Pembrolizumab + Chemoradiation vs. Trimodality Therapy for Muscle-Invasive Bladder Cancer: The KEYNOTE-992 Trial - Neal Shore

May 23, 2024

Sam Chang interviews Neal Shore about the KEYNOTE-992 trial comparing immunotherapy combined with chemoradiation to standard trimodality therapy for muscle-invasive bladder cancer. Dr. Shore explains that the trial evaluates Pembrolizumab with chemoradiation versus placebo with chemoradiation in patients suitable for bladder-sparing approaches. He emphasizes the importance of offering bladder-preserving options and highlights the global study's design, which includes patients with non-metastatic muscle-invasive bladder cancer. The study aims to improve bladder-intact event-free survival and overall survival. Dr. Shore notes the trial's potential to change clinical practice and provide new options for patients who prefer to avoid cystectomy. Both Drs. Chang and Shore stress the significance of multidisciplinary collaboration and patient selection in advancing bladder-preserving treatments, with no safety concerns raised so far in the study.


Neal Shore, MD, FACS, Director, CPI (Certified Principal Investigator by the Association of Clinical Research Professionals), Medical Director for the Carolina Urologic Research Center and practices with Atlantic Urology Clinics in Myrtle Beach, South Carolina

Sam S. Chang, MD, MBA, Urologist, Patricia and Rodes Hart Professor of Urologic Surgery, Vanderbilt University Medical Center, Chief Surgical Officer, Vanderbilt-Ingram Cancer Center Nashville, TN

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Sam Chang: Hi, I'm Sam Chang. I'm a urologist at Vanderbilt University Medical Center, which is located in Nashville, Tennessee. We are lucky to be connected by Zoom to another area in the South. I have great affection for Carolina and we have Dr. Neal Shore, who's the medical director of the Carolina Urologic Research Center.

Dr. Shore, as you all know, has been instrumental in many of the key trials in urologic cancer, including prostate, bladder, and kidney cancer. So, we're quite fortunate to have him. He's going to be discussing a trial of immunotherapy in conjunction with and in comparison to standard trimodality therapy for muscle-invasive bladder cancer. So Dr. Shore, Neal, thank you so much for being part of this today, and I look forward to you enlightening us regarding this trial.

Neal Shore: Well, thanks very much, Sam. It's always my great pleasure to chat with you. It's interesting you bring up Tennessee and South Carolina. Fascinating, the demographics happening in the US and more and more people moving to the South. Not sure of the reasons for it. Maybe it's the weather, maybe it's employment opportunities, but-

Sam Chang: Maybe for you, Neal, maybe it's for you. I mean, don't discount that fact, all right?

Neal Shore: But the one thing that we're clearly seeing is more patients aging and more patients with cancer, which is a correlate to aging. So we have so many really great trials to try to change clinical care so it's a pleasure and an honor for me to be here with you today.

Well, I had the pleasure at AUA 2024 at the trials in progress session, which by the way was a really great and innovative session that was sort of standing-room only this year. And kudos to Dave Penson, the secretary, for organizing this new program or new session within AUA. I thought it was really great to hear about trials in progress. And this particular one, as you can see, is pembro plus chemoradiation versus prospective placebo infusion with chemoradiation therapy for patients with muscle-invasive bladder cancer. Really a great steering committee. It's a global study.

It's always been near and dear to my heart for patients if they can avoid cystectomy and we could do it in a way that's efficacious and safe. And I know, Sam, you probably have one of the highest volumes of cystectomies case experiences. But always, of course, as in all surgery, we're always trying to figure out ways to limit our extirpative intensity and removing a bladder is not for the faint of heart. So if we can do something that's bladder-sparing, and in this particular case, trimodal aggressive resection, chemoradiation, and now does a checkpoint inhibitor such as pembro make a difference?

We know that chemoradiation therapy as a bladder-preserving option has been available. It has had different levels of adoption throughout the world and even within the United States. I think there are certain colleagues who've had some really nice results and others who've said, "Ah, I just feel more comfortable doing a complete radical cystectomy and a diversion."

We know that pembro has now been approved and phenomenal results as per the recent 301 data as now first line when you combine it with the antibody drug conjugate enfortumab vedotin. There's also really good data on pembro now as adjuvant therapy that was recently presented for patients who are high-risk post-cystectomy. And then, of course, the sole indication among the checkpoint inhibitors for BCG-unresponsive CIS.

So we organized this study a few years ago to see if chemoradiation, a traditional approach in the guidelines for the right patients who have the right anatomic lesions away from the bladder base, not involving prostatic urethra or the bladder neck, no hydronephrosis, would adding pembro be of benefit to chemoradiation. And the combination would be evaluated in a prospective way at various regimens for chemotherapy, but a fairly standard agreement amongst the radiation oncologists of the radiation dosaging.

And here's the study design, a global study. T2 to T4 patients, no evidence of metastatic disease on conventional CT scan imaging, MR also allowed, and patients clearly had to be either refusing or really be an appropriate option to choose a bladder-sparing approach. So hydronephrosis involvement near the ureteral orifice, bladder neck, prostatic urethra, all excluded, significant histologic variance also. We really tried to make sure this was clearly greater than 50% urothelial histology.

