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Pseudoprogression on Immunotherapy in Squamous NSCLC

Panelists: Mark A. Socinski, MD, Florida Hospital Cancer Institute; Tracey L. Evans, MD, University of Pennsylvania; David M. Jackman, MD, Dana-Farber Cancer Institute; Edward S. Kim, MD, Levine Cancer Institute; Jared Weiss, MD, UNC Lineberger Comprehensive Cancer Center
Published: Tuesday, Mar 07, 2017



Transcript:

Mark Socinski, MD:
So, this is a question that also comes up commonly in my world from community doctors, this whole issue of pseudoprogression. We haven’t talked about that. I don’t believe that it happens that frequently in lung cancer. I recently spoke to a couple of doctors 1 to 2 days ago, and what they said is that they believe in immunotherapy. They said, “We’re hanging on with these people that look worse, but we hear a lot about this pseudoprogression. How long should we hang on?”

Jared Weiss, MD: I’ve seen some disturbing cases in my consultation practice around this. So this, you brought up duration of response rate.

Mark Socinski, MD: Duration of therapy.

Jared Weiss, MD: Duration of therapy, right. There were people on the phase I trial of ipilimumab in melanoma that came off, were put them on hospice, and they’re still alive and thriving today. They’ve gotten 1 to 2 doses. That illustrates both the pseudoprogression issue in melanoma as well as the duration of therapy issue you were raising. So, this whole idea is that, certainly, in melanoma, I’ve seen patients that the cancer seems to be growing perhaps due to immune infiltration, and then later, wonderful things happen. How does this translate to lung cancer if you count patients in the spider plot? I actually queried the major companies to try to do a pulled analysis of this and no one gave me data. But when you go counting one-by-one the spider plots in the major published studies, it’s very hard to actually find clear pseudoprogressors in lung cancer that are seen for head and neck. It’s probably maybe 5% of apparent progression than a pseudoprogression.

What I’m seeing in my consultative practice is that we’ve gone back to decades ago where no one believed progression exists, right? Because, you’re holding on to a drug; and this is hurting people, right? People get sicker as you watch them progress, it’s a big problem. So, I think the lesson in lung cancer is that if you see what appears to be progressive disease, unless the patient is feeling much, much better and there’s nothing scary about it. Everything lines up, it’s not central disease, it’s not rapidly growing, the patient says they feel better, all the stars align, okay, then you can go another cycle or 2 and try. But if everything isn’t perfectly aligned, I think the right thing to do in clinical practice is rather simple: stop and move on to the next line of therapy.

Tracey L. Evans, MD: But this is a concept that has reached the patients and they want to stick with the treatment.

Jared Weiss, MD: They want durable control, so do we.

Tracey L. Evans, MD: They’re feeling this is the miracle that they wanted and it’s not working. And in a second-line setting, I was a little bit more willing to go along with it because getting them to the next line of cytotoxic chemotherapy wasn’t great either. But in the first-line, it’s really doing patients a disservice if you allow them to progress on their immunotherapy and you don’t get them to that first-line chemotherapy.

Edward S. Kim, MD: I always thought it was very biased, and this will take us back 15 years, when investigators would report minor responses, right? Because, you used RECIST (Response Evaluation Criteria in Solid Tumors) and it’s got to be 30%. If it doesn’t have 30%, then it’s a minor response. Now we call it disease control or stable disease. There were never minor progressions.

Mark Socinski, MD: Well, there were, but…

Edward S. Kim, MD: Right, but nobody ever talked about that, and I tell them it’s between less than 30% and to 20%. So, 19% to 29% is stable disease, and you might have a radiology report. I think this is where it really gets people confused, it says “progression” on a scan. The community general oncologist who pulls that up will say, “Oh, it’s progression.” And I totally agree. It’s the patient. If they’re feeling better, or not worse, I really put less value on that scan regardless of what therapy they’re on. They could be on cytotoxic chemotherapy, they could be on an EGFR drug, or immunotherapy. And I agree, everyone made a big deal about pseudoprogression, and whoever published the first case report got some press about that.

Jared Weiss, MD: Sure, changing the rules always makes more press than saying, “Wait, the rules are the same.”

Edward S. Kim, MD: That’s right, but I’ve never seen it. I don’t think any of my colleagues have seen it – maybe there was one case among us. It does exist, but I don’t think we would be able to put them out on the table here and get a big collection.

David M. Jackman, MD: Yes, and I think we need to remind ourselves that we can’t draw lines across diseases as easily as we’d like to. I think you mentioned that it’s gotten to the patients, they’ve heard from the melanoma world that this is real. And this is not just for immunotherapy, this holds for all the targeted therapies, too—experience with BRAF in melanoma versus colon cancer. This is very different. And so, we have to make sure we don’t fool ourselves into thinking that every time we find a miracle, it’s going to be a miracle for everybody that shares those characteristics.

