Navigating the Complex Landscape of Adjuvant Trials in Urothelial Carcinoma - Robert Dreicer

May 2, 2022

Sam Chang and Robert Dreicer delve into the evolving landscape of adjuvant trials for urothelial carcinoma. Dr. Dreicer discusses three pivotal studies: IMvigor010, CheckMate 274, and AMBASSADOR, each exploring different drugs like atezolizumab, nivolumab, and pembrolizumab in high-risk patient populations. While IMvigor010 showed negative results, CheckMate 274 demonstrated a disease-free survival advantage, leading to FDA approval for nivolumab in urothelial cancer. The conversation also touches on the challenges and future of personalized care in urothelial cancer, emphasizing the need for biomarker-directed treatment and acknowledging the hurdles posed by an older patient population and limited trial volumes. Dr. Dreicer predicts significant progress in the field over the next five years, despite these challenges.


Robert Dreicer, MD, MS, MACP, FASCO, Associate Director for Clinical Research, Deputy Director of the University of Virginia Cancer Center, Head of Medical Oncology, Co-Director, the Paul Mellon Urologic Institute, Professor of Medicine and Urology at the University of Virginia School of Medicine, Charlottesville, VA

Sam S. Chang, MD, MBA, Patricia and Rodes Hart Endowed Chair of Urologic Surgery Professor Department of Urology at Vanderbilt University Medical Center

Read the Full Video Transcript

Sam Chang: Hello, everyone. My name is Sam Chang. I'm a urologist in Nashville, Tennessee, and we are incredibly fortunate to have with us today Dr. Robert Dreicer. Dr. Dreicer is the Deputy Director of the UVA Comprehensive Cancer Center and the Director of Solid Tumor Oncology at the University of Virginia. He is also a Professor of Oncology and Urology. Obviously, he is quite fortunate to have that role at the University of Virginia. Dr. Dreicer has been one of the iconic leaders in medical oncology for GU cancers for quite some time, so we are honored and privileged to have him. Today, we are going to focus on adjuvant trials for urothelial carcinoma. Dr. Dreicer, take it away.

Robert Dreicer: Dr. Chang, thank you very much for the invitation to spend a few minutes chatting with you about this. I have just a handful of slides to set the agenda. Adjuvant studies in terms of immuno-oncology are a relatively recent dataset. IMvigor010 was the first of these trials to be reported. It looked at atezolizumab versus observation in high-risk patients. As you can see on the slide, the eligibility criteria indicate that this disease subset is a very high-risk group of patients, with anywhere from a 50% to 100% chance of systemic failure. Nobody argues it's a bad disease population. Unfortunately, this trial was completely negative, as you can see below.

That was followed up more recently by CheckMate 274. This is a similar study in terms of the high-risk patient population eligible for enrollment. Obviously, it involves a different drug, nivolumab, compared to atezolizumab. This study also had a placebo control, which may or may not be a significant issue when we look at the results.

As reported by Dr. Bajorin in the New England Journal of Medicine about six or seven months ago, there was a disease-free survival advantage favoring nivolumab. The study was not yet mature for overall survival. On the basis of this data, the FDA granted a broadening of the label for nivolumab in urothelial cancer, and it is now FDA-approved.

AMBASSADOR is the third study. This study looks at a very similar patient population, comparing pembrolizumab to observation with co-primary endpoints of both PFS and overall survival. This trial has been accrued, and we are awaiting data.

To close out, this is just a sampling and not a complete list of trials in the muscle-invasive bladder cancer space. Some of these are adjuvant; some are perioperative studies. There is an enormous amount of interest, and some of these include both chemotherapies as well as immune checkpoints.

Sam Chang: Rob, let's take that last slide first. What really excites you the most in the adjuvant field? Is it a combination of ADCs with chemotherapy? Is it an immunotherapy combination?

