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Check Point Inhibition in Muscle-Invasive Bladder Cancer

Panelists:Raoul S. Concepcion, MD, FACS, Urology Associates; Michael S. Cookson, MD, MMHC, University of Oklahoma Health Sciences Center; Daniel P. Petrylak, MD, Yale School of Medicine; Daniel I. Quinn, MBBS, PhD, FRACP, FACP, University of Southern California; Neal D. Shore, MD, FACS, Carolina Urologic Research Center; Charles J. Ryan, MD, UCSF Helen Diller Family Comprehensive Cancer Center
Published: Friday, Aug 12, 2016


Transcript:

Raoul S. Concepcion, MD:
Let’s just say she gets her radical cystectomy, and she in fact has pathologic T0 disease in the bladder, but is lymph node–positive. And, she’s already received four rounds of neoadjuvant platinum-based chemotherapy. What’s next for her at this point?

Daniel P. Petrylak, MD: Well, there is no standard treatment at this particular point. So, observation would be the standard of care with serial imaging every 3 to 4 months, at least for the first 2 years afterwards. But, she is at a very high risk of relapse. There are clinical trials that are being designed to look at some of the newer checkpoint inhibitors in this situation. There’s some interesting biology behind that and that’s related to the paper that was just published that Jonathan Rosenberg led with atezolizumab. Atezolizumab is a PD-L1 inhibitor that has demonstrated significant activity in patients with refractory urothelial carcinoma to platinum-based treatment. A paper that was published in the Lancet found that those patients who are PD-L1-positive have the highest response rate. It’s about 25%. Those who have lower levels of PD-L1 in the immune cells have lower response rates. The drug is up for approval at the FDA. And, hopefully, we’ll see within the next couple of months whether that drug is approved for second-line urothelial carcinoma. But, why does this have relevance to this particular case?

Well, data out of MD Anderson have shown that the basal subtype of urothelial carcinoma is responsive to platinum-based chemotherapy. In Jonathan’s paper, in the Lancet, there was an analysis based upon TCGA (The Cancer Genome Atlas) subgroup. And the type 2 luminals were the ones who had the responses to atezolizumab. So, if you look at this particular case, this is a perfect situation to look at adjuvant therapy. And, indeed, there is a randomized trial that’s being done with atezolizumab versus observation in PD-L1-positive patients. Other checkpoint inhibitors, such as pembrolizumab and nivolumab are being looked at in the same situation. But, I think this is an ideal place to use checkpoint inhibitors. We have a low volume of disease and you’re seeing chemotherapy failures, and these may be non-cross-resistant treatments.

Raoul S. Concepcion, MD: Dave, what’s the difficulty in testing for the expression of PD-L1, whether it be in the primary or in the nodal disease?

David I. Quinn, MBBS, PhD: There are several assays, and I think we’re having some harmonization on that. The difficulty is going to become less and less because the assays for PD-L1 expression in the lymphocytes of the residual tumor often have been paired with the drugs. And, we have 3 or more of these drugs being developed in different cancers. So, urologists will see reports on melanoma, lung cancer, non-Hodgkin lymphoma or a variety of other things where there’s some variation. Those assays are now becoming easier to get. The problem is, you can’t quite order them routinely on your residual bladder tumor yet. They’ve got to go on the trial. That’s good and bad because what are you going to do with a PD-L1 result in a patient you’re observing?

From that perspective, what we’re trying to do with that adjuvant trial, and now the subsequent trials, is pick out a group of patients we think might best benefit. And, remember, we’ve treated these patients generally with platinum-based chemotherapy. So, we’ve selected out the basal layer, and that’s hopefully responded. What we’ve got left is luminal cells at a low volume that we think might be quite sensitive—at least theoretically—to this sort of treatment, especially if they’re PD-L1-positive. And so, we’re hoping that this will move adjuvant treatment forward quickly. But, importantly, we’ve got to do those trials. Trying to get compassionate access checkpoint inhibitors or people paying for them is something that we need to avoid. We need to do the trials.

Transcript Edited for Clarity
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Transcript:

Raoul S. Concepcion, MD:
Let’s just say she gets her radical cystectomy, and she in fact has pathologic T0 disease in the bladder, but is lymph node–positive. And, she’s already received four rounds of neoadjuvant platinum-based chemotherapy. What’s next for her at this point?

Daniel P. Petrylak, MD: Well, there is no standard treatment at this particular point. So, observation would be the standard of care with serial imaging every 3 to 4 months, at least for the first 2 years afterwards. But, she is at a very high risk of relapse. There are clinical trials that are being designed to look at some of the newer checkpoint inhibitors in this situation. There’s some interesting biology behind that and that’s related to the paper that was just published that Jonathan Rosenberg led with atezolizumab. Atezolizumab is a PD-L1 inhibitor that has demonstrated significant activity in patients with refractory urothelial carcinoma to platinum-based treatment. A paper that was published in the Lancet found that those patients who are PD-L1-positive have the highest response rate. It’s about 25%. Those who have lower levels of PD-L1 in the immune cells have lower response rates. The drug is up for approval at the FDA. And, hopefully, we’ll see within the next couple of months whether that drug is approved for second-line urothelial carcinoma. But, why does this have relevance to this particular case?

Well, data out of MD Anderson have shown that the basal subtype of urothelial carcinoma is responsive to platinum-based chemotherapy. In Jonathan’s paper, in the Lancet, there was an analysis based upon TCGA (The Cancer Genome Atlas) subgroup. And the type 2 luminals were the ones who had the responses to atezolizumab. So, if you look at this particular case, this is a perfect situation to look at adjuvant therapy. And, indeed, there is a randomized trial that’s being done with atezolizumab versus observation in PD-L1-positive patients. Other checkpoint inhibitors, such as pembrolizumab and nivolumab are being looked at in the same situation. But, I think this is an ideal place to use checkpoint inhibitors. We have a low volume of disease and you’re seeing chemotherapy failures, and these may be non-cross-resistant treatments.

Raoul S. Concepcion, MD: Dave, what’s the difficulty in testing for the expression of PD-L1, whether it be in the primary or in the nodal disease?

David I. Quinn, MBBS, PhD: There are several assays, and I think we’re having some harmonization on that. The difficulty is going to become less and less because the assays for PD-L1 expression in the lymphocytes of the residual tumor often have been paired with the drugs. And, we have 3 or more of these drugs being developed in different cancers. So, urologists will see reports on melanoma, lung cancer, non-Hodgkin lymphoma or a variety of other things where there’s some variation. Those assays are now becoming easier to get. The problem is, you can’t quite order them routinely on your residual bladder tumor yet. They’ve got to go on the trial. That’s good and bad because what are you going to do with a PD-L1 result in a patient you’re observing?

From that perspective, what we’re trying to do with that adjuvant trial, and now the subsequent trials, is pick out a group of patients we think might best benefit. And, remember, we’ve treated these patients generally with platinum-based chemotherapy. So, we’ve selected out the basal layer, and that’s hopefully responded. What we’ve got left is luminal cells at a low volume that we think might be quite sensitive—at least theoretically—to this sort of treatment, especially if they’re PD-L1-positive. And so, we’re hoping that this will move adjuvant treatment forward quickly. But, importantly, we’ve got to do those trials. Trying to get compassionate access checkpoint inhibitors or people paying for them is something that we need to avoid. We need to do the trials.

Transcript Edited for Clarity
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