Combining Pembrolizumab and BCG Immunotherapies: The KEYNOTE-676 Trial in High-Risk NMIBC - Neal Shore

March 5, 2024

Sam Chang converses with Neal Shore about the KEYNOTE-676 trial, focusing on combining pembrolizumab with BCG for high-risk NMIBC patients previously treated with BCG. This study aims to explore the potential synergy between two immunotherapeutic agents, leveraging pembrolizumab's success in MIBC to improve outcomes in NMIBC. With enrollment progressing well, the trial signals a collaborative future between urology and medical oncology, emphasizing the importance of managing immune-related adverse events and the growing need for comprehensive bladder cancer care. Dr. Shore envisions a future where advanced, bladder-preserving treatments significantly reduce the need for cystectomies, driven by innovative drug delivery methods and early diagnosis. This discussion highlights the evolving landscape of NMIBC treatment and the collaborative efforts required to advance patient care.


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, Vanderbilt University Medical Center, Nashville, TN

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Sam Chang: Hello everyone. My name is Sam Chang. I'm a urologist in Nashville, Tennessee, and I have, I would say, not only an honor but a privilege here to have a chance to have a conversation with Dr. Neal Shore. And we're going to be talking about the KEYNOTE-676 trial, which is a trial looking at pembrolizumab and looking at it with BCG in a patient population that actually already had been exposed to BCG. It's a trial in progress submission for ASCO GU 2024. So Neal, first of all, welcome and give us a little idea of what this trial is about.

Neal Shore: Sure. Thanks, Sam. As always, fabulous to be with you. Thanks for everything that you've done for educating all of our colleagues in bladder cancer. This is a really good study. We know that pembrolizumab is approved, and for BCG unresponsive CIS based upon the KEYNOTE-57 study, which is really a very, very important study leading the way for IO in MIBC. Of course, we have IO in so many other aspects of advanced urothelial cancer. But in this study, we take the patients who have high-risk NMIBC, TaG3, T1, CIS, and they're randomized if all had one induction course.

Sam Chang: Okay. And that's defined as five out of six?

Neal Shore: Five out of six.

Sam Chang: Okay.

Neal Shore: Five out of six, no need for maintenance, and then they get randomized to Q six-week pembrolizumab versus with BCG.

Sam Chang: With BCG. Okay.

Neal Shore: Versus BCG maintenance therapy. It's accrued extremely well. We're really excited to see, can this make a difference? Will we get synergy from adding two immunotherapeutic agents? As everybody knows, BCG is one of the first immunomodulating agents in part of uro-oncology.

Sam Chang: And so with that in mind, you're looking at the same type of endpoint, looking at complete response and then looking for obviously disease-free rate over periods of time. With kind of the early enrollment, you said enrollment's going well. Is it close to finishing accrual or how much longer do you think it'll be?

Neal Shore: Yeah, no, it's done extremely well. And so we've actually capped out at our site, we've enrolled so well with it. I think the one thing that a lot of urologists, medical oncologists have really understood since the approvals of the IOs in 2016, not that long ago, just now, a little over seven plus years ago, is just getting comfortable with recognizing immune-related adverse events. And the grade threes and above are really only around 10 to 12, maybe 15%, depends on the series, but they're absolutely, my message to my urology colleagues, just like our medical oncologists have recognized this, and not just with pembrolizumab but with other checkpoint inhibitor therapies, that these events are very manageable, and it's all about educating patients. Our advanced practice providers, our nurses help out with that and just keeping patients alert to issues regarding rash or colitis. Of course, the thyroiditis things we check lab work regularly.

And I think this is all part of expanding the advanced bladder cancer clinic that we want to have. So it's no longer about the internecine concerns of one specialty versus another. We have this personnel shortage. We've got advancing age, more patients with bladder cancer, more NMIBC patients, particularly high risk. Uro-oncology needs to work closely with medical oncology, and I'm really excited about this study. There are several other studies that are looking at different IOs and IO with induction maintenance BCG, just induction BCG. And so we're going to see a lot of this data come forward in the next few years. So I'm happy to be part of it.

Sam Chang: I think, to your point, Neal, a huge explosion in the whole area of non-muscle invasive bladder cancer with different delivery systems, different synergistic combinations, perhaps looking at kind of upregulating the immune response and then hopefully having longevity associated with that. I mean, if you look at the IO therapies for other advanced cancers, advanced renal, advanced bladder, that signal, not everyone obviously gets a benefit. But for those that do, that long-term signal and benefit would be obviously really appealing for our patients with non-muscle invasive bladder cancer. And I'd want to hear from your point of view, I think there really is an understanding and a push to move them away from cystectomy. I mean, that is the guideline-recommended statement, but for the vast majority of these patients, if we can avoid that and have them continue to have a functional bladder for a period of time, I think that's a win. I want to know what your thoughts are regarding that.

