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Isolated Progression of NSCLC on Immunotherapy

Panelists: Everett Vokes, MD, University of Chicago Medicine and Biological Sciences; Roy Herbst, MD, PhD, Yale Cancer Center; Fred Hirsch, MD, PhD, University of Colorado School of Medicine; Suresh Ramalingam, MD, Winship Cancer Institute Emory University; Naiyer Rizvi, MD, Columbia University Medical Center
Published: Thursday, Sep 28, 2017



Transcript: 

Naiyer Rizvi, MD: One point I’d like to make, which I think is really important for physicians using these drugs, is that response evaluations can be very complex. And agreed, pseudo progression is not common, so I wouldn’t necessarily worry about that. But very often, and increasingly, we’re seeing patients who respond in 3 areas but progress in a fourth area. I think it’s important that those aren’t considered failures of immunotherapy. My practice has been to manage patients that are mostly responding but have isolated progression of a lung lesion, or adrenal lesion, or bone lesion, with isolated resections or radiation. You’d be surprised that patients can continue to have durable benefit with managing these local failures. I think it’s probably related to the heterogeneity of a tumor. Most of the clones may be responding nicely, but you have another one that isn’t. You can address that with local therapies. I don’t know if others have had the same experience.

Everett Vokes, MD: We’ve learned this from targeted therapies, and I think extrapolating that project, or that kind of an approach, is very logical. After you radiate a lesion, have you seen enhanced response in the other lesions (for what some people are advocating as a remote radiation enhancing effect)?

Naiyer Rizvi, MD: In general, no. Their lesions have already mostly responded, so it’s hard to gauge that. I think what would be interesting, I guess, would be if you monitored ctDNA or something. But I haven’t seen any such effects.

Suresh Ramalingam, MD: It’s also important to look at what line of therapy the patient was on with regards to our willingness to tolerate some degree of progression. If you start somebody on a PD-1 inhibitor first, and they are beginning to progress, you still have the option of giving platinum-based doublets. You may tolerate progression to a lesser extent, as opposed to somebody getting it in a second- or third-line setting, where you don’t have much else to give so you’ll tolerate progression a little more.

Naiyer Rizvi, MD: Right. There certainly is some data from the 2017 ASCO Annual Meeting regarding atezolizumab treatment beyond progression. And I think that my thinking is, it’s likely these cases are mostly benefitting. Then, it’s worth continuing.

Everett Vokes, MD: As mentioned, we’ve talked a lot about first-line therapies for non–small cell lung cancer. Initially, PD-1 and PD-L1 inhibitors were tested in the second-line setting. Now it’s available first-line, and we talked about PD-L1 testing for first-line therapy. Now somebody progresses. At that point, whether or not the patient has had a PD-L1 inhibitor, would you suggest repeating PD-L1 testing, Fred?

Fred Hirsch, MD, PhD: Based on the data we have so far, I would say for clinical practice, the initial diagnosis and diagnostic material with PD-L1 result should be sufficient for guiding second-line therapy. There are very sparse data out there to tell us what first-line therapy does with PD-L1 expression. But with the data set we have so far, based on the pembrolizumab studies where they compared archived material with fresh material (I think this goes beyond pembrolizumab), it looks like there is a good concordance between the fresh material and the archived material. But again, for research purposes and for the future, I would certainly encourage professionals to look into what first-line therapy means for the immune system and for PD-L1 expression. For clinical practice, I will say archived material and results should be sufficient for guidance of further therapy.

Everett Vokes, MD: There’s no good evidence that chemotherapy administration influences PD-L1 expression at this point?

Fred Hirsch, MD, PhD: Not sufficient data for bringing it to clinical practice.

Everett Vokes, MD: Yes.

Roy Herbst, MD, PhD: I think it would be nice, at some point, to study that and see. I don’t know that it would change the PD-L1 as much as it might change the inflammation. That could be important because even if you have PD-L1 up in a tumor, if you don’t have T-cell inflammation, you might not see a response. So, I would agree with Fred. I typically don’t order this in the second-line setting. The KEYNOTE-010 trial showed that with about half the biopsies being fresh and half being archived. But in a research setting, absolutely. Let’s look at the microenvironment and let’s look at the T cells. I think that in many of the second-line trials, we might want to think about combinations, based on the tumor, in the future.

