hamid, MD: Well, there’s been some data reported that demonstrate that there are responses after RECIST progression. It’s not a significant proportion. It’s about 4% of all-comers. But it is something that I may do if there aren’t other options or if it’s a first look. Again, with PD-1 therapy, I don’t expect to see the late responses in the magnitude of what we’ve seen with anti–CTLA-4 therapy. In the metastatic setting, we’ve seen that patients who respond or have stable disease after multiple doses can get to a partial or complete response. It depends on how that patient has progressed, what options are available, and how early the look is. If there’s progression on 2 imaging time points, then I would switch and look for something else. I think it’s important to bring that forward, because I have seen patients who have been referred, who have continued on and are slow progressors. We have options that have a survival advantage. I’ve also seen patients who have been taken off too early.

Robert Andtbacka, MD, CM: Do you mind if I ask a question?

Jeffrey S. Weber, MD, PhD: No, go ahead.

Robert Andtbacka, MD, CM: How do you decide this? When is that progression? Is it at 12 weeks, 24 weeks, or 36 weeks?

Jeffrey S. Weber, MD, PhD: Michael, how do you decide who you’re going to treat beyond RECIST progression? What qualities do you consider? Are there 3 additional Rs that you look for?

Michael A. Postow, MD: Not yet. One group I would think about would be patients who have some degree of benefit, yet technically would have been considered for RECIST progression. If you have some lesions at baseline that are starting to shrink, but maybe there’s a new little lesion, I would continue that patient because there seems like there’s something that’s going on that might be beneficial. A lot of the patients for whom we say have responded after progression have progressed with a new lesion, but their index lesions were still shrinking from baseline.

Jeffrey S. Weber, MD, PhD: I have 3 proposed Rs. You want to see a patient who had some regression, not 0% regression. You want to see a patient with a mixed response, perhaps. And then, you want to see a patient with regularization of labs and without significant toxicity. So, there are your 3 Rs.

Michael A. Postow, MD: I love it.

Jeffrey S. Weber, MD, PhD: Jason?

Jason J. Luke, MD, FACP: For me, it’s what’s going on with the patient, right? My patients love this. When I go in the room, I say, “How are you doing?” They always think it’s just an icebreaker, but, in fact, I am asking them, “How are you doing?” That can really make a big difference. Especially when you talk about patients who are getting diagnosed earlier, they have less disease seemingly now than they used to. A lot of these people are well. So, are they still well? If they’re still well, then I’m willing to kind of continue for a little longer, but not for too long. The other thing that we see is that people do get this drug out for way too long.

Omid Hamid, MD: If you came in and you said, “How are you doing,” and they said, “I’m alright, I’m remarkably better,” and that would be another R, then you can feel comfort in going there. Obviously, we do have options on progression, but even with the best options, those response rates are low. You would hate to throw that away or introduce more toxicity.

Michael A. Postow, MD: One other R that we have to be a little careful of is too much reassurance. In patients who are clearly progressing, I think there’s a real sense that’s out there, and a lot of hope, of, “I have heard that immunotherapy takes a long time to respond. Maybe I’m going to be fine with just staying on this.” Unfortunately, most of the patients who have every lesion growing or new things growing after several months, at least of PD-1, unfortunately will continue to progress. I think we have to be careful about too much reassurance, and we need to be thinking, in our heads, “What is my backup plan?” Even if you keep going for a bit more time, I think you have to be ready. “What am I going to do if we need to switch?” Most people will probably need to switch at some point.


Transcript Edited for Clarity
 
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Transcript:
Jeffrey S. Weber, MD, PhD: Omid, there is a very interesting report. I believe it was actually an FDA report from a number of investigators at the FDA. They have the capacity to take data from multiple large randomized studies. Essentially, they have a meta-analysis, which wouldn’t be possible any other way. You or I, or a pharmaceutical company, would not have access to other companies’ data, but the FDA does. And, with permission, they can do a meta-analysis. For example, there’s a recent article in Lancet Oncology that looked at what happens when you continue PD-1 blockade beyond RECIST progression. Is that something that you would routinely do? Do you think the data would change practice?

Omid Hamid, MD: Well, there’s been some data reported that demonstrate that there are responses after RECIST progression. It’s not a significant proportion. It’s about 4% of all-comers. But it is something that I may do if there aren’t other options or if it’s a first look. Again, with PD-1 therapy, I don’t expect to see the late responses in the magnitude of what we’ve seen with anti–CTLA-4 therapy. In the metastatic setting, we’ve seen that patients who respond or have stable disease after multiple doses can get to a partial or complete response. It depends on how that patient has progressed, what options are available, and how early the look is. If there’s progression on 2 imaging time points, then I would switch and look for something else. I think it’s important to bring that forward, because I have seen patients who have been referred, who have continued on and are slow progressors. We have options that have a survival advantage. I’ve also seen patients who have been taken off too early.

Robert Andtbacka, MD, CM: Do you mind if I ask a question?

Jeffrey S. Weber, MD, PhD: No, go ahead.

Robert Andtbacka, MD, CM: How do you decide this? When is that progression? Is it at 12 weeks, 24 weeks, or 36 weeks?

Jeffrey S. Weber, MD, PhD: Michael, how do you decide who you’re going to treat beyond RECIST progression? What qualities do you consider? Are there 3 additional Rs that you look for?

Michael A. Postow, MD: Not yet. One group I would think about would be patients who have some degree of benefit, yet technically would have been considered for RECIST progression. If you have some lesions at baseline that are starting to shrink, but maybe there’s a new little lesion, I would continue that patient because there seems like there’s something that’s going on that might be beneficial. A lot of the patients for whom we say have responded after progression have progressed with a new lesion, but their index lesions were still shrinking from baseline.

Jeffrey S. Weber, MD, PhD: I have 3 proposed Rs. You want to see a patient who had some regression, not 0% regression. You want to see a patient with a mixed response, perhaps. And then, you want to see a patient with regularization of labs and without significant toxicity. So, there are your 3 Rs.

Michael A. Postow, MD: I love it.

Jeffrey S. Weber, MD, PhD: Jason?

Jason J. Luke, MD, FACP: For me, it’s what’s going on with the patient, right? My patients love this. When I go in the room, I say, “How are you doing?” They always think it’s just an icebreaker, but, in fact, I am asking them, “How are you doing?” That can really make a big difference. Especially when you talk about patients who are getting diagnosed earlier, they have less disease seemingly now than they used to. A lot of these people are well. So, are they still well? If they’re still well, then I’m willing to kind of continue for a little longer, but not for too long. The other thing that we see is that people do get this drug out for way too long.

Omid Hamid, MD: If you came in and you said, “How are you doing,” and they said, “I’m alright, I’m remarkably better,” and that would be another R, then you can feel comfort in going there. Obviously, we do have options on progression, but even with the best options, those response rates are low. You would hate to throw that away or introduce more toxicity.

Michael A. Postow, MD: One other R that we have to be a little careful of is too much reassurance. In patients who are clearly progressing, I think there’s a real sense that’s out there, and a lot of hope, of, “I have heard that immunotherapy takes a long time to respond. Maybe I’m going to be fine with just staying on this.” Unfortunately, most of the patients who have every lesion growing or new things growing after several months, at least of PD-1, unfortunately will continue to progress. I think we have to be careful about too much reassurance, and we need to be thinking, in our heads, “What is my backup plan?” Even if you keep going for a bit more time, I think you have to be ready. “What am I going to do if we need to switch?” Most people will probably need to switch at some point.


Transcript Edited for Clarity
 
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