Neal Shore: Yeah, I completely agree with you. I appreciate your perspective. You are one of the highest volume series of radical cystectomies probably in the last 10, 15 years, 20 years. You've been at it, and you do them extremely well. And you're at Vanderbilt where you have a great support system. But you're right, I mean, I think 95% of patients, if we can offer them something other than bladder removal, so trimodal bladder-sparing strategies that involve IO, some other trimodal bladder-sparing strategies that are looking at different devices and dwell times in the bladder to help improve local treatment in conjunction with radiation and IO therapy, is a very exciting time. So trimodal bladder sparing. And then also even some neoadjuvant studies as well, whether we're going to combine IO with an antibody-drug conjugate. We just saw the incredible data that came out at ESMO recently, the 302 and the 901. I mean, these were remarkably successful studies. So IO is here. I'm very excited about MERCK's 676, both the A and there's a B cohort too. But this is very important for moving the field forward.

Sam Chang: Right. And with the understanding, it's just as you said, the idea of exclusionary disciplines I think has to be a thing of the past, understanding that we all work together toward a common goal. Who gives what I don't think is as important as we are giving. What really are the best possible agents for our patients? And understanding that and hopefully educating the surgeons from a standpoint of, "Hey, these are side effects you need to start thinking about, you need to be aware of, and you need to help track and take ownership of these patients in terms of being able to help support them with the different options of care," I think is really important in an area that I think will continue to expand, especially as we introduce this into our residencies, into our fellowships, et cetera. And I want to thank you and all your efforts that you really put into educating actually the next generation of, "Hey, these are our kind of treatment choices that we as a group can involve ourselves in, help our patients, and understand kind of their mechanisms and how they work best."

If you were to look at your... I want to make this the last question because I want to put you on the spot a little bit. If you are to look into your crystal ball like Neal Shore's crystal ball, it's a very big crystal ball. Okay, so Neal's looking at his crystal ball. Tell me, five years from now... I'll give you five to ten years from now, is our treatment for non-muscle invasive bladder cancer going to be radically different, or is it going to be similar in that we're going to have intravesical treatments, et cetera, et cetera, we're going to have things that we will be giving to try to control the disease? Are we going to be able to eradicate non-muscle invasive bladder cancer? So it's a difficult question. What do you think in five to ten years?

Neal Shore: I really enjoy the question because when I was a medical student-

Sam Chang: 12 years ago.

Neal Shore: Yeah, just a couple of years ago, I went and I did a summer clerkship at MD Anderson, and I was still trying to figure... it was anesthesia, and I was still trying to figure out what I wanted to do. I was leaning towards surgery, and I was going with all these anesthesiologists doing all this preoperative work, and then I'd go into all the different operating rooms. And the surgery that was most appealing to me was when I went into the urology room and I saw them doing the radical cystectomies and the ileal conduits. I mean, they weren't even doing neobladders or continent diversions back then. And I was like, "Okay, I'm sold. I'm hooked on this. This is what I want to do."

But now you fast-forward and I realize after doing a lot of cystectomies in the early part of my career, I was like, "Okay, this is hard work and there's a lot of toxicity to it, and it's great surgical exercise, and I loved it, but at the same time, it was hard and hard on patients." So I think that in your crystal ball question, I think we're at this inflection point where we have so many fascinating ways to get drug delivery into the bladder with different new devices, but other just plain intravesical delivery. It's easy, it's right in the urology wheelhouse, whether it's viral gene vectors of various iterations, chemotherapies, IO-ADC combinations. So I think that ten years from now, five years from now, if we were to look at the absolute volume of cystectomies, I would think it'd be dramatically decreased.

Sam Chang: It's not often, but I agree with you, Neal. I think that you are absolutely right. I think we'll get to the point where if we do a good enough job of diagnosing these patients early, that there's a very good chance that we'll hopefully be able to prevent them from getting more advanced disease, invasive disease, et cetera. And that should lead to a decrease in the number of cystectomies we ultimately do. So Neal, thank you as always, great to see you and great getting your insight regarding not only the ongoing 676 trial but also looking forward to your insights regarding non-muscle invasive bladder cancer. So thanks again.

Neal Shore: Thank you.