Some of the stratification factors you can see at the bottom. We check using the PD-L1 CPS interrogation, one-to-one randomization, and there's a whole different, and you could see at the very bottom of the slide, different chemotherapeutic regimens, which can vary around the world. Some folks, whether it's platinum-based, 5-FU and mitomycin, or gemcitabine even by itself. So we did account for the different medical oncology, radiation oncology preferences.

And so one can see that the primary endpoint here is bladder intact with event-free survival. Of course, OS is important, and other really key secondary outcomes, if and when they would have recurrence or potential ultimate cystectomy, PROs, etc., and rigorous disease assessment. So we're really excited about this.

I'm doing some other bladder-sparing trials as well. I have one other one that's competing. I think you're involved with one, Sam, and I think this is where our global network is for the study.

But at the end of the day, I think this is all about bringing options to patients. Yes, radical cystectomy is the gold standard, but if we can show that chemoradiation is appropriate and correct, which it already is in some patients, but then augment those findings with a PD blocker, I think that'll be a real advance for the field.

So thanks very much.

Sam Chang: Neal, that's fantastic. I think the realization by urologists that trimodal therapy, that bladder-preserving therapy really should be an option discussed with patients depending on their disease, depending on their characteristics, their health, etc. Multiple factors go into that decision-making. But I think the first point is that there should be at least a discussion.

As you look at this trial and as it enrolls a combination of immunotherapy plus chemotherapy and radiation therapy, what do you think will be the challenges of patients actually adopting this? Because we're adding therapy upfront, we're adding therapy afterward. In terms of therapy burden, tell me your thoughts regarding that.

Neal Shore: Yeah, I appreciate that question. Sometimes, depending on the patient's location, some comorbidities, their proclivity for intravenous or parenteral administration of therapies, concerns about additive toxicities, whether they're from the chemotherapy or the IO, which these are all real issues. And for some patients, they may just say, "Hey, Doc, I can't do this. Let's just go with the cystectomy," and I think we have to respect that. But I do think for the overwhelming majority of my patients, if they're having good voiding function and they're not having a lot of dysfunctional issues, persistent hematuria, clot retention, etc., they'd like to keep their bladders.

And this is, to me, we talk about the vaunted notion of the multidisciplinary team. This is a perfect example. So you're working together with uro-oncology and medical oncology unless you're comfortable in giving IO. But you're probably going to be having your medical oncologist deliver the chemotherapeutic, for sure, and maybe the IO as well, and then, of course, the radiation oncologist. It does take a lot of coordination. You're absolutely right. I mean, if you're out in a rural part of the world and you're besieged by a lack of personnel, power, support, and there are logistical issues, this could be very challenging.

But nonetheless, if you have really good interdisciplinary communication, I think this can really ultimately help patients. And not only by getting them cured, which is obviously the gold standard, but maintaining quality of life. And there's no doubt that the PRO literature, the patient-reported outcome literature on this is really very good. Colleagues of ours, Jason Efstathiou at Mass General, he's done a great amount of work on this, and he's been a big champion of this.

So I'm excited to be part of this. We're doing this Merck 992, we're doing the SunRISe, too, and I know you're doing an additional trial as well, and this is how we make changes. This is how we improve patient options.

Sam Chang: No, I agree with you. Absolutely. And I will say that I think in the US we're starting to overcome this very strong-seated bias from, honestly, some of our previous leaders, who really advocated that cystectomy was greater than, better than any type of bladder-preservation therapy.

But in point of fact, just as you said, unquestionably for certain patients, just as certain patients shouldn't undergo cystectomy and perhaps certain patients shouldn't undergo combination trimodal therapy, that for a lot of patients this actually does make sense and can result in excellent, not only oncologic control and cure, but also symptomatically the ability to avoid a diversion and to be able to maintain their urinary control without significant side effects. Just as we've improved surgical techniques, there's no question that radiation therapy has improved step in step. And so I think that discussion point and the way you've been leading these trials, I think, are very, very important.

As you enroll these patients, obviously, the larger trials have independent safety and data monitoring committees that look at either futility or side effects, etc. And obviously, no red flags at this point, which is encouraging as well. Correct?

Neal Shore: Absolutely. No red flags. Yeah, I think there are now three really substantial phase three trials now addressing this notion of bladder-sparing. Of course, you've got to really select appropriately, and there are some logistical issues. But look, if we could get this across the finish line, I think this will only be very beneficial to our patients and to physicians who are seeing more and more of these patients. It's an aging population and in different parts of the world, there's just quite a significant amount of muscle-invasive bladder cancer.

So yeah, I'm excited about it. I'm happy that you're part of this, and I really enjoy the fact that we're trying to push our boundaries and try to see whether we can expand that toolbox or armamentarium that we like to talk about.

Sam Chang: Well, Neal, thank you for this presentation, but thank you actually for all the many trials you've helped actually get across the finish line. I mean, without your particular research center and without your leadership, I can think of multiple trials that probably would not have been accomplished to the ability and the scope that they've been able to in prostate cancer, kidney cancer, and bladder cancer. So thanks to you and we look forward to more trials in the future.

Neal Shore: Thanks, Sam. It's a great pleasure to be with you today. Really appreciate it.