Pembrolizumab in Combination With Gemcitabine and Concurrent Hypofractionated Radiation Therapy As Bladder Sparing Treatment for Muscle-Invasive Bladder Cancer - Arjun Balar

June 10, 2021

In this conversation with Alicia Morgans, MD, MPH, Arjun Balar, MD highlights a multicenter study first designed in 2014 of gemcitabine hypofractionated radiation therapy and pembrolizumab all in combination as bladder-sparing therapy for patients with muscle-invasive bladder cancer that had a total of 54 patients. The goal of the study was to test the role of immunotherapy pembrolizumab added to standard trimodality bladder preservation treatment to see if there is a role for immunotherapy and if immunotherapy improves the outcomes of bladder preservation treatment in muscle-invasive disease. Dr. Arjun Balar presented the results from this phase 2 trial at the 2021 ASCO annual meeting. The primary endpoint is 2-year bladder-intact disease-free survival, defined as first of muscle-invasive bladder cancer or regional nodal recurrence, distant metastases, or death. There are several  take-home messages from this  study, and  importantly, trimodality bladder preservation therapy is an effective non-surgical option for patients with muscle-invasive bladder cancer with curative intent.  


Arjun V. Balar, MD, Associate Professor, Department of Medicine at NYU Grossman School of Medicine, Medical Director, Clinical Trials Office, Perlmutter Cancer Center, and Director of the genitourinary medical oncology program at NYU Langone‚Äôs Perlmutter Cancer Center. NYU Langone Health, New York, New York.

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

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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'm so excited to have here with me today, Dr. Arjun Balar, who is an Associate Professor of Medicine and the Director of the GU Medical Oncology Program at NYU Langone's Perlmutter Cancer Center in New York. Thank you so much for being here to talk with me today, Dr. Balar.

Arjun Balar: Thanks so much for having me.

Alicia Morgans: Wonderful. I wanted to talk with you about your presentation at ASCO 2021 about your bladder-sparing protocol, which involves gemcitabine concurrent with radiation and involves pembrolizumab as well. Can you tell us a little bit about this bladder-sparing approach involving immunotherapy for muscle-invasive bladder cancer? What did you present?

Arjun Balar: So what we presented is a bit of a labor of love. This is a study that I first designed in 2014. It was a study of gemcitabine hypofractionated radiation therapy and pembrolizumab all in combination as bladder-sparing therapy for patients with muscle-invasive bladder cancer. It was a multicenter trial. We lead it at NYU. We had five total centers; the University of North Carolina, the University of Michigan, the University of Chicago, Memorial Sloan Kettering, and us. It was a total of 54 patients.

The goal here was to test the role of immunotherapy pembrolizumab added to a kind of standard trimodality bladder preservation treatment and to see, is there a role for adding immunotherapy to this and can immunotherapy improve the outcomes that we typically see with bladder preservation treatment in muscle-invasive disease?

Alicia Morgans: Great. I'm really impressed and happy that you and the team have actually used quite a geographic array, at least on the East Coast, but a geographic array of different centers that may have varying experiences with chemoradiation, or varying buy-in because even within centers that do a lot of chemoradiation for bladder-sparing protocol, sometimes there are clinicians who are more in favor or less in favor.

So to have this diverse array of sites, I think is really, really important to demonstrate, not just efficacy, but really feasibility across these different centers. So kudos to you on engaging so broadly. It took several years to enroll and you presented the one-year follow-up results. What were your findings in terms of disease control?

Arjun Balar: Absolutely. Just to kind of walk through the trial design, all patients had clinically localized muscle-invasive bladder cancer, ECOG performance status at zero or one. Patients could have either refused cystectomy or elected bladder preservation, which I like saying rather than saying refusing cystectomy, they chose bladder preservation. Perioperative chemotherapy was not allowed as part of this trial.

All patients received a single dose of pembrolizumab. Two to three weeks later, they got a maximal TURBT, and then three to four weeks later, they got hypofractionated radiation treatments. So 52 gray, whole bladder only, 20 fractions, IMRT was preferred and then gemcitabine twice weekly, 27 per meter, two days apart. And then concurrent pembrolizumab 200 mg every three weeks for three doses.

I know that's a mouthful, but as you watch the presentation, you will kind of watch through the treatment schema. And then 12 weeks post-radiation, they get a TUR of the tumor bed, urine cytology, and contrast-enhanced imaging for an assessment of response.

The primary endpoint of this study was bladder intact disease-free survival. This was a primary endpoint that we decided upon way back in 2014, 2015 when we designed the study. And we felt that was the most important and relevant endpoint. It includes the first of any muscle-invasive recurrence, regional or distant metastasis, needs for cystectomy, or death. And that we felt was the most conservative measure by which treatment fails our patients, so if any of those happened, that was an event for the primary endpoint of the study.

Our control rate based on an RTOG pooled analysis that was actually published just around that time in 2014 was about 60% at two years. And we felt, based on our power calculations, et cetera, that we could enroll up to 48 patients in the efficacy cohort of the study. We had a phase one group and an efficacy cohort. 48 patients, we had 85% power to detect a 20% absolute improvement to 80%. So 60% to 80% we could detect at a two-year rate. And so, that was our goal in this study.

Over the course of basically, three and a half to four years, we enrolled between May 2016 to October 2020, pandemic notwithstanding, we were able to fully enroll in this study. What we found, again, typical of the bladder cancer patient population, these were patients that were generally a bit older, but despite that, about a majority of our patients, 75% had actually declined radical cystectomy. They were surgical candidates but chose radical cystectomy. And what we found as per our preliminary analysis of our primary endpoint, bladder intact disease-free survival, our one year estimated bladder intact disease-free survival rate is actually 88%.

When we look at other key metrics such as metastasis-free survival, when we look at the entire study population of 54 patients, because we had six patients enrolled in the safety cohort and 48 in the efficacy court, when we combine everything together, 85% metastasis-free survival rate at one year. If we look at the entire bladder intact disease-free survival rate in all patients in 54 patients, it's actually 89%.

These data are preliminary, and they are quite promising, but so far, the rates of disease control and the event-free rate are actually quite promising. When we look at safety, overall treatment was very well tolerated, whole bladder only radiation and avoiding pelvic nodes is actually kind of the standard of care in Europe and the UK in particular. I think it's something that we need to be doing in the US and I think the data from this trial support that as well.

Alicia Morgans: That is really exciting, very, very encouraging. Of course, there are other studies of bladder preservation strategies for patients with the muscle-invasive disease. This is really the one that is leading the way and giving hope, I think, for us as we continue to enroll in those trials.  So congratulations. Just to comment and clarify, the pembrolizumab was only given, how many doses after completion of chemo rads? Because that's not a huge burden on patients either in terms of [crosstalk 00:06:34].

Arjun Balar: Yeah, we designed this study not to have a long tail. Whether it's SWOG 1806 or KEYNOTE 992, those studies have a long tail. They have kind of a maintenance component, which might actually improve outcomes. In our study, one dose pre maximal TURBT and then three doses concurrent. That is it. So a total of four total doses.

Alicia Morgans: That is fantastic. Thank you so much for sharing this data with us and congratulations again on a wonderful study and a fantastic presentation.

Arjun Balar: Thanks so much, Alicia. Thanks for having me.