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FDA Approval of Atezolizumab for 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: Tuesday, Mar 28, 2017


Transcript:

Daniel P. Petrylak, MD:
I’d like to move on to the approval of atezolizumab. Arjun, could you describe the use of atezolizumab in the second-line setting following platinum-based chemotherapy?

Arjun V. Balar, MD: Obviously, atezolizumab was the first anti-PD-L1 antibody to be tested in advanced bladder cancer, first with Tom Pals presenting the phase Id experience at ASCO in 2014. And, since then, we’ve had the very large multi-national phase II study, IMvigor-210. It focused on 2 cohorts, cohort 2 and cohort 1. Cohort 2 focused, which is the large part of the study, roughly 310 patients with advanced bladder cancer, and those who had progressed on prior platinum-based chemotherapy. And, in those 310 patients, what we observed, patients received 1200 mg of atezolizumab, flat dose every 3 weeks until loss of clinical benefit.

And what that study demonstrated was that there was a roughly 15% to 16% response rate in the all-comer group. There was a strong correlation or at least some correlation with PD-L1 expression and probability of response, whereas the patients who had the highest level of PD-L1 expression, this is measured using the SP142 assay on infiltrating immune cells. And the patients who had the highest level of PD-L1 expression had roughly 27% to 28% response rate, in that range. Whereas the patients who had the lowest level of PD-L1 expression, what they called IC0 or 1s, had a response rate roughly in the 8% to 10% range. Clearly, the message here is that even though there is a correlation with PD-L1 expression and response, the patients who had the lowest level of PD-L1 expression did not preclude response. And, in fact, there were complete responses also observed in the PD-L1-negative patients. And so, this alludes to what Dr. Quinn was mentioning, that PD-L1 expression really shouldn’t be used to justify excluding patients from therapy.

The median survival was on the range of about 8 months, and the responses were durable. I think that’s the most important message from this particular trial. Because on first glance, a response rate of 15% is not eye-popping by any means, but when we put that data into the context of what patients previously experienced, which was a uniformly fatal disease, there were no complete responses, no long-term survival in the second-line setting. Now we have a fraction of patients, if they achieve a response, these are durable, and we have patients who are still on therapy 2 or 3 years since starting treatment.

Robert Dreicer, MD, MS: Yes. I think one of the other interesting things about longer-term follow-up for the atezolizumab study was that with median follow-up of 18 months, there were patients that were converting from stable disease to PR, and some patients from PRs to CRs even late. And that’s really, obviously, unprecedented.

Daniel P. Petrylak, MD: Which comes into the fact of when you should stop treatment because you presented some data last year about treating past progression, which is actually a very, very interesting phenomenon.

Robert Dreicer, MD, MS: Yes. The challenge we all face is, and David was obviously discussing this in a different context, cost. We would like to be able to deliver a therapy moving us up earlier and provide subsets of patients with long-term benefit without having to treat them again. That’s aspirational at this point, but we can perhaps foresee it. Even at that point, we have to figure out, how much do we need to use? And the fact that we’re converting some patients with ongoing therapy does make it a little bit of a challenge when to say you’re doing well and we’re going to give you a drug holiday. We had to figure it out in kidney cancer, mostly empirically over time, but you could argue that there was more of a toxicity burden. This is more of an economic burden and a hassle because of the parenteral requirements, a lot of challenges. But we have to figure this out if for no other reason, just not bankrupt the system so we can treat people who need it.

Elizabeth R. Plimack, MD, MS: Absolutely.

Daniel P. Petrylak, MD: Right, exactly.

Dean F. Bajorin, MD: I think that point of treating past progression is really a good point. That is that all these studies require RECIST criteria. We measure and we come down to a certain level, however, in terms of response. And then, the criterion for progression is a 20% increase over baseline. And so, you could have a small increase in your tumor and that is radiographic progression, but all of us here are clinicians and it’s not clinically meaningful. I think that’s where the science may end and our clinical judgment begins, and that’s really an important issue.

Daniel P. Petrylak, MD: I think that several cases illustrate that. Your colleague, Dr. Rosenberg, at Memorial Sloan Kettering Cancer Center has shown some slides of a patient who had 1 hepatic metastasis and then on reevaluation, he had 6. And then, Jonathan went and treated him because the patient had good performance status and he had no other treatments to give at that particular point. And this patient eventually responded. I recently had a very, very similar experience with a patient with hepatic metastases. I think what you’re saying is that you have to listen to your patient, see how they’re feeling, see what their symptoms are, but also interpret their scans in the context of what their overall clinical picture is.

