Antibody-Drug Conjugates in Advanced Urothelial Cancer: Clinical Perspective - Scott Tagawa

April 14, 2022

Scott Tagawa joins Sam Chang to highlight the key topics of his discussion at the American Society for Clinical Oncology (ASCO) Genitourinary Cancer Symposium 2022. Dr. Tagawa provided a clinical perspective on antibody-drug conjugates in the treatment of urothelial carcinoma.


Scott T. Tagawa, MD, Associate Professor of Clinical Medicine, Clinical Urology, Medical Director, Genitourinary Oncology Research Program, Weill Cornell Medicine, New York, NY

Sam S. Chang, M.D., M.B.A. Patricia and Rodes Hart Endowed Chair of Urologic Surgery Professor Department of Urology at Vanderbilt University Medical Center

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Sam Chang: Hi, my name is Sam Chang. I'm a Urologist in Nashville, Tennessee, and I work at Vanderbilt. We're lucky today to have Dr. Scott Tagawa. Scott is a Professor of Medicine and Urology at Cornell University at the Weill School of Medicine.

He is actually speaking at GU ASCO this year, focusing on antibody-drug conjugates in the treatment of urothelial carcinoma. We've asked Scott today to give us some highlights of his talk.

Scott Tagawa: Sure.

Sam Chang: Welcome, Scott. Thank you.

Scott Tagawa: Thanks very much for the invitation.

Sam Chang: Tell us some key points that I think practicing clinicians would find helpful in looking at this whole new treatment regimen for urothelial carcinoma.

Scott Tagawa: Sure, so we've known that urothelial carcinoma is chemosensitive, especially cisplatin-based chemotherapy for a very long time. But that has limitations in terms of patients who can tolerate it. And unfortunately, most are not cured with advanced disease. We also know that there are toxicities of chemotherapeutics, especially. And if we can target them, then that may either allow us to give more potent drugs and/or give directed toxicities to the cancer rather than to the patient's body. And that's where we have antibody-drug conjugates that are now approved in a number of different cancers and may sometime take over chemotherapy.

Sam Chang: Oh so, I guess for the urologists and those that see these patients usually at an earlier stage as to an advanced stage. When we think about ADCs, where did this all start? Which of the cancers did ADCs really start off in terms of being, "Hey, this is something that we can use as a strategy. And then now we can start looking at other cancers." Where did it start?

Scott Tagawa: If I think of hematology-oncology as a broad field, a lot of our targeted therapy started in the hematologic malignancies and that includes antibody-drug conjugates. In part, because they have cell surface targets or pathway targets that are unique and targetable. In an antibody-drug conjugate, we're looking for something that is only on the cancer and not anywhere else, or at least mostly on the cancer and not in other vital organs. And that's more common in the hematologic malignancies than solid tumors.

I would say in solid tumors, the first real main target has been HER2. First in breast cancer, then gastro cancer. And actually, now maybe becoming relevant in your urothelial carcinoma. But now, there are a number of different cell surface targets across different solid tumor malignancies, including urothelial carcinoma.

Sam Chang: Right, so as they look at HER2/neu or HER2, we know that at least not a huge number of invasive bladder cancers express HER2 changes. The agent that I've heard about the most is enfortumab. Can you tell us a little bit about not only its target, but I think more importantly for clinicians is how do we use it, when do we use it, and then what should we be on the lookout for in terms of possible side effects?

Scott Tagawa: Enfortumab vedotin or EV is an antibody-drug conjugate directed against Nectin-4. Nectin-4 is on the cell surface of the vast majority of urothelial tumors. We knew that it advanced cancer it looked like in clinical localized disease, so that's up and coming. But of the newer therapies, it really is the only one that has level 1 evidence post platinum and post immune checkpoint inhibitor therapy, with overall survival advantage versus control. In addition to progression-free survival response rate, et cetera.

That's great to have this drug with level 1 evidence. The response rate is quite high compared to historical controls even if we didn't have the randomized data. The toxin is an antimicrotubule toxin that given freely wouldn't be tolerated by most humans, but because ...

Sam Chang: Basically intravenously or anything like that, it would ...

Scott Tagawa: Correct.

Sam Chang: The toxicity ... Okay.

Scott Tagawa: Correct. Kind of going everywhere. That being said, even though a lot of us don't refer to this as chemotherapy with ADCs and it is targeted, doesn't mean there is no toxicity. There are a few important ones to know about. Neuropathy and rash are in up to 50% of the patients.

Sam Chang: And this is a skin rash? Occular? What? It could be ...

Scott Tagawa: It could be anywhere.