Transcript Edited for Clarity 

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Transcript: 

Naiyer Rizvi, MD: One point I’d like to make, which I think is really important for physicians using these drugs, is that response evaluations can be very complex. And agreed, pseudo progression is not common, so I wouldn’t necessarily worry about that. But very often, and increasingly, we’re seeing patients who respond in 3 areas but progress in a fourth area. I think it’s important that those aren’t considered failures of immunotherapy. My practice has been to manage patients that are mostly responding but have isolated progression of a lung lesion, or adrenal lesion, or bone lesion, with isolated resections or radiation. You’d be surprised that patients can continue to have durable benefit with managing these local failures. I think it’s probably related to the heterogeneity of a tumor. Most of the clones may be responding nicely, but you have another one that isn’t. You can address that with local therapies. I don’t know if others have had the same experience.

Everett Vokes, MD: We’ve learned this from targeted therapies, and I think extrapolating that project, or that kind of an approach, is very logical. After you radiate a lesion, have you seen enhanced response in the other lesions (for what some people are advocating as a remote radiation enhancing effect)?

Naiyer Rizvi, MD: In general, no. Their lesions have already mostly responded, so it’s hard to gauge that. I think what would be interesting, I guess, would be if you monitored ctDNA or something. But I haven’t seen any such effects.

Suresh Ramalingam, MD: It’s also important to look at what line of therapy the patient was on with regards to our willingness to tolerate some degree of progression. If you start somebody on a PD-1 inhibitor first, and they are beginning to progress, you still have the option of giving platinum-based doublets. You may tolerate progression to a lesser extent, as opposed to somebody getting it in a second- or third-line setting, where you don’t have much else to give so you’ll tolerate progression a little more.

Naiyer Rizvi, MD: Right. There certainly is some data from the 2017 ASCO Annual Meeting regarding atezolizumab treatment beyond progression. And I think that my thinking is, it’s likely these cases are mostly benefitting. Then, it’s worth continuing.

Everett Vokes, MD: As mentioned, we’ve talked a lot about first-line therapies for non–small cell lung cancer. Initially, PD-1 and PD-L1 inhibitors were tested in the second-line setting. Now it’s available first-line, and we talked about PD-L1 testing for first-line therapy. Now somebody progresses. At that point, whether or not the patient has had a PD-L1 inhibitor, would you suggest repeating PD-L1 testing, Fred?

Fred Hirsch, MD, PhD: Based on the data we have so far, I would say for clinical practice, the initial diagnosis and diagnostic material with PD-L1 result should be sufficient for guiding second-line therapy. There are very sparse data out there to tell us what first-line therapy does with PD-L1 expression. But with the data set we have so far, based on the pembrolizumab studies where they compared archived material with fresh material (I think this goes beyond pembrolizumab), it looks like there is a good concordance between the fresh material and the archived material. But again, for research purposes and for the future, I would certainly encourage professionals to look into what first-line therapy means for the immune system and for PD-L1 expression. For clinical practice, I will say archived material and results should be sufficient for guidance of further therapy.

Everett Vokes, MD: There’s no good evidence that chemotherapy administration influences PD-L1 expression at this point?

Fred Hirsch, MD, PhD: Not sufficient data for bringing it to clinical practice.

Everett Vokes, MD: Yes.

Roy Herbst, MD, PhD: I think it would be nice, at some point, to study that and see. I don’t know that it would change the PD-L1 as much as it might change the inflammation. That could be important because even if you have PD-L1 up in a tumor, if you don’t have T-cell inflammation, you might not see a response. So, I would agree with Fred. I typically don’t order this in the second-line setting. The KEYNOTE-010 trial showed that with about half the biopsies being fresh and half being archived. But in a research setting, absolutely. Let’s look at the microenvironment and let’s look at the T cells. I think that in many of the second-line trials, we might want to think about combinations, based on the tumor, in the future.

Transcript Edited for Clarity 
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