Variant Histologies of Bladder Cancer - Petros Grivas

April 29, 2021

Alicia Morgans is joined by Petros Grivas to discuss a unique study focusing on patients with variant histologies of bladder cancer. The study aims to improve complete response rates by combining chemotherapy with pembrolizumab in a neoadjuvant setting. With only 17 patients, it's a pilot study that tackles the difficulty in finding effective treatments for varying histologies such as squamous cell adenocarcinoma, plasmacytoid, micropapillary, nested, sarcomatoid, and neuroendocrine. Dr. Grivas describes the treatment plan, involving a combination of dose-dense MVAC, growth factor support, and pembrolizumab. The primary endpoint of the study is to achieve a pathological complete response rate while evaluating a wide range of biomarkers. Drs. Morgans and Grivas emphasize the importance of this study, its focus on patient safety, and how it fills a significant gap in addressing rare tumor types, offering potential insights and treatments for patients with these variant histologies.


Petros Grivas, MD, PhD, Professor, Clinical Director of Genitourinary Cancers Program, University of Washington, Professor, Clinical Research Division, Fred Hutchinson Cancer Center

Alicia Morgans, MD, MPH Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts.

Read the Full Video Transcript

Alicia Morgans: Hi, my name is Alicia Morgans. I'm a GU medical oncologist and Associate Professor of Medicine at Northwestern University. I am so excited to have here with me today, Dr. Petros Grivas, who is an Associate Professor of Medicine and a GU medical oncologist at The University of Washington. He is joining me today to talk about a really exciting study that he and his team are performing for patients with variant histologies to give them a combination of chemotherapy, and actually pembrolizumab to see if we can get better complete response rates in the neoadjuvant setting.

Petros, can you tell us a little bit more about this study? It's very exciting that we are actually focusing on variant histologies and trying to get some options for these patients.

Petros Grivas: Thank you so much, Alicia, for highlighting this trial. As you know very well yourself, you are doing a fantastic job in the field; it is so hard to find treatments for patients with variant histologies of bladder cancer, squamous cell adenocarcinoma, plasmacytoid, micropapillary, nested, sarcomatoid, neuroendocrine. And I think, it is such a difficult, I would say, endeavor to accrue in those trials. So after discussion with our team here at the University of Washington Seattle Cancer Care Alliance and Fred Hutch, we put together a study, I would call it a pilot study. It is only 17 patients in the neoadjuvant setting of localized muscle-invasive bladder cancer. It was patients with either pure or predominant non-urothelial histology, and every histology is allowed except for pure small cells. If someone has a pure small cell, we did not feel comfortable putting them on a trial. We usually give platinum–etoposide and ideally cisplatin etoposide, if it's possible.

In this particular trial, as I mentioned, 17 patients, we utilized a combination of dose-dense MVAC, plus growth factor support, plus pembrolizumab. So it's a combination of chemo, plus anti-PD-1. We give four doses of dose-dense MVAC every two weeks, and we give three doses of pembro every three weeks. So patients, the same day they get chemo, and then pembro two weeks later, they come for dose-dense MVAC, and a week later, they come for a second dose of pembro, and a week later for the third dose of dose-dense MVAC, and then two weeks later, it's dose-dense MVAC and pembro.

The primary endpoint is a pathological complete response rate. We try to evaluate the plethora of biomarkers, and we do a collection of tumor tissue, blood, urine, and stool for the microbiome. We are very excited because we're accruing better than we expected. I think the reason for that is our multi-specialty bladder cancer clinic that we have with Dr. Jonathan Wright and other, many other colleagues, at The University of Washington Medical Center every Tuesday morning. And the providers in the state, and from other states, are aware of the study. So we try to, again, help our patients with this, some important unmet need. Hopefully, we will be able to accrue and look at the clinical data, the safety of course, and efficacy, as well as biomarker data.

Alicia Morgans: Fantastic. So just a couple of questions. Do patients need to have some component of urothelial carcinoma on this trial if we are using this dose-dense MVAC approach in addition to pembro, or could they have completely sarcomatoid, or squamous histology, for example?

Petros Grivas: Great question, Alicia. The answer is, with the exception of pure small cell, all the other histologies are allowed, either in a pure non-urothelial form, pure squamous, or pure adenocarcinoma, or if it's a mixed urothelial with differentiation, as long as the urothelial field component is more than half, it's predominant. So we call it a kind of predominant or pure non-urothelial histology. And someone can argue, rightfully, that it's a mixed bag of different histologies, and different biologic disease, and of course, heterogeneity, across those histologies, which I think is a very good criticism, and we accepted it. It's just not possible to do it any other way, just because it is so rare to have these tumor types. So we pretty much accepted this inherent limitation, and we said we'll go ahead. We will do the study, establish feasibility, try to get it through, and try to learn, with a plethora of biological assays and biomarker work.

Alicia Morgans: Absolutely. These kinds of studies, these pilot studies, are all about feasibility and safety. And so as long as we are keeping our patients safe and demonstrating that they can tolerate treatment, we then look for these biological indicators as the secondary reasons for us to move to larger-scale studies. So this makes complete sense. I really am encouraged that you are able to do that within this feasibility study.

For the primary endpoint, I know you have a lot of correlatives that you are investigating. Is that path CR, or what is your primary endpoint?

Petros Grivas: Absolutely. I will say the primary endpoint, as you said, is the pathological complete response rate. And this is I think, a reasonable endpoint when you think about efficacy. Obviously, we want to evaluate, as you mentioned, feasibility and safety, so we have built in a lot of safety landmarks. We will look at grade 3/4 primary adverse events, as well as the proportion of patients who complete the radical cystectomy lymph node dissection within 10 weeks from the end of chemotherapy, and systemic therapy. So we tried to evaluate both components of feasibility, safety, and efficacy, but pathological complete response is the key efficacy endpoint, then again, plus the biomarker work.

Alicia Morgans: Fantastic. So we will make sure that we post the schema with this recording, as well as the information for clinicians and for patients who are facing these challenging histologies to reach out, to connect with your coordinators, potentially refer patients for inclusion on this trial. I congratulate you and your team for thinking outside the box and for really, truly addressing a severely unmet need for patients with urothelial carcinoma, or rather for patients with bladder cancers that are these variant histologies. So thank you for your time, for your efforts. And I wish you and your team speedy enrollment and some quick answers for our patients. Thank you.

Petros Grivas: Thank you so much, Alicia. I appreciate your discussion today, and all of the discussions we do about bladder cancer and urothelial cancer in general.