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Bladder Cancer: Immunotherapy in the Perioperative Setting

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: Wednesday, Apr 26, 2017



Transcript:

Daniel P. Petrylak, MD:
We often are presented with a case of a patient who has undergone neoadjuvant chemotherapy and despite either dose-dense MVAC or gemcitabine and cisplatin, they have residual disease, either positive margins, infiltration to the fat, or positive lymph nodes. So, Dean, what about the use of immune therapy in this situation? What’s known and what’s not known?

Dean F. Bajorin, MD: We’re at the exploratory stage right now, but trials are ongoing. So, let’s take a look at that population of patients who have neoadjuvant chemotherapy and then they have residual muscle-invasive disease, either pT2 or node-positive. They’ve had their cystectomy and their pelvic lymph node dissection. We know from modeling those patients, in fact, and in even doing a prospective trial looking at a dendritic cell vaccine with HER2, that the median time to progression or recurrence of disease is about 9 months in that population. Median survival is 18 to 24 months. So, that is a population that actually does very, very poorly, and it’s also clearly an unmet need.

There are several trials that have been focusing on that patient population, asking a simple question: does early immunotherapy in that setting, single-agent treatment, make a difference in terms of survival? And so, there are 3 studies that have been proposed; 2 are up and running. The first one is the atezolizumab trial, which is straightforward. Randomization between atezolizumab as a single agent versus surveillance, which is standard of care, and that trial is already accruing.

The second trial is slightly different in design, same set of criteria coming into the patient population in terms of eligibility. It’s still the persistent muscle-invasive patients, and the patients have nodal positivity after neoadjuvant chemotherapy. Both trials will also include patients who did not have neoadjuvant chemotherapy, but have high-risk features as well, T3- or N-positive disease. And in that trial, it’s nivolumab versus placebo, and so the schedule is different, obviously, because nivolumab is an every-2-week therapy.

And then there’s a third trial that has been proposed in the in-group mechanism. That trial is looking at pembrolizumab for the exact same population, in terms of those who receive neoadjuvant therapy, persistent muscle-invasive or greater disease, or for those who didn’t have it but have T3- or N-positive disease. That’s going to be pembrolizumab versus surveillance in that population. So, that’s the perioperative immunotherapy on the adjuvant side.

Then, we have the neoadjuvant setting. Cisplatin-based chemotherapy is the only therapy that confers a survival advantage in the neoadjuvant setting. But there are a number of patients who are not eligible for it. And so, what do you do in a patient who is cisplatin-ineligible? Now that space is being tested in terms of therapy. So, there’s a durvalumab/tremelimumab trial in that space. There’s actually also a nivolumab/ipilimumab trial in that space. We’re going to see more of those, and the question is not going to be just response. What we know from all the studies so far is we can see rapid responses. The question is going to be the durability of response post surgery, etc. And I think we, as academicians, are going to have to try to figure out how to measure that in terms of surrogate endpoints as well.

Daniel P. Petrylak, MD: As we’ve seen in the SWOG data with neoadjuvant MVAC, that if you have a pathologic complete response (pCR), you have an 85% chance of being disease-free at 5 years. So, the pCRs may not be seen with these patients. You may see down-staging. It’s going to force us to rethink how we look at this particular disease. So, upper tract disease, are these included in these trials?

Dean F. Bajorin, MD: Yes. In terms of, for example, the nivolumab trial, patients who have high-risk upper tract disease, they are eligible for the trial. Same thing with atezolizumab. I think that cohort is accrued. And so, we will have those there. There’s a question as to whether upper tract disease might be more sensitive. We’ve kicked that can around a little bit because of more Lynch syndrome patients, more MSI, and potentially a higher response rate. So, we’ll get a readout with regard to these trials.

Transcript Edited for Clarity

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Transcript:

Daniel P. Petrylak, MD:
We often are presented with a case of a patient who has undergone neoadjuvant chemotherapy and despite either dose-dense MVAC or gemcitabine and cisplatin, they have residual disease, either positive margins, infiltration to the fat, or positive lymph nodes. So, Dean, what about the use of immune therapy in this situation? What’s known and what’s not known?

Dean F. Bajorin, MD: We’re at the exploratory stage right now, but trials are ongoing. So, let’s take a look at that population of patients who have neoadjuvant chemotherapy and then they have residual muscle-invasive disease, either pT2 or node-positive. They’ve had their cystectomy and their pelvic lymph node dissection. We know from modeling those patients, in fact, and in even doing a prospective trial looking at a dendritic cell vaccine with HER2, that the median time to progression or recurrence of disease is about 9 months in that population. Median survival is 18 to 24 months. So, that is a population that actually does very, very poorly, and it’s also clearly an unmet need.

There are several trials that have been focusing on that patient population, asking a simple question: does early immunotherapy in that setting, single-agent treatment, make a difference in terms of survival? And so, there are 3 studies that have been proposed; 2 are up and running. The first one is the atezolizumab trial, which is straightforward. Randomization between atezolizumab as a single agent versus surveillance, which is standard of care, and that trial is already accruing.

The second trial is slightly different in design, same set of criteria coming into the patient population in terms of eligibility. It’s still the persistent muscle-invasive patients, and the patients have nodal positivity after neoadjuvant chemotherapy. Both trials will also include patients who did not have neoadjuvant chemotherapy, but have high-risk features as well, T3- or N-positive disease. And in that trial, it’s nivolumab versus placebo, and so the schedule is different, obviously, because nivolumab is an every-2-week therapy.

And then there’s a third trial that has been proposed in the in-group mechanism. That trial is looking at pembrolizumab for the exact same population, in terms of those who receive neoadjuvant therapy, persistent muscle-invasive or greater disease, or for those who didn’t have it but have T3- or N-positive disease. That’s going to be pembrolizumab versus surveillance in that population. So, that’s the perioperative immunotherapy on the adjuvant side.

Then, we have the neoadjuvant setting. Cisplatin-based chemotherapy is the only therapy that confers a survival advantage in the neoadjuvant setting. But there are a number of patients who are not eligible for it. And so, what do you do in a patient who is cisplatin-ineligible? Now that space is being tested in terms of therapy. So, there’s a durvalumab/tremelimumab trial in that space. There’s actually also a nivolumab/ipilimumab trial in that space. We’re going to see more of those, and the question is not going to be just response. What we know from all the studies so far is we can see rapid responses. The question is going to be the durability of response post surgery, etc. And I think we, as academicians, are going to have to try to figure out how to measure that in terms of surrogate endpoints as well.

Daniel P. Petrylak, MD: As we’ve seen in the SWOG data with neoadjuvant MVAC, that if you have a pathologic complete response (pCR), you have an 85% chance of being disease-free at 5 years. So, the pCRs may not be seen with these patients. You may see down-staging. It’s going to force us to rethink how we look at this particular disease. So, upper tract disease, are these included in these trials?

Dean F. Bajorin, MD: Yes. In terms of, for example, the nivolumab trial, patients who have high-risk upper tract disease, they are eligible for the trial. Same thing with atezolizumab. I think that cohort is accrued. And so, we will have those there. There’s a question as to whether upper tract disease might be more sensitive. We’ve kicked that can around a little bit because of more Lynch syndrome patients, more MSI, and potentially a higher response rate. So, we’ll get a readout with regard to these trials.

Transcript Edited for Clarity
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