Dean F. Bajorin, MD: Absolutely. It’s clinical judgment.

Elizabeth R. Plimack, MD, MS: The treating beyond progression is going to the more complex when we start to talk about moving immunotherapy to the frontline where they haven’t had chemotherapy yet. It’s a much easier conversation when you don’t have anything good next. It’s a lot harder when someone perhaps hasn’t gotten their platinum-based therapy because we’re using it frontline and then deciding what to do. So, I think we owe it to our patients, to the community, to define how many patients really benefit from this treatment beyond progression. It’s been reported in kidney. That literature is a little more mature, and I think we really need to take a deeper look in bladder.

Arjun V. Balar, MD: And I would agree with that, having treated many patients in the frontline setting, both on KEYNOTE-052 as well as IMvigor-210 cohort 1. The clinical judgment is paramount, and what that means is that patients who receive several cycles of therapy, if they’re not feeling well, if they’re progressing clinically, you really have to really put that as your first priority in terms of what you’re going to use to make a treatment decision. And that’s a patient that you obviously do not want to continue on immunotherapy because they probably need chemotherapy. It’s also important to note that this rate of pseudoprogression is basically what we’re talking about where patients are feeling exceptionally well; blood work looks great, but their scans look worse. That’s actually a fairly uncommon event, and, in my experience, it’s more likely that what’s happening is true progression rather than pseudoprogression.

Robert Dreicer, MD, MS: One of the challenges that Betsy brings up that’s in the frontline setting is with the asymptomatic patient. Because as we start to treat more of those who have no change in their symptom complex and are not having problems with therapy, then judging the time of progression and making the switch is really going to get to be more challenging.

Daniel P. Petrylak, MD: Exactly. And I think also for clinical trials, this is an important concept because if a patient is going to respond past progression and you’re putting them on another study, that actually may contaminate results of your subsequent clinical trials. So, this is something we really have to define carefully if we’re going to be coming up with third-line studies for this disease.

Transcript Edited for Clarity
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Transcript:

Daniel P. Petrylak, MD:
I’d like to move on to the approval of atezolizumab. Arjun, could you describe the use of atezolizumab in the second-line setting following platinum-based chemotherapy?

Arjun V. Balar, MD: Obviously, atezolizumab was the first anti-PD-L1 antibody to be tested in advanced bladder cancer, first with Tom Pals presenting the phase Id experience at ASCO in 2014. And, since then, we’ve had the very large multi-national phase II study, IMvigor-210. It focused on 2 cohorts, cohort 2 and cohort 1. Cohort 2 focused, which is the large part of the study, roughly 310 patients with advanced bladder cancer, and those who had progressed on prior platinum-based chemotherapy. And, in those 310 patients, what we observed, patients received 1200 mg of atezolizumab, flat dose every 3 weeks until loss of clinical benefit.

And what that study demonstrated was that there was a roughly 15% to 16% response rate in the all-comer group. There was a strong correlation or at least some correlation with PD-L1 expression and probability of response, whereas the patients who had the highest level of PD-L1 expression, this is measured using the SP142 assay on infiltrating immune cells. And the patients who had the highest level of PD-L1 expression had roughly 27% to 28% response rate, in that range. Whereas the patients who had the lowest level of PD-L1 expression, what they called IC0 or 1s, had a response rate roughly in the 8% to 10% range. Clearly, the message here is that even though there is a correlation with PD-L1 expression and response, the patients who had the lowest level of PD-L1 expression did not preclude response. And, in fact, there were complete responses also observed in the PD-L1-negative patients. And so, this alludes to what Dr. Quinn was mentioning, that PD-L1 expression really shouldn’t be used to justify excluding patients from therapy.

The median survival was on the range of about 8 months, and the responses were durable. I think that’s the most important message from this particular trial. Because on first glance, a response rate of 15% is not eye-popping by any means, but when we put that data into the context of what patients previously experienced, which was a uniformly fatal disease, there were no complete responses, no long-term survival in the second-line setting. Now we have a fraction of patients, if they achieve a response, these are durable, and we have patients who are still on therapy 2 or 3 years since starting treatment.

