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Combination Trials in Advanced Bladder Cancer

Panelists: Daniel P. Petrylak, MD, Yale University Cancer Center; Dean F. Bajorin, MD, Memorial Sloan Kettering Cancer Center; Robert Dreicer, MD, MS, Virginia Cancer Center; Arjun V. Balar, MD, Laura and Isaac Perlmutter Cancer Center; Elizabeth R. Plimack, MD, MS, Fox Chase Cancer Center; David I. Quinn, MBBS, PhD, USC Norris Cancer Hospital
Published Online: Thursday, Apr 20, 2017



Transcript:

Daniel P. Petrylak, MD:
Moving on to more discussion about combination immune therapies, Betsy, why don’t you describe the DANUBE trial? Where does that stand right now? How does that fit in with all the other treatments we’ve been talking about?

Elizabeth R. Plimack, MD, MS: The DANUBE trial is durvalumab/tremelimumab versus chemotherapy, which can be for cisplatin-eligible or cisplatin-ineligible patients, as I understand it. What’s interesting about this trial—and it’s a trend we’re seeing—is the trial was launched as a phase III before there was any phase I safety data for the combination published, or at least publicly available, and certainly before there was any efficacy data in bladder, which we still haven’t seen. There are cohort studies looking at that combination in bladder and urothelial cancer. We anticipate those results soon, but this trial is already going and enrolling. So, we hope they got it right. We hope it’s safe and extremely effective, and that it will win in the phase III trial. But we never used to see trials launching so much ahead of release of the data.

I would say that the only data we do have for that CTLA4/PD-1/PD-L1 checkpoint combination comes from the ipilimumab/nivolumab data that Pam Sharma presented at SITC (Society for Immunotherapy of Cancer) . And there, we did see, as expected, a higher adverse event rate. Again, durable responses when they were seen, but response rates were 26% to 38% in small numbers with completely overlapping confidence intervals for the 2 different dosing schemes. I would just say we don’t know a lot yet about this combination. And the studies were all launched at the same time, so we may get all the answers at once.

Daniel P. Petrylak, MD: I believe that there are second-line data for the combination, but they’re not yet available. The trial is completed, so we’ll have a better understanding, but, of course, probably before the trial will be fully accrued. It’s interesting. There are different combination approaches that we’re all taking. We all have heard and have seen in melanoma the abscopal effect. Chemotherapy or radiation therapy plus immune therapy, Arjun, can you describe some of the trials that are going on or planned?

Arjun V. Balar, MD: One of these trials that I’m very excited about is a study I’m leading at NYU and that’s open at 4 other centers. As we have seen, immunotherapy second-line, immunotherapy first-line, and now seeing the safety, tolerability, and durable responses, the natural question we ask is, is this a therapy we can use in the localized disease setting? And are there existing standards of care with which immunotherapy could synergize well with? And so, one particular study that I’m looking at is combining standard chemotherapy and radiation and adding an immune checkpoint inhibitor. The background behind this is that there are many studies now, preclinical and some clinical evidence now, that demonstrate that radiation can actually be quite immunogenic. The process by which this happens is that radiation induces what’s called “immunogenic cell death,” and we know that the process of tumor antigen is being displayed to the immune system via dendritic cells and then developing anti-tumor immunity through the development of antigen-specific T cells. That process of immunogenic cell death can be accelerated with the use of radiation.

In this particular trial, we’re combining it with gemcitabine. Gemcitabine was chosen because the radiation sensitizing doses are actually quite small, a fraction of the systemic doses that we typically use. So, we try to minimize the systemic toxicity because, obviously, one of the questions we naturally ask is that as we combine immunotherapy and chemotherapy, are we killing off the very cells we’re trying to stimulate with immune therapy? And so, that’s part of the reason why we use it. There are phase I and phase II data showing that gemcitabine and radiation can be effectively combined, and it has actually excellent outcomes in the elderly population. And then, there’s PD-1. So, if we are inducing immunogenic cell death and we’re developing antigen-specific T cells, perhaps then they can be stimulated with checkpoint blockade.

If there are a proportion of patients who are responding to single-agent immunotherapy, those are probably what we call the TIL-inflamed or TIL-infiltrated tumors. But there’s clearly a proportion of patients who have cold tumors, which means they’re absent of dense T cell infiltrates. It’s perhaps possible that radiation might convert some of these cold tumors into immunotherapy-sensitive tumors, and that’s the rationale behind that particular trial. And there’s similarly another study of durvalumab, which is a PD-L1 antibody, in combination with radiation as well in a similar patient population, patients with localized muscle-invasive disease.

Both of these studies will be focusing on patients either who refuse radical cystectomy or those who are poor surgical candidates. And, as we are seeing now, the bladder cancer patient population truly is one that is older with many other comorbidities, and many of these patients are not able to successfully undergo radical cystectomy. So, these are 2 studies that I feel, really, if they report out positive results, could have another significant impact on how we manage these patients.