Transcript Edited for Clarity

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Transcript:

Mark Socinski, MD:
So, this is a question that also comes up commonly in my world from community doctors, this whole issue of pseudoprogression. We haven’t talked about that. I don’t believe that it happens that frequently in lung cancer. I recently spoke to a couple of doctors 1 to 2 days ago, and what they said is that they believe in immunotherapy. They said, “We’re hanging on with these people that look worse, but we hear a lot about this pseudoprogression. How long should we hang on?”

Jared Weiss, MD: I’ve seen some disturbing cases in my consultation practice around this. So this, you brought up duration of response rate.

Mark Socinski, MD: Duration of therapy.

Jared Weiss, MD: Duration of therapy, right. There were people on the phase I trial of ipilimumab in melanoma that came off, were put them on hospice, and they’re still alive and thriving today. They’ve gotten 1 to 2 doses. That illustrates both the pseudoprogression issue in melanoma as well as the duration of therapy issue you were raising. So, this whole idea is that, certainly, in melanoma, I’ve seen patients that the cancer seems to be growing perhaps due to immune infiltration, and then later, wonderful things happen. How does this translate to lung cancer if you count patients in the spider plot? I actually queried the major companies to try to do a pulled analysis of this and no one gave me data. But when you go counting one-by-one the spider plots in the major published studies, it’s very hard to actually find clear pseudoprogressors in lung cancer that are seen for head and neck. It’s probably maybe 5% of apparent progression than a pseudoprogression.

What I’m seeing in my consultative practice is that we’ve gone back to decades ago where no one believed progression exists, right? Because, you’re holding on to a drug; and this is hurting people, right? People get sicker as you watch them progress, it’s a big problem. So, I think the lesson in lung cancer is that if you see what appears to be progressive disease, unless the patient is feeling much, much better and there’s nothing scary about it. Everything lines up, it’s not central disease, it’s not rapidly growing, the patient says they feel better, all the stars align, okay, then you can go another cycle or 2 and try. But if everything isn’t perfectly aligned, I think the right thing to do in clinical practice is rather simple: stop and move on to the next line of therapy.

Tracey L. Evans, MD: But this is a concept that has reached the patients and they want to stick with the treatment.

Jared Weiss, MD: They want durable control, so do we.

Tracey L. Evans, MD: They’re feeling this is the miracle that they wanted and it’s not working. And in a second-line setting, I was a little bit more willing to go along with it because getting them to the next line of cytotoxic chemotherapy wasn’t great either. But in the first-line, it’s really doing patients a disservice if you allow them to progress on their immunotherapy and you don’t get them to that first-line chemotherapy.

Edward S. Kim, MD: I always thought it was very biased, and this will take us back 15 years, when investigators would report minor responses, right? Because, you used RECIST (Response Evaluation Criteria in Solid Tumors) and it’s got to be 30%. If it doesn’t have 30%, then it’s a minor response. Now we call it disease control or stable disease. There were never minor progressions.

Mark Socinski, MD: Well, there were, but…

Edward S. Kim, MD: Right, but nobody ever talked about that, and I tell them it’s between less than 30% and to 20%. So, 19% to 29% is stable disease, and you might have a radiology report. I think this is where it really gets people confused, it says “progression” on a scan. The community general oncologist who pulls that up will say, “Oh, it’s progression.” And I totally agree. It’s the patient. If they’re feeling better, or not worse, I really put less value on that scan regardless of what therapy they’re on. They could be on cytotoxic chemotherapy, they could be on an EGFR drug, or immunotherapy. And I agree, everyone made a big deal about pseudoprogression, and whoever published the first case report got some press about that.

Jared Weiss, MD: Sure, changing the rules always makes more press than saying, “Wait, the rules are the same.”

Edward S. Kim, MD: That’s right, but I’ve never seen it. I don’t think any of my colleagues have seen it – maybe there was one case among us. It does exist, but I don’t think we would be able to put them out on the table here and get a big collection.

David M. Jackman, MD: Yes, and I think we need to remind ourselves that we can’t draw lines across diseases as easily as we’d like to. I think you mentioned that it’s gotten to the patients, they’ve heard from the melanoma world that this is real. And this is not just for immunotherapy, this holds for all the targeted therapies, too—experience with BRAF in melanoma versus colon cancer. This is very different. And so, we have to make sure we don’t fool ourselves into thinking that every time we find a miracle, it’s going to be a miracle for everybody that shares those characteristics.

Transcript Edited for Clarity
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