Antibody Drug Conjugates for the Treatment of Metastatic Urothelial Carcinoma - Petros Grivas

July 8, 2019

Alicia Morgans and Petros Grivas discuss the use of antibody-drug conjugates (ADC) as a new approach for the treatment of metastatic urothelial carcinoma (mUC). The two review the latest data presented at the 2019 American Society of Clinical Oncology meeting, specifically the use of enfortumab vedotin. Dr. Grivas further discusses sacituzumab govitecan, another popular ADC, and the promising clinical trials involving these new drugs. Additionally, Dr. Grivas reviews the benefits and risks of antibody-drug conjugates use and discusses the future of these drugs in the treatment of mUC.

Petros Grivas, MD PhD, Associate Professor, Clinical Director of Genitourinary Cancers Program, University of Washington, Associate Member, Clinical Research Division, Fred Hutchinson Cancer Research Center

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 am a GU Medical Oncologist at Northwestern University. I am delighted to speak today with a friend and colleague, Dr. Petros Grivas, who is a GU Medical Oncologist and Associate Professor of Medicine at the University of Washington where he practices in the Seattle Cancer Care Alliance in the Fred Hutch. Thank you so much for joining us today, Dr. Grivas.

Petros Grivas: Thank you so much for having me, Alicia. I appreciate it.

Alicia Morgans: Of course. So, Petros, we are recording one of our quick takes, a brief sort of encapsulated piece of information on a particular topic really to give high yield information to folks who need to get the information now, and they need to know what's most important. And we're going to be recording and talking about antibody-drug conjugates, which are, it's a new approach to the treatment of urothelial carcinoma, and there's one, in particular, that is sort of rising to the fore of all of our thoughts after ASCO presentations and other presentations Enfortumab Vedotin.

So I'm wondering if you can tell us a little bit about what are antibody-drug conjugates? We in GU have not been using those often. What is it about Enfortumab Vedotin that actually seems to be promising, including your take on some of the latest data presented at ASCO 2019, and where do we go from here in terms of where these antibody-drug conjugates may fit into our landscape both now and over time?

Petros Grivas: Thank you, Alicia. It's a great question. And the field of urothelial cancer is really moving very fast. It's very exciting to have this emerging data that might alter the way we treat this very challenging and lethal disease, metastatic urothelial cancer. Particularly, the antibody-drug conjugates have raised significant interest and attention in the last couple of years, and there are probably two of them that are far ahead in the development and clinical trial testing. You mentioned one of them, Enfortumab Vedotin. The other is sacituzumab govitecan.

People start with Enfortumab Vedotin. I think the data that we saw at ASCO 2019 annual meeting by Dr. Petrylak and Dr. Rogersbech and the rest of the team, it was really impressive with an overall response rate approaching 40% in patients without any particular biomarker for selections because [inaudible 00:02:28] commerce, and in the middle of the original response, you know they probably approached seven months or so. It's meaningful in this type of setting especially patients who have prior treatments with platinum-based chemotherapy in sacituzumab govitecan. 

So we talk about the little third-line patients there, so helping a response rate of 40% or so is very impressive in reaching about the historical data with the deductions, for example, of how their response rate about 15 to 20% in that particular setting. So definitely very promising response rate. If you look at the data more carefully, there were 125 patients, if I recall correctly, the number of [inaudible]. Of those, 110 had subsequent scans after baseline. And this subset of patients had data presented about the redaction of tumor size, tumor burden, and it was interesting that I think it was around 80% or so, maybe a little bit more, but had a redaction of the tumor size. So very impressive number. Some of them met, half of them or so, met the definition of RECIST 1.1 response. 

So definitely Sacituzumab Govitecan. The median progression-free survival was very promising. As I always say, we have to be very careful how we interpret complementary curves, from single-arm studies in the absence of comparator, however, they do look very promising for sure. And there is now a phase three trial ongoing, comparing Enfortumab Vedotin compared to conventional hydro toxic chemotherapy. For example, [00:04:22 inaudible]. But many of us I think, are really, I would say, impressed with the ongoing data so far. And the question will become the regulatory fate of this agent. I think the data, I would assume, is going to be some need to the regulatory agencies for potential accelerated approval. We'll have to see how that process goes. 

But overall the data is very promising. Of course, we've got to be very cautious about toxicity, education, and management. There are a number of potential adverse events with Enfortumab Vedotin like other agents as well.  Every time we do the development of new drugs in cancer, we've got to think about benefits and risks.