Sam Chang: Okay.

Scott Tagawa: Up to 50% are usually not high grade. Usually, it's kind of an annoying thing that doesn't necessarily need to lead to dose delays or dose reductions. But it is important to know that is the way ... Early identification and management can be dose delays and or dose reduction. There are cases of truly severe Stevens Johnson-type reactions. They're uncommon, but we really need to know about them because they can happen. And you know, relatively recently, this may have had slowed down European availability.

Sam Chang: These are the possible concerns. I see. A question that we had been discussing earlier with the neuropathy and/or the rash you've mentioned both dose reduction as well as dose delay. What are the next steps if those don't seem to be working? Is it discontinuation of the drug totally? And then, is there anything that can improve the rash? Do we talk about steroids? Do we talk about creams? And what about the neuropathy? Is that then irreversible, or do we not know yet in terms of the number of patients that have actually developed it? Do we have any idea?

Scott Tagawa: Yeah, there's a reasonable number because of the initial phase ones, relatively large phase twos. And then obviously the randomized phase three with additional randomized phase threes that are ongoing. I think it's just easiest to remember around 50%. It's a little bit lower than that in the 40%, and generally single digits in terms of grade three.

But in answer to your question about what to do about it, it simply is withholding the drug. Generally speaking, the rash gets better, and neuropathy gets better by withholding the drug. It does not always 100% resolve. The rash usually does, although sometimes leads to more permanent hyperpigmentation, but the actual rash usually gets better. Neuropathy almost always gets better but sometimes remains at grade one. We can reintroduce the drug down the line and get a response.

Sam Chang: Good to know.

Scott Tagawa: I generally don't push it, particularly now that it's available outside of clinical trials. In a clinical trial, I know I'm not going to be able to get it again if they come off, so I might push it a little bit more. But since approval, I know that if I stop it today and I want to come back to it three months later, I can.

Sam Chang: You can safely do that. And with that, in terms of the Nectin-4, for the target, are there other areas of expression in the body that have Nectin-4 that may lead to some of the side effects? You talked about the skin and neuropathy. Where else is Nectin-4 possibly found?

Scott Tagawa: Nectin-4, it is expressed in the skin. That, I think, is the key for that toxicity. The toxin, as I mentioned, is an antimicrotubule. Antimicrotubules, as a general rule, will often have some element of neuropathy as a component.

Sam Chang: I see. The second ADC that I think you'll be mentioning in talking about at your discussion at GU ASCO is sacituzumab, which I don't have as much familiarity with this, and I know urologists, as a group, don't either. Tell us a little bit about that in terms of targeting, as well as its effectiveness, as well as side effect profile.

Scott Tagawa: Sacituzumab govitecan or an SG is an anti-Trop-2 antibody-drug conjugate. The drug that's attached to it is SN-38, which is the active metabolite of the chemotherapeutic called irinotecan. It has full approval for triple-negative breast cancer with positive phase three area. There was interesting early data during the phase one where six patients with urothelial carcinoma, those of us using it that knew about bladder cancer said, you know this looks like it may work. That led to an expanded basket study arm, and then a dedicated phase two that led to the accelerated approval of the drug with a response rate significantly better than historical controls, but not randomized data. Those confirmatory randomized data are ongoing. There are clinical trials.

The nice thing I think in the current context is that it's a different target and a different toxin. It's early days, but it does not look like there's complete cross-resistance to targeting Nectin-4 and Trop-2, particularly with the different toxins. A patient may receive EV and then respond to SG or vice versa. That was, for instance, in the trial leading to the accelerated approval for SG. The response rate with the same inpatients that had received EV versus those that had not, so around 30%; small numbers. That is in line with a hypothesis. It's nice for the patients that are out there that will get a maximal benefit from one drug and still have something that's out there, or because of the differences in the toxicity profiles. If someone was not eligible for one drug, say walked in the door with bad neuropathy, or can't walk in the door because neuropathy is so bad from diabetes or some other reason. Well, there's another drug that's out there that doesn't appear to have very much, if any, neuropathy.

Sam Chang: And so, along those neuropathy lines, if someone who has already had a little bit of neuropathy from the chemotherapy that he or she may have received, are they more likely to have that neuropathy worsen, or are these upfront, or does it vary?

Scott Tagawa: It varies. It varies.

Sam Chang: You can't predict, necessarily, who is more or less likely to develop neuropathy.

Scott Tagawa: Correct.

Sam Chang: And what about the side effect profile with sacituzumab? Is it very similar, or is it different?