Robert Dreicer, MD, MS: Yes. I think one of the other interesting things about longer-term follow-up for the atezolizumab study was that with median follow-up of 18 months, there were patients that were converting from stable disease to PR, and some patients from PRs to CRs even late. And that’s really, obviously, unprecedented.

Daniel P. Petrylak, MD: Which comes into the fact of when you should stop treatment because you presented some data last year about treating past progression, which is actually a very, very interesting phenomenon.

Robert Dreicer, MD, MS: Yes. The challenge we all face is, and David was obviously discussing this in a different context, cost. We would like to be able to deliver a therapy moving us up earlier and provide subsets of patients with long-term benefit without having to treat them again. That’s aspirational at this point, but we can perhaps foresee it. Even at that point, we have to figure out, how much do we need to use? And the fact that we’re converting some patients with ongoing therapy does make it a little bit of a challenge when to say you’re doing well and we’re going to give you a drug holiday. We had to figure it out in kidney cancer, mostly empirically over time, but you could argue that there was more of a toxicity burden. This is more of an economic burden and a hassle because of the parenteral requirements, a lot of challenges. But we have to figure this out if for no other reason, just not bankrupt the system so we can treat people who need it.

Elizabeth R. Plimack, MD, MS: Absolutely.

Daniel P. Petrylak, MD: Right, exactly.

Dean F. Bajorin, MD: I think that point of treating past progression is really a good point. That is that all these studies require RECIST criteria. We measure and we come down to a certain level, however, in terms of response. And then, the criterion for progression is a 20% increase over baseline. And so, you could have a small increase in your tumor and that is radiographic progression, but all of us here are clinicians and it’s not clinically meaningful. I think that’s where the science may end and our clinical judgment begins, and that’s really an important issue.

Daniel P. Petrylak, MD: I think that several cases illustrate that. Your colleague, Dr. Rosenberg, at Memorial Sloan Kettering Cancer Center has shown some slides of a patient who had 1 hepatic metastasis and then on reevaluation, he had 6. And then, Jonathan went and treated him because the patient had good performance status and he had no other treatments to give at that particular point. And this patient eventually responded. I recently had a very, very similar experience with a patient with hepatic metastases. I think what you’re saying is that you have to listen to your patient, see how they’re feeling, see what their symptoms are, but also interpret their scans in the context of what their overall clinical picture is.

Dean F. Bajorin, MD: Absolutely. It’s clinical judgment.

Elizabeth R. Plimack, MD, MS: The treating beyond progression is going to the more complex when we start to talk about moving immunotherapy to the frontline where they haven’t had chemotherapy yet. It’s a much easier conversation when you don’t have anything good next. It’s a lot harder when someone perhaps hasn’t gotten their platinum-based therapy because we’re using it frontline and then deciding what to do. So, I think we owe it to our patients, to the community, to define how many patients really benefit from this treatment beyond progression. It’s been reported in kidney. That literature is a little more mature, and I think we really need to take a deeper look in bladder.

Arjun V. Balar, MD: And I would agree with that, having treated many patients in the frontline setting, both on KEYNOTE-052 as well as IMvigor-210 cohort 1. The clinical judgment is paramount, and what that means is that patients who receive several cycles of therapy, if they’re not feeling well, if they’re progressing clinically, you really have to really put that as your first priority in terms of what you’re going to use to make a treatment decision. And that’s a patient that you obviously do not want to continue on immunotherapy because they probably need chemotherapy. It’s also important to note that this rate of pseudoprogression is basically what we’re talking about where patients are feeling exceptionally well; blood work looks great, but their scans look worse. That’s actually a fairly uncommon event, and, in my experience, it’s more likely that what’s happening is true progression rather than pseudoprogression.

Robert Dreicer, MD, MS: One of the challenges that Betsy brings up that’s in the frontline setting is with the asymptomatic patient. Because as we start to treat more of those who have no change in their symptom complex and are not having problems with therapy, then judging the time of progression and making the switch is really going to get to be more challenging.

Daniel P. Petrylak, MD: Exactly. And I think also for clinical trials, this is an important concept because if a patient is going to respond past progression and you’re putting them on another study, that actually may contaminate results of your subsequent clinical trials. So, this is something we really have to define carefully if we’re going to be coming up with third-line studies for this disease.

Transcript Edited for Clarity
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Clinical Interchange™: Translating Research to Inform Changing Paradigms: Assessment of Emerging Immuno-Oncology Strategies and Combinations across Lung, Head and Neck, and Bladder CancersOct 31, 20182.0
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