The Potential of Breakthrough Trials in Urothelial Carcinoma: ECOG-ACRIN 8192 - Petros Grivas

April 16, 2021

Alicia Morgans and Petros Grivas discuss several ongoing or recently launched trials on urothelial carcinoma. Dr. Grivas provides an update on the ECOG-ACRIN 8192 trial for upper tract urothelial carcinoma, which follows the ECOG-ACRIN 8141 trial. The latter set a benchmark for expected pathological complete response rates with standard care chemotherapy for bladder cancer. The upcoming 8192 trial is a randomized phase II/III trial, evaluating two cohorts: cisplatin-eligible and cisplatin-ineligible patients. The former cohort will examine the potential benefits of adding durvalumab to dose-dense MVAC, while the latter will study the effects of a gemcitabine plus durvalumab combination. Despite the rarity of upper tract disease, Dr. Grivas is optimistic about accruing sufficient patients for the trials, hoping to improve the understanding and treatment of this disease.


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

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

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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU medical oncologist and Associate Professor of medicine at Northwestern University. I am so delighted to have here with me today, a friend and colleague, Dr. Petros Grivas, who is also an Associate Professor of Medicine, and a GU medical oncologist at the University of Washington. Thank you so much for being here with me today.

Petros Grivas: Thank you, Alicia, for having me. It's always a pleasure to discuss with you.

Alicia Morgans: Wonderful. I wanted to speak with you today about several different trials and we will talk about each of these trials separately. These are cooperative groups, or National Clinical Trials Network (NCTN) trials, that are really ongoing, or recently launched, for patients with urothelial carcinoma. Let's start with the first. That is a study that has been really in development for several years, focusing on patients with upper tract urothelial carcinoma. This is a labor of love that I know Jean Hoffman-Censits has been working on, and you've been working on, with the Eastern Cooperative Oncology Group (ECOG) group, but really collaborating across all cooperative groups. Can you tell me a little bit about this trial?

Petros Grivas: Absolutely, Alicia. Thank you for this question, and I want to highlight the great efforts by Dr. Hoffman-Censits, Dr. Vitaly Margulis, Dr. Noah Hahn, and others in the ECOG-ACRIN group. And Dr. Hoffman-Censits presented the data from the ECOG-ACRIN 8141 trial. I think this was at AUA, I want to say about three years ago, time flies, especially with COVID-19. This trial, just to remind the audience, ECOG-ACRIN 8141 was a trial looking at cisplatin eligible patients and evaluated dose-dense MVAC in those patients with, about 30 patients, with upper tract localized urothelial carcinoma. And so they noted pathological complete response rates of 14, 14% in those patients. And pretty much set the benchmark, the stage, in a phase II design single-arm, of what you would potentially expect, in terms of pathological complete response rate, with kind of the standard of care chemo for bladder cancer. So how can you use that standard of care for urothelial bladder cancer, and establish the same benchmark pathological complete response data in upper tract disease?

I remember at that time when Jeanie presented the data, we were together, we were sitting at the bladder cancer advocacy network, the BCAN as we pronounced it, meeting in August, I think it was 2018 or so, or 2017, time flies. And we were discussing, what is the next step here? How can we do better in this disease? And through this wonderful breakout session, we started the design of the next trial, and it has been such a pleasure working with Jeanie and the team on this study.

And the new trial, it is called ECOG-ACRIN 8192, is going to be launched very soon. So this is the first announcement of this trial here at UroToday. This trial is a randomized phase II/III trial in upper tract disease. It has two different cohorts, different modules, as I say. The cohort that is eligible for cisplatin, cisplatin free patients, is to get randomized to dose-dense MVAC plus durvalumab, an anti PD-L1, or dose-dense MVAC alone. And the benchmark is, again, this data from ECOG-ACRIN 8141, and we will try to see whether we can improve upon the pathological complete response rate, the cancer survival, and overall survival, I think it will be important to see how this, what we call event-free survival specifically, works in a randomized phase II/III design. I think that this style has the potential to impact a practice because it is a large, one of the largest studies ever done in upper tract disease. And of course, as you pointed out, is launched through ECOG-ACRIN and the national ECOG network with support from all the other cooperative groups and of course, NCI and CTAP. So we are very excited about this.

The study has also another cohort, another module, for cisplatin unfit, cisplatin-ineligible patients who will get in a single-arm phase II design, gemcitabine plus durvalumab combination, to see whether the combination of these two agents, that has some very strong mechanistic rationale, could improve upon pathological complete response rates because we don't know how to treat these patients with no ability to get cisplatin. Usually, the specialists go straight to radical nephrectomy. So I think it will be interesting to see if we could have an interesting pathological complete response rate in those patients.

Hopefully, the study will launch soon, and we will definitely encourage people to open other sites. It's hard to accrue fast in upper tract disease trials because it is less common compared to other cancer, but still very important.

I think the last point that we'll make is, I want to highlight and emphasize the great work by Dr. Alison Birtle, and the other team members in the UK, with the POUT phase III trial, which was a separate phase III adjuvant trial establishing chemotherapy, cisplatin gemcitabine, for example, a standard of care for patients who never received neoadjuvant chemo. I think the POUT trial is an example of a gigantic effort that Dr. Birtle put together with her team, and showed that it is feasible to do dedicated phase III large randomized trials in upper tract disease. So inspired by Alison and her team, I think we can do great work. And Dr. Hoffman-Censits, Jeanie, has done great work already in this field in the United States, with her team.

Alicia Morgans: Fantastic. So for those of us who are taking care of patients with upper tract urothelial carcinoma, who are interested, we will make sure to put the schema on the page where we are displaying this information. And certainly, we will have a link to the site, where you can look up sites that may have this trial open. And if you are a community site or an academic site that participates in these efforts, you are welcome to review the protocol, and hopefully, open it at your site, or consider sending a patient to a nearby site, to have access to this trial. How many patients do you need to have, approximately, on the study, to really answer these questions? Given that there are these two parts, it makes it a little complicated. Do we need more patients for that?

Petros Grivas: You raise a great point, Alicia. We have this phase II/III design, so it's a smaller sample size and a larger sample size. It's probably a few hundred patients. But this makes the point that we need to open as many sites as possible. We think it is feasible, based on feasibility assessments that we worked out with urologists, and medical oncologists, like you and others. We think that the sample size is feasible to accrue, to attain, in the next couple of years or so.

The second cohort, which is only gemcitabine durvalumab, is a smaller cohort. I think it's 28 patients or so. I think it will be hopefully easier to accrue with smaller sample size. But it was important to learn the lesson from the ECOG-ACRIN 8141 when we use carboplatin gemcitabine for the cisplatin eligible cohort, and people were not interested in that. I remember we had only seven patients enrolled in two years or so. The enthusiasm is important in how much you have an equipoise to occur in the trial. So I'm glad we are discussing this today with your initiative, and hopefully, the word gets out there to the bladder cancer focus network, and position their clinical trial dashboard, and hopefully get the word out.

Alicia Morgans: Absolutely. We, as the community, definitely need to do some work in improving outcomes for patients, particularly with upper tract urothelial carcinoma. This is an unmet need, for sure. So I commend you and the team for putting this together. Great work, Dr. Hoffman-Censits, of course, Dr. Hahn, Dr. Margulis, everybody, wonderful work, and we all hope to come together soon to really get this trial going, get it finished, and get some answers.

So thank you so much for your time.

Petros Grivas: Thank you so much, Alicia, for the great discussion.