Scott Tagawa: It's different. It's predominantly neutropenia and diarrhea. The neutropenia, I think, most medical oncologists are used to dealing with, with particular combination chemotherapy. Again, dose reductions and dose holds are the way I typically manage that. Other people use growth factors. Both have been used in prospective data sets. The febrile neutropenia rate; that's what we worry about. Neutropenic fever is, in most studies, in the high single digits. Nine to 10%, something that looks like that. It's something we need to watch out for, but it doesn't look like it's 50%, or something like that.

The diarrhea is usually low grade, but grade two diarrhea is not something that is necessarily not life-altering. Someone having six or seven loose bowel movements a day is grade two, and that can keep them at home. Luckily, with this drug, it's generally temporary. We know if that's going to happen, it's timed with the chemotherapy. They know that for those two days, they need to maybe be aware of it. But usually, it's grade one and can be managed with antidiarrheals.

Sam Chang: I see. For those individuals, then they know it's usually related to the timing of the dosage of the medication. I see. With those two different targets and different side effect profiles, and perhaps the ability to sequence and still be able to treat successfully, where are the next steps, or where are we looking at now in terms of incorporating these in different states of the disease spectrum?

Scott Tagawa: That's different states, typically earlier is generally what we do. Drug development starts where the unmet need is greatest when there's nothing else. And then move forward where the potential benefit is also greatest, ie: cure. Both EV and SG are moving to earlier line, including front-line metastatic disease. And EV has also moved into the perioperative space with data that are being presented at this conference, as well as an ongoing randomized trial in that area. Earlier lines of therapy is one key. The other is combinations.

Sam Chang: I see. What's the biggest excitement, do you think? Is it the combination of the medications? Timing of the medications in terms of that disease spectrum? What for practicing oncologists really represent wow, this could be the next big step?

Scott Tagawa: I think it's actually the combination of the combination therapy, as well as moving earlier. For instance, EV plus Pembrolizumab anti-PD1, a non-randomized Phase I/II presented data with an impressive response rate and an impressive spider plot with randomized Phase II data that are coming that could lead to accelerated approval. With that is also a Phase III in the frontline setting, going head to head against platinum chemotherapy. There are issues with the trial design in terms of lack of maintenance, but that could be quite exciting because we've been looking to replace chemotherapy. We love and hate Cisplatin.

It actually cures some patients with advanced disease but is toxic. And most people, people are not cured. It'd be great to have that. A different way of looking at it, we have a small fraction of patients with a number of different cancers, including urothelial that have a long-term durable, deep-response to immunotherapy, but just a small subset. If we can add to that by adding an antibody conjugate, that would also be a major step forward. And again, that combination is also in the perioperative setting. Getting a course of combination EV with Pembrolizumab and then continuing the Pembrolizumab.

Sam Chang: The last question we'd mentioned, or you had mentioned a possible new target in terms of the ADC. Do you want to talk a little bit about that in terms of is there one now looking at HER2 as a target for urothelial carcinoma? You'd mentioned that.

Scott Tagawa: Yeah, so there are several. There is a drug that has been called RC-48, a Chinese drug that was presented at ASCO a couple of years ago in somewhat selected HER2, and then more heavily selected HER2 and was published in the clinical cancer research with a very high response rate in that patient population. The neuropathy rate was relatively high. About a quarter had grade three neuropathy. I'm not sure how long that lasted, but in any case, that is a potential issue that is now being developed by Seattle genetics in the United States. We'll see what happens. Not just in the United States but outside of just China. We'll see if it's any different. Looking best in terms of response rates in a more selected patient population. And then there are two antibody-drug conjugates using trastuzumab, the original anti-HER2 antibody in that includes data alone, as well as ... Actually same with the Chinese drug. Alone, as well as in combination with immune checkpoint inhibitors.

Sam Chang: To end, when, Scott, do you think you will not be using Cisplatin first line?

Scott Tagawa: I don't know. I would love to say soon. I want to see the data, basically. The main Phase III trial that could replace Cisplatin is against platinum chemotherapy, which I'm going to guess is going to be half CIS and half [crosstalk]. We'll look at the fourth plots and see how big a difference is. But we do know that there's a subset that's out there that are cured with Cisplatin. I might use a non-Cisplatin regimen as my bread and butter, but for someone with node-only disease that's young and healthy, I might use this Cisplatin, and that's with or without available maintenance therapy.

Sam Chang: Great. Well, thanks for spending some time with us, and I look forward to your presentation. Again, I always learn so much whenever we have discussions, so appreciate it very much, Scott.

Scott Tagawa: Thanks.

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