Daniel P. Petrylak, MD: SWOG is actually planning a trial looking at PD-L1 inhibition along with radiation therapy. So, that actually will be opening up in the Cooperative Groups hopefully within the next 6 months or so. I think that we’re excited about that. I think that’s really a great way to move forward, combining modalities that we have that show efficacy.

Transcript Edited for Clarity

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Transcript:

Daniel P. Petrylak, MD:
Moving on to more discussion about combination immune therapies, Betsy, why don’t you describe the DANUBE trial? Where does that stand right now? How does that fit in with all the other treatments we’ve been talking about?

Elizabeth R. Plimack, MD, MS: The DANUBE trial is durvalumab/tremelimumab versus chemotherapy, which can be for cisplatin-eligible or cisplatin-ineligible patients, as I understand it. What’s interesting about this trial—and it’s a trend we’re seeing—is the trial was launched as a phase III before there was any phase I safety data for the combination published, or at least publicly available, and certainly before there was any efficacy data in bladder, which we still haven’t seen. There are cohort studies looking at that combination in bladder and urothelial cancer. We anticipate those results soon, but this trial is already going and enrolling. So, we hope they got it right. We hope it’s safe and extremely effective, and that it will win in the phase III trial. But we never used to see trials launching so much ahead of release of the data.

I would say that the only data we do have for that CTLA4/PD-1/PD-L1 checkpoint combination comes from the ipilimumab/nivolumab data that Pam Sharma presented at SITC (Society for Immunotherapy of Cancer) . And there, we did see, as expected, a higher adverse event rate. Again, durable responses when they were seen, but response rates were 26% to 38% in small numbers with completely overlapping confidence intervals for the 2 different dosing schemes. I would just say we don’t know a lot yet about this combination. And the studies were all launched at the same time, so we may get all the answers at once.

Daniel P. Petrylak, MD: I believe that there are second-line data for the combination, but they’re not yet available. The trial is completed, so we’ll have a better understanding, but, of course, probably before the trial will be fully accrued. It’s interesting. There are different combination approaches that we’re all taking. We all have heard and have seen in melanoma the abscopal effect. Chemotherapy or radiation therapy plus immune therapy, Arjun, can you describe some of the trials that are going on or planned?

Arjun V. Balar, MD: One of these trials that I’m very excited about is a study I’m leading at NYU and that’s open at 4 other centers. As we have seen, immunotherapy second-line, immunotherapy first-line, and now seeing the safety, tolerability, and durable responses, the natural question we ask is, is this a therapy we can use in the localized disease setting? And are there existing standards of care with which immunotherapy could synergize well with? And so, one particular study that I’m looking at is combining standard chemotherapy and radiation and adding an immune checkpoint inhibitor. The background behind this is that there are many studies now, preclinical and some clinical evidence now, that demonstrate that radiation can actually be quite immunogenic. The process by which this happens is that radiation induces what’s called “immunogenic cell death,” and we know that the process of tumor antigen is being displayed to the immune system via dendritic cells and then developing anti-tumor immunity through the development of antigen-specific T cells. That process of immunogenic cell death can be accelerated with the use of radiation.

In this particular trial, we’re combining it with gemcitabine. Gemcitabine was chosen because the radiation sensitizing doses are actually quite small, a fraction of the systemic doses that we typically use. So, we try to minimize the systemic toxicity because, obviously, one of the questions we naturally ask is that as we combine immunotherapy and chemotherapy, are we killing off the very cells we’re trying to stimulate with immune therapy? And so, that’s part of the reason why we use it. There are phase I and phase II data showing that gemcitabine and radiation can be effectively combined, and it has actually excellent outcomes in the elderly population. And then, there’s PD-1. So, if we are inducing immunogenic cell death and we’re developing antigen-specific T cells, perhaps then they can be stimulated with checkpoint blockade.

If there are a proportion of patients who are responding to single-agent immunotherapy, those are probably what we call the TIL-inflamed or TIL-infiltrated tumors. But there’s clearly a proportion of patients who have cold tumors, which means they’re absent of dense T cell infiltrates. It’s perhaps possible that radiation might convert some of these cold tumors into immunotherapy-sensitive tumors, and that’s the rationale behind that particular trial. And there’s similarly another study of durvalumab, which is a PD-L1 antibody, in combination with radiation as well in a similar patient population, patients with localized muscle-invasive disease.

Both of these studies will be focusing on patients either who refuse radical cystectomy or those who are poor surgical candidates. And, as we are seeing now, the bladder cancer patient population truly is one that is older with many other comorbidities, and many of these patients are not able to successfully undergo radical cystectomy. So, these are 2 studies that I feel, really, if they report out positive results, could have another significant impact on how we manage these patients.

Daniel P. Petrylak, MD: SWOG is actually planning a trial looking at PD-L1 inhibition along with radiation therapy. So, that actually will be opening up in the Cooperative Groups hopefully within the next 6 months or so. I think that we’re excited about that. I think that’s really a great way to move forward, combining modalities that we have that show efficacy.

Transcript Edited for Clarity
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