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Measuring Response in Non-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: Tuesday, Aug 23, 2016


Transcript:

Raoul S. Concepcion, MD:
I know from the medical oncology guys’ side, you don’t see a lot of the non-muscle invasive bladder cancer patients. Clearly, we know that BCG (Bacillus Calmette-Guerin), which is an immune modulator, has some toxicity. There are some patients that don’t do well with BCG; it can cause a lot of irritative symptoms. And then you have this subset of patients that won’t respond to BCG or are refractory. Often times, we give them a second induction round. There is another agent for BCG-refractory CIS (carcinoma in situ), which is Valstar. What about some of the newer agents? What about the use of systemic chemotherapy for CIS or, in this particular case, T1 disease?

David I. Quinn, MBBS, PhD: I think it’s important to understand that when you get muscle-invasive disease, you get an alteration in the biology of the disease. And then intravenous chemotherapy, based on that, becomes very useful. I’m not talking about intravesical chemotherapy. And so, whilst there have been some protocols that have used transurethral resection of bladder tumors (TURBTs) with chemotherapy, the reproducibility of those have been questionable. And the patients that have benefitted, paradoxically, probably had muscle-invasive disease that we haven’t been able to detect. So, chemotherapy for these patients is not part of the standard.

We do have some things in the works, immunotherapeutically, to look at this. There are a series of data that suggests that patients that have had tuberculin vaccine do better with BCG therapy in their bladder. In Europe, tuberculin vaccine was continued much longer than in the United States. So, most of the data comes from Europe. But we have a SWOG study that will be led by Rob Svatek that will start soon, which sensitizes patients, potentially, with an injection of tuberculin vaccine before they start their BCG. That will test whether, in fact, we can get more mileage out of that first BCG therapy.

And we also have integrated, into a refractory setting, the use of a drug that Dan has worked on extensively through the phase I and phase II studies. Atezolizumab, a PD-L1 blocker, which will be given intravenously to patients who are refractory to BCG in a study led by Peter Black and Parminder Singh that will run in SWOG, and that’s SWOG 1605. So, I know you’re all just looking out for urology trials from SWOG. We’ve got a couple that are coming that are going to build on the work of Don Lamm all those years ago with BCG, and move that forward. Dan, have you got anything to add there in terms of the early disease?

Daniel P. Petrylak, MD: I think that the overall expression of PD-L1, after BCG, is still a little controversial. There have been some studies that have shown upregulation. We’ve actually looked back at our data set at Yale and found that the expression of PD-L1 goes along with the number of TURBTs that a patient actually has. So, we’re not necessarily seeing a correlation with BCG or not. But, nonetheless, it’s immune-targeted, it needs to be evaluated.

There are actually old data looking at a drug called bropirimine, an oral interferon inducer, which, unfortunately, had some cardiovascular side effects that led to the cessation of its development, but had activity in refractory CIS. I certainly think that this is something that merits study. It may actually hopefully spare patients from cystectomies, and I’m very excited about its future.

Raoul S. Concepcion, MD: Dan, in the study that you’re leading, you’re giving an anti-PD-L1 systemically intravenously. What’s the comparator arm in that?

Daniel P. Petrylak, MD: Well, actually this is being led in SWOG, but by the urologists. The comparator is observation, if I remember correctly.

David I. Quinn, MBBS, PhD: I think we have a phase II run-in on that to look at whether we think it’s different from historical rates, and then there will be some comparison.

Michael S. Cookson, MD, MMHC: One of the things that we know—and we glossed over this a little bit—but it takes sometimes more than a single dose of immunotherapy. Six is the induction, then usually three as part of the maintenance, or two inductions. But, usually, after two courses, or a six plus three, and it’s been 6 months, enough time for the immunotherapy to work, that’s when we start to declare patients as BCG-refractory. There are other patients that are relapsers after that response at 6 months, and those collectively can be referred to as BCG-unresponsive. And I believe that’s the group that’s the hardest for us to treat. We have some agents—as you mentioned, valrubicin—some chemotherapies. Some of those have up to a 20% response rate, maybe a little bit higher, but it doesn’t seem very durable, even with maintenance.

And so, really, the excitement around this new immune-based therapy is ever present. I believe that most of the discussions that I’m aware of, from FDA approval, don’t need a comparator because there is no standard. Cystectomy is the standard. So, if they have about a 20% to 30% response rate, and you can get them 6 to 12 months down the road, you’ve moved the needle. That would have probably set the stage for approval.

Raoul S. Concepcion, MD: Mike, where do we stand? Because, obviously, in years past, we’ve also used interferon. There were a lot of people using BCG in combination with interferon, cutting the dose of BCG. What are the data on BCG and interferon combined?

Michael S. Cookson, MD, MMHC: So, people talk about the dose reductions of BCG, which are necessary in some patients due to intolerance. But once you go below about one-third the dose of BCG, you don’t get the response. And for those highest-risk patients—like the one we described, T1 CIS—usually, they need a full dose. And they need long duration, hopefully a 2- or 3-year duration. In terms of those patients who can’t tolerate or fail, there have been studies. There was a large Intergroup study that looked at adding 50 million units of interferon. Interferon alone doesn’t seem to work; it needs to be combined.

The problem is there’s a lot of heterogeneity. And those trials were developed at a time when we didn’t have good definitions for BCG failure. When you go back and you look at them, there were many patients who maybe just had a 6-week course or maybe had a lower-stage disease and they had good response. So, there is activity there. But when you really look at two failed cycles, recurrence within 6 months, you don’t get the bang-for-your-buck that you wish you could get. It’s an alternative, and in some patients, they do respond. But I don’t think it’s enough for us to say that’s the standard of care.