So particularly with this agent, there are probably a few adverse events that need some discussion. For example, neuropathy is relevant, and a significant proportion of patients may get some neuropathy, usually grade one or grade two, with Enfortumab Vedotin. Only a small proportion, very small, get grade three or more. I think this is relevant to recognize early because it can impact the quality of life of patients and it can be debilitating in some cases, especially patients who may get Enfortumab after prior treatment with platinum-based chemotherapy, cisplatin or carboplatin that could potentially have some neuropathy, especially the cisplatin agent in the previous line of treatment, so we have to know and have a good discussion with the patient about that. [inaudible 00:05:59] and potential dose hold or even dose reduction, if needed, for neuropathy findings.

Many of those neuropathy symptoms may improve after holding off the drug. But it's important to discuss with the patient in detail. The challenge is sometimes if you look at the traditional guidelines, if you have a grade two or more neuropathy, you may need to halt the drug until there's a resolution to grade one or zero. Sometimes it's hard, it may take time to resolve, and the disease can potentially progress or accelerate in between. We have to be some discussion about when to resume treatment and maybe a little lower dose. And the benefit-risk ratio discussion with the patient about the pros and cons and when to re-institute therapy after holding at which dose.

The other relevant, I'd say common, adverse event is skin rash, and we don't know much about the phytogenesis from the management of the skin rash in those patients. But definitely it's something to keep an eye on and to try to understand it better and see what treatments may be more effective for the management of the skin rash. But definitely, something to educate the providers and the patients about, to well recognize and properly manage.

Third, I would say a relevant and interesting kind of unique side effect is hyperglycemia. High glucose levels. This can apply to both diabetic patients but also patients without prior diabetes. So I think it's important for providers to pay attention to the glucose level when they take this metabolic panel back. Don't ignore a high glucose level because in about one out of 10 patients you may have hyperglycemia. If you do the treatments within Enfortumab Vedotin. And about half of them may be severe grade two or more. And it's a small number but can be potentially life-threatening if we don't pay attention to it. It's important to have a good understanding that this can happen. We don't know why, but it's important to pay close attention and quickly counsel with an endocrinologist if need be. 

Some of those patients may have resolution with subsequent doses and glucose levels may get normalized but some of them may persist. Proper educational cognition and management becomes important and of course, there's some other side effects... loss of appetite or low blood counts, taste changes can happen with this agent and of course I talk with the benefit-risk ratio with the patients. But overall, very promising agent. I think it has a high potential to be added in the future upon regulatory review. In my opinion in the momentary for treatment of metastatic urothelial cancer.

Alicia Morgans: Absolutely. And forgive me for focusing on EV or Enfortumab Vedotin as that was just discussed at ASCOS 2019 Conference. I actually was a co-investigator on another very exciting antibody drug, conjugate trial. It was presented at GU ASCO 2019 by Scott Tagawa. The nickname here is IMMU-132. And I think we heard Petros mention it's sacituzumab govitecan. This is actually targeting TROP-2 with SN-38 and again, these are drugs that have antibodies against specific proteins that are expressed on the cancer cells. Either TROP-22 in the case of IMMU-132 or Nectin 4 in the case of EV. 

And they deliver this high potency chemotherapy hopefully really on the target with fewer off-target activities. Both have quite high response rates, and both are moving forward in the regulatory process. We do expect to see these drugs moving into the third line space, hopefully in the future. Some unique side effects as we heard Petros mentioning for IMMU-132, this is going to be different side effects, more fatigue and diarrhea, I think without necessarily some of the issues with hyperglycemia and the neuropathy, although neuropathy actually affects patients who are treated in either of these categories. But I think, the landscape is changing, and these are going to be additional drugs that will give us opportunities, both in the third-line setting, but I anticipate these are going to be moving forward, given the response rates that they have even in patients who have liver metastases and other visceral metastases.

Thank you so much for your time today, Dr. Grivas. We look forward to seeing where these drugs go. And remember, these are response rates that are reported in unselected populations. A majority of patients seem to express these proteins and so these antibody-drug conjugates may be a way to have effective therapies in unselected populations. More to come on all of this. Thanks for sharing some time with me today, Dr. Grivas, on another quick take.

Petros Grivas: Thank you so much for having me. I fully agree with you. Very exciting data. Both antibody-drug conjugates look very promising. And we hope we get more agents in the treatment of those patients.