Robert Dreicer: Needless to say, Dr. Chang, we recognize that this is a solid tumor with the oldest patient population, with a median age of about 73 years old. Even though we are talking about patients who are probably enriched in terms of comorbidities, the fact that they can undergo a cystectomy puts them in a somewhat different group. They're fit enough to have this very invasive surgical procedure, and the requirements—whether they are having neobladders or whatever—are an assault on the system. It's a bit of an admixture. In the adjuvant setting, you select your patients based on surgical pathology, and we understand the better risk. We have a neoadjuvant paradigm that you and I painfully know has developed over 25 or 30 years. It's restricted to a group of patients, and depending on your practice, anywhere from 40% to 60% of your patients can get cisplatin-based therapy; 40% can't. Many of those can have cystectomies, and we want to be able to move the needle and change the natural history of the disease.

Conceptually, I think we all say, "Look, if we're treating micrometastatic disease with adjuvant therapy, which is what we're doing both with neoadjuvant as well as adjuvantly, if something really works, we want to use it earlier." Nothing about that is particularly earth-shattering. We all get that. But I would like to replace the paradigm of giving cisplatin only to certain people to broaden the population. If you're going to take a patient to cystectomy and we have reason to believe they are relatively high-risk because they have muscle-invasive disease, then we should be able to offer perioperative therapy. That's just a high-level observation.

Sam Chang: Along those lines, then, Rob, what is going to be the most important factor in determining the best treatment for each population in the neoadjuvant regimen? Is it personalization? Is it the broad decreased side effects so that everybody gets a little bit of benefit? What do you think?

Robert Dreicer: That's a great question. Obviously, we would all love to biomarker-select our patients because theoretically, we are enriching whatever group we have with the best therapy likely to provide better outcomes, at least in that group. We have to care for all-comers. Not everyone may have a biomarker-directed ability to treat. I think it's going to be a combination of things. My sense is that over the next few years, as many of these perioperative studies begin to report and weget smarter about selection, we will see progress. For a while, it will be broad brush, and then eventually, we will get smarter and say, "This for this group, this for that group."

Sam Chang: My knowledge of lung cancer, breast cancer, and all these other cancers is obviously minimal, but I know you've got exposure to it. Are we getting to the point where we will be as sophisticated as our breast cancer colleagues in terms of really being able to have two or three different submarkers and then maximize care? Or is it that we don't have enough patients to run through trials to determine this? What's your prediction on the timeframe for individualized, personalized care?

Robert Dreicer: Yeah, that's a great question. In breast cancer, because of the volume and, frankly, because our breast cancer colleagues have been thoughtful in conducting the kinds of trials they have, there's sequence information and molecular targeted therapies that you can sequence. We haven't been able to do the same thing. Again, you and I both know this; we've been in this business for a long time. Up until maybe the last five to 10 years, getting anyone interested in conducting trials or new drug development in urothelial cancer was absent. You and I both marvel at the progress that's been made. There are wonderful new drugs, and that's exciting, but in fairness, the hard work of the science, the translational science, and then the integration into the clinic is just now beginning.

As you pointed out, the volumes aren't there. It's an older patient population, so when you deal with folks—again, you're in a moderately-sized city but you draw patients from very rural parts of your state and region. I'm also not in a big city and I draw patients from very far away. It's hard for older patients to get on a trial. I think we're always going to be somewhat hamstrung. We'll have to extrapolate from smaller trials. We probably won't have a multitude of sequence data simply because we can't have it. So, I think we will be challenged, but I do think that five years from now when we look back and say, "What was happening 10 years ago?" we'll be in a very different place. It will still be an uphill slog, but I think you will look back and say, "Wow, that was significant progress."

Sam Chang: Well, Rob, thanks again for spending some time with us. Every time I interact with you, I always gain nuggets and pearls of wisdom based on your expertise. Obviously, the fact that you spend time actually treating these patients and learning from them is invaluable. I really appreciate your insight, as always. Thanks again for spending some time with us.

Robert Dreicer: Pleasure, Dr. Chang. A great pleasure. Thank you very much.