Transcript Edited for Clarity
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Transcript:

Raoul S. Concepcion, MD:
I know from the medical oncology guys’ side, you don’t see a lot of the non-muscle invasive bladder cancer patients. Clearly, we know that BCG (Bacillus Calmette-Guerin), which is an immune modulator, has some toxicity. There are some patients that don’t do well with BCG; it can cause a lot of irritative symptoms. And then you have this subset of patients that won’t respond to BCG or are refractory. Often times, we give them a second induction round. There is another agent for BCG-refractory CIS (carcinoma in situ), which is Valstar. What about some of the newer agents? What about the use of systemic chemotherapy for CIS or, in this particular case, T1 disease?

David I. Quinn, MBBS, PhD: I think it’s important to understand that when you get muscle-invasive disease, you get an alteration in the biology of the disease. And then intravenous chemotherapy, based on that, becomes very useful. I’m not talking about intravesical chemotherapy. And so, whilst there have been some protocols that have used transurethral resection of bladder tumors (TURBTs) with chemotherapy, the reproducibility of those have been questionable. And the patients that have benefitted, paradoxically, probably had muscle-invasive disease that we haven’t been able to detect. So, chemotherapy for these patients is not part of the standard.

We do have some things in the works, immunotherapeutically, to look at this. There are a series of data that suggests that patients that have had tuberculin vaccine do better with BCG therapy in their bladder. In Europe, tuberculin vaccine was continued much longer than in the United States. So, most of the data comes from Europe. But we have a SWOG study that will be led by Rob Svatek that will start soon, which sensitizes patients, potentially, with an injection of tuberculin vaccine before they start their BCG. That will test whether, in fact, we can get more mileage out of that first BCG therapy.

And we also have integrated, into a refractory setting, the use of a drug that Dan has worked on extensively through the phase I and phase II studies. Atezolizumab, a PD-L1 blocker, which will be given intravenously to patients who are refractory to BCG in a study led by Peter Black and Parminder Singh that will run in SWOG, and that’s SWOG 1605. So, I know you’re all just looking out for urology trials from SWOG. We’ve got a couple that are coming that are going to build on the work of Don Lamm all those years ago with BCG, and move that forward. Dan, have you got anything to add there in terms of the early disease?

Daniel P. Petrylak, MD: I think that the overall expression of PD-L1, after BCG, is still a little controversial. There have been some studies that have shown upregulation. We’ve actually looked back at our data set at Yale and found that the expression of PD-L1 goes along with the number of TURBTs that a patient actually has. So, we’re not necessarily seeing a correlation with BCG or not. But, nonetheless, it’s immune-targeted, it needs to be evaluated.

There are actually old data looking at a drug called bropirimine, an oral interferon inducer, which, unfortunately, had some cardiovascular side effects that led to the cessation of its development, but had activity in refractory CIS. I certainly think that this is something that merits study. It may actually hopefully spare patients from cystectomies, and I’m very excited about its future.

Raoul S. Concepcion, MD: Dan, in the study that you’re leading, you’re giving an anti-PD-L1 systemically intravenously. What’s the comparator arm in that?

Daniel P. Petrylak, MD: Well, actually this is being led in SWOG, but by the urologists. The comparator is observation, if I remember correctly.

David I. Quinn, MBBS, PhD: I think we have a phase II run-in on that to look at whether we think it’s different from historical rates, and then there will be some comparison.

Michael S. Cookson, MD, MMHC: One of the things that we know—and we glossed over this a little bit—but it takes sometimes more than a single dose of immunotherapy. Six is the induction, then usually three as part of the maintenance, or two inductions. But, usually, after two courses, or a six plus three, and it’s been 6 months, enough time for the immunotherapy to work, that’s when we start to declare patients as BCG-refractory. There are other patients that are relapsers after that response at 6 months, and those collectively can be referred to as BCG-unresponsive. And I believe that’s the group that’s the hardest for us to treat. We have some agents—as you mentioned, valrubicin—some chemotherapies. Some of those have up to a 20% response rate, maybe a little bit higher, but it doesn’t seem very durable, even with maintenance.

And so, really, the excitement around this new immune-based therapy is ever present. I believe that most of the discussions that I’m aware of, from FDA approval, don’t need a comparator because there is no standard. Cystectomy is the standard. So, if they have about a 20% to 30% response rate, and you can get them 6 to 12 months down the road, you’ve moved the needle. That would have probably set the stage for approval.

Raoul S. Concepcion, MD: Mike, where do we stand? Because, obviously, in years past, we’ve also used interferon. There were a lot of people using BCG in combination with interferon, cutting the dose of BCG. What are the data on BCG and interferon combined?

Michael S. Cookson, MD, MMHC: So, people talk about the dose reductions of BCG, which are necessary in some patients due to intolerance. But once you go below about one-third the dose of BCG, you don’t get the response. And for those highest-risk patients—like the one we described, T1 CIS—usually, they need a full dose. And they need long duration, hopefully a 2- or 3-year duration. In terms of those patients who can’t tolerate or fail, there have been studies. There was a large Intergroup study that looked at adding 50 million units of interferon. Interferon alone doesn’t seem to work; it needs to be combined.

The problem is there’s a lot of heterogeneity. And those trials were developed at a time when we didn’t have good definitions for BCG failure. When you go back and you look at them, there were many patients who maybe just had a 6-week course or maybe had a lower-stage disease and they had good response. So, there is activity there. But when you really look at two failed cycles, recurrence within 6 months, you don’t get the bang-for-your-buck that you wish you could get. It’s an alternative, and in some patients, they do respond. But I don’t think it’s enough for us to say that’s the standard of care.

Transcript Edited for Clarity
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