Transcript:Daniel P. Petrylak, MD: I think that moving earlier in this disease, of course, has been where immune therapy has been a standard of care, particularly with BCG for non—muscle invasive disease. So, what are some of the challenges, Rob, in developing checkpoint inhibition therapy for patients who are refractory to BCG?

Robert Dreicer, MD, MS: We all deal at that interface. The interface of urology and medical oncology, historically, has been at the neoadjuvant chemotherapy level. In academic centers, where the unmet need of BCG-refractory disease is real, these are patients, many of whom are technically fit to have a cystectomy. Cystectomy is potentially curative, but patients want to maintain their bladders. For the last 10 years, many of us have been engaged with looking at other kinds of therapies, targeted agents, earlier in the course in trying to, in a sense, convert BCG-refractory disease to a responsive disease using a variety of relatively soft measures of outcome. This has been part of the problem with drug development. And, actually, Dean has been heavily involved working with the FDA and the AUA to try to develop a pathway for drug development.

So, as we begin to think about bringing systemic therapies—because heretofore, obviously, BCG is an intravesical therapy—as we begin to interface with intravenously administered systemic therapies, which have, albeit, toxicities that our urologic colleagues would typically be uncomfortable working with, how do you interface to do the trials? And, actually, we can figure that out. The larger issue is going to be, what happens if we’re successful? We all know that in the broader community in the United States, the interface with community urology and medical oncology is somewhat a different dynamic. It’s really going to require rewiring that. Now, that’s a good problem to have if we get there. The trials that are beginning to look at this are now just beginning. There are a number of these trials, including several potential randomized trials that will begin to address BCG alone, BCG combinations with checkpoint, and checkpoint alone. It’s a particularly challenging place, but, again, it’s a big-time unmet need, and there is a bit of an FDA pathway to a regulatory approval. Dean probably should comment on that.

Dean F. Bajorin, MD: I think this is really important. Our FDA colleagues have actually met with academic leaders in the field and asked, “How can we be proactive with regard to the various subsets?” And point-of-fact, actually, they worked with us with regard to paradigms for approval for these drugs. So, a good example is this BCG-refractory, BCG-unresponsive population. The standard of care for those patients actually is a cystectomy. And many patients will say, “I have so-called superficial disease or early-stage disease.” One of my patients said, “You know, I’ve had my bladder for 70 years, I’m kind of fond of it. I’d like to keep it.” And so, a point-of-fact, actually, this is an area that has been under intense study. The FDA said, “Well, we can’t randomize against cystectomy. We can’t randomize against ineffective therapy because we really don’t have good effective therapies now.” So, they have accepted that a single noncomparator arm with endpoints of response and durability of response at landmark intervals will be satisfactory for approval in that disease setting.

Now we’re seeing, for example, atezolizumab plus BCG, and we’re seeing pembrolizumab used in that setting. There we’re seeing that the systemic side effects of the drugs, in terms of concern, still have concern, but we still have a disease that can be quite lethal. These patients can have 10% to 15% nodal positivity at the time of cystectomy, so be aware of that.

It’s moving down further. We have the patients who are on studies that are looking at BCG-relapsing disease; they do a little bit better. But there’s a trial looking at that population, too. And here, we’re getting into the radiation plus checkpoint blockade. And, point-of-fact, different courses of radiation therapy may affect immunological exposure or exposure of neoantigens. It may not be the same amount of radiation that we use typically for bladder preservation, and so those studies are now ongoing. And then, we’re, very soon I think in the United States and Europe, about to see studies looking at checkpoint blockade as frontline therapy, and that’s going to be much more challenging. Again, we still need our medical oncology colleagues, along with our urologic colleagues, to be able to do these studies together because of the toxicities we’re seeing. But that’s also an unmet need because we’re having international shortages of BCG. We’ve had companies leave the space, and we now have 2 strains left in the world—the Tokyo and TICE, but Connaught is now discontinued. We need drugs in that space.

Robert Dreicer, MD, MS: Just a reminder to our audience that bladder cancer is the most expensive disease to manage in the United States. Now, the bulk of those are lower-grade, lower-stage recurrent disease. But the reality is that there is potential for these therapeutics to really become pretty critical along the way. One day, its earlier use in a major economic impact will be there, and we also have to figure out how long to treat because this is also a group of patients in whom indefinite therapy is likely to be a significant challenge.

Elizabeth R. Plimack, MD, MS: So, you think moving it earlier will save cost?

Robert Dreicer, MD, MS: Well, if you could treat 1 time and not have to continue.

Elizabeth R. Plimack, MD, MS: It depends on efficacy, right.

Dean F. Bajorin, MD: So, you both bring up very good points, and that is that actually, in some of the designs of these trials that are under consideration, the standard of care is maintenance. The standard of care is 3 years of maintenance of BCG. And the trials are looking at checkpoint blockade for a far shorter period of time—up to a year and shorter treatment—looking at durability. These are important questions to ask, and hopefully, we can answer them together.

David I. Quinn, MBBS, PhD: I think, in a health economic sense, if you can reduce the burden of having to take a patient in cystectomy that early, the high-grade superficial-disease patient is the one that is most unpredictable for me. If you send them to cystectomy, you think, “Wow! We really probably didn’t need to take that bladder out,” or alternatively, whether the patient will be dead in 6 months from metastatic disease. It’s a big spectrum. From a pharmaco and health economics perspective, if you can reduce the need for cystectomy by 10% or 20%, that can have a real impact on the cost of the disease. And then, if you have some of the relapsing and refractory disease that responds, and even if you delay the next need for treatment, that may have a significant saving and outweigh the cost of the therapy.

Daniel P. Petrylak, MD: So, I think we have a lot of very important questions to ask. I think that this is an unmet medical need and that this is simply going to have an important impact on both the quantity and quality of life of our patients.

Transcript Edited for Clarity