Bladder Cancer: Monoclonal Antibodies Under Investigation
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
Daniel P. Petrylak, MD: Not only are checkpoint inhibitors being evaluated in metastatic bladder cancer, but a whole variety of different targets are being evaluated as well at this particular point. HER2/neu targeted therapy, that’s actually been around for a long time. There have been some early studies combining Herceptin (trastuzumab) with chemotherapy. Arjun, were there any studies at this meeting or have you been aware of any other studies that looked at HER2/neu therapy?
Arjun V. Balar, MD: You’ve obviously referenced a prior study of gemcitabine/carboplatin with Herceptin. More recently, people are looking at Herceptin with pertuzumab. There was one poster that I saw here at ASCO GU looking at Herceptin and pertuzumab, a relatively small study. There were actually some durable responses. In fact, I actually spoke to one of the lead investigators. Therapy was well tolerated. There was 1 CR that was quite durable. And combining HER2-directed therapies, actually it makes some sense in this disease. Actually, we look back at the TCGA. What was unique is that we did see some HER2 amplification in the TCGA, but there was also HER2 mutations, which we actually don’t really see too often in the other solid tumor malignancies.
Daniel P. Petrylak, MD: The interesting thing about Maha Hussain’s study, when you look at the characteristics of those patients who were on the trial—and there were a variety of different ways of measuring HER2 expression—but most of them had poor prognostic features. And perhaps this may be a marker of more advanced disease. There have also been some TKI trials. Tom Powles has actually looked at giving a HER2/TKI as adjuvant therapy post treatment; really didn’t see much of a difference in overall progression-free survival. But I think the data that were presented with the checkpoints here in combination with Herceptin were very, very intriguing.
Dean F. Bajorin, MD: One of the issue is the biology of HER2. There’s overexpression, there’s amplification, there’s mutation. For example, in Maha’s study, it was overexpression, and they used the breast data. The dacomitinib study agrees with Erb2B mutations, and that’s not the case here. It’s very challenging.
Arjun V. Balar, MD: And mutations may not be sensitive to monoclonal antibodies. In fact, HER2 mutations may require a small molecule inhibitor to target the intracellular domain.
Dean F. Bajorin, MD: And those studies are ongoing.
Daniel P. Petrylak, MD: Actually, Maha’s study was 1 of 4 different methods. If you hit positive on any one, you could be entered on the trial. I think it was more a trial to define toxicity rather than actually efficacy, but interesting nonetheless. So, certainly, this is a target we want to move forward with. Angiogenesis is also an important target. We’re still waiting on Jonathan Rosenberg’s trial from CALGB looking at bevacizumab plus gemcitabine and cisplatinum versus cisplatinum alone. And I think that all of us are anticipating that final result. But there are other antiangiogenesis agents that are now being evaluated. Betsy, do you want to talk about ramucirumab and docetaxel?
Elizabeth R. Plimack, MD, MS: Ramucirumab actually presented phase II data, I think a couple of years ago, and based on preliminary encouraging results from those data, a phase III trial was launched, which is underway. I think we’ll have a real answer on that, and I think none of the drugs in that trial are immunotherapeutic per se. I think we’ll then need to figure out where it fits based on what the data show. So, I think it’s too early to really comment, except that we look forward to seeing it.
Dean F. Bajorin, MD: Do we know that VEGF inhibition is not immunotherapeutic?
Elizabeth R. Plimack, MD, MS: Per se. You bring up a great point. It may absolutely have immunotherapeutic indications, but I think that’s how once we have, hopefully, a positive trial—right, we hope all our trials are positive—once we have that, where are we going to put it? Is it better first and then immunotherapy? Is it better second?
Robert Dreicer, MD, MS: It’s a good problem to have. Elizabeth R. Plimack, MD, MS: It is, but I think we can start to think about what we might do.
Arjun V. Balar, MD: Angiogenesis in bladder cancer is nothing new. We have old data that show that higher VEGF expression levels in blood and the urine of these patients, actually those patients do worse. So, we know that this is a poor prognostic factor. The study that I was very lucky to participate in when I was a Fellow with you, Dean, was the gemcitabine/carboplatin/bevacizumab study, and, similarly, the gemcitabine/cisplatin/bevacizumab study that Noah Hahn led. And both of those trials demonstrated encouraging PFS and survival compared to what we would consider the historical standard. What was interesting in our gemcitabine/carboplatin/bevacizumab study, in fact, was that the patients who actually continued on maintenance bevacizumab had some further tumor regression on single-agent bevacizumab in that particular study. So, there are some compelling evidence. And now actually we’re looking at bevacizumab as an immunotherapeutic agent, which is really something that’s relatively new over the last several years. We’re looking at that in a phase II trial of atezolizumab with or without bevacizumab in the frontline setting in cisplatin-ineligible patients with metastatic disease. I think that study is well poised to answer the question, can bevacizumab truly be immunotherapeutic beyond just being an antiangiogenic agent?
Dean F. Bajorin, MD: The pre- and post-treatment biopsies, prepared biopsies, in patients getting bevacizumab, you see upregulation of T cells, infiltration, etc, in a tumor. So, this has been true for many years. We think we know how a drug works, and then we get more information and it may work a little differently. Gemcitabine, for example, works against MDSCs, something we’ve recently learned. So, many of these drugs actually may have immunotherapeutic actions in addition to cytotoxicity.
David I. Quinn, MBBS, PhD: We all have a feeling that VEGF targeted therapy should work in urothelial cancer. We’ve just had difficulty proving it. If you look at the TKIs for VEGF receptor 2, like pazopanib, for example, or sunitinib—you guys did trials—you get a very variable response. You can have 1 phase II set that says you get a durable response with pazopanib and another phase II set that says there’s nothing. So, I think the variability and the biology is a bit of a challenge. It may be that these agents are good partners with checkpoint inhibitors, and whether it’s a monoclonal antibody like ramucirumab, whether it’s bevacizumab, or whether it’s some of the TKIs that we’ve used more in renal cell cancer, I think it’s interesting. So, I think we may not have had the partnership right, and exploring the biology may lead us down the right path. Hopefully, we’ll end up with a different set of therapeutics.
Daniel P. Petrylak, MD: Finally, amongst the new agents, the ADCs, Dean, what about the targeting nectin as a potential target in bladder cancer?
Dean F. Bajorin, MD: There are early data that that might be, in fact, active. I think what it does is it points out an issue that all of us are facing, and that is new drug development, and new drug development in patients who may not respond to immunotherapy. That’s the vast majority of patients. This also, at least in early data, looked like there is activity there. So, we’ll need more follow-up with regard to that drug, but there is some early activity that is certainly worth exploring.
Daniel P. Petrylak, MD: It certainly looks interesting. The other area that I think we’re also moving into is therapeutic vaccines. You mentioned before, the HER2/neu dendritic cell vaccine, the Neuvenge, but there is also PANVAC and also NY-ESO. Any of the panel members have experience with any of those other vaccines in this disease?
Dean F. Bajorin, MD: So, I have with NY-ESO-1 because it was developed at the Ludwig when we were there. We’ve actually had several vaccines that we’ve attempted over the years, regarding the NY-ESO-1 vaccine. It’s part of the cancer/testis antigens, MAGE, phage, etc, and NY-ESO-1 is a member of that group. First issue is, yes, they’re actually immunogenic. We actually, years ago, identified a patient who expressed NY-ESO-1 who had a high T cell recognition of that particular antigen. I think we will start seeing studies that expose antigens or neoantigens or induce neoantigens that we can then allow recognition in terms of I-O checkpoint blockade. But these are all in their infancy.