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Alicia Morgans: Hi. I am delighted to have here with me today Dr. Scott Tagawa, who is an Associate Professor of Clinical Medicine and Urology, as well as the Medical Director of the GU Oncology Research Program at Weill Cornell. Thanks so much for being here with us today.

Scott T. Tagawa: Thanks for inviting me.

Alicia Morgans: Of course. So I really wanted to talk with you about some work that you presented recently at GU ASCO, a project you've been working on for years, looking at an antibody-drug conjugate in bladder cancer patients, metastatic muscle-invasive bladder cancer patients. So tell me a little bit about the drug, about the findings, the study. Just tell us more.

Scott T. Tagawa: Sure. So the drug is sacituzumab govitecan. It's also known at IMMU-132. It's an antibody-drug conjugate that's directed against Trop-2. Trop-2 is a cell-surface antigen present on a number of different epithelial tumor types, including urothelial carcinoma. There's some expression studies showing that it's over-expressed particularly in invasive tumor types, so fairly ubiquitous. The antibody-drug conjugate itself is comprised against a humanized antibody that recognizes Trop-2. It has a relatively interesting linker when we think of antibody-drug conjugates, it is one that is designed to release its payload inside cells, like most ADCs, but also in the stroma around it, and is linked at a high drug to antibody ratio to SN-38, which is the most active metabolite of the normal chemotherapeutic drug, irinotecan.

So that overall construct was initially used in a basket Phase 1 study, kind of all-comers, refractory epithelial tumor types not selected for Trop-2, where they receive this drug in a dose escalation phase one. And what was determined is that the dose-limiting toxicity was myelosuppression, and the recommended Phase 2 dose was 10 mg/kg on a day one to eight; acute 21-day schedule.

What we saw as a small handful of refractory urothelial carcinoma patients that did well, was anecdotal, but it was interesting, and that small subset was published by my friend and colleague, Bishoy Faltas, who you've also interviewed.

Alicia Morgans: Yes.

Scott T. Tagawa: And so we pushed the company and were able to do an expansion Phase 2 study. So that was the subset that I presented at GU ASCO, which were 45 patients; mostly men, mostly white, as, unfortunately, a lot of our studies, with refractory urothelial carcinoma, measurable disease and ECOG performance at a 0-1. They received a number of different therapies; a medium of two, but up to six prior therapies. So three-fourths of the patients have visceral disease, with a third with liver metastases. And despite that, what we could generally would consider a poor prognostic group, there were responses. So the primary endpoint of the study was overall objective response rate, and we saw a 31% objective response rate. Even though the subsets were relatively small, that looked like it was maintained. It was 33% in those with liver mets. Was maintained in those that had a number of different lines of therapy, including immune checkpoint inhibitors.

So as you mentioned, the study went on from 2014 to 2017 for a number of different reasons. The last patient went on only seven weeks after the approval of atezolizumab, so there wasn't a lot of overlap, but the 17 patients that did receive both chemotherapy and immune checkpoint inhibitor looked to have a similar type of response.

That was at the cost of some toxicity, but overall, I would describe it as manageable. So, myelosuppression was the most common Grade 3 or 4 toxicity. So, 38% had Grade 3 or 4 neutropenia, with 7% with febrile neutropenia. Grade 3 diarrhea and fatigue were the most common non-hematologic higher-grade toxicities. That limited to 9%. So overall, reasonably well-tolerated. We did not see, fortunately for this patient population that might've received platinum or taxanes, everything else, we did not see any significant neurotoxicity or neuropathy. And also, some people, I think, may equate some antibody-drug conjugates with ocular toxicity. I think that's more often related to the conjugates. But that did not occur in this disease subset. So, a reasonable number and percentage had Grade 1 and Grade 2 fatigue and diarrhea, but overall manageable with supportive care, or occasional dose reductions.

Five patients came off study for potentially related adverse events, but overall, well tolerated, and there were no treatment-related deaths.

For the overall population, the progression-free survival was over seven months, and the overall survival was over 16 months, which is much better than we expect versus historical control. So not a randomized study, but looks pretty good.

Alicia Morgans: Absolutely. I mean, when you think about patients who have already had two lines of therapy to six lines of therapy, 16 months of survival is actually huge. And the other thing that I think is really striking and interesting about this population is that you had similar responses, essentially, in those patients who had liver metastases versus patients who did not. And with the checkpoint inhibitors, we don't necessarily see that equivalent response rate in patients with liver metastases. So that, I thought, was a really important aspect of the analysis, overall, and then the subgroups that you guys were looking at, to really make sure that you understood which populations may benefit with the treatment.

Scott T. Tagawa: Right, yeah. No, I totally agree. So, cisplatin-based chemotherapy is great. There's a fraction that do really well, long-term survival. The PD-1 and PD-L1 immune checkpoint inhibitors, a fraction, about one in five do really well, but the others, we desperately additional therapies. And it's nice to see that there are a number that's in development. So a couple of different antibody-drug conjugates. The nice thing I see, I think the clinical space, a need for more than one. They have different targets, different payloads. We know, anecdotally, patients can receive one. Whether or not they respond, they can also receive another one and respond to that one. So I think overall, it's nice that there's different targets, different payloads, and different toxicity profiles. So we can pick and choose based on what we think is right for the individual patient.

Alicia Morgans: Absolutely. So what percentage of patients do you expect to express a target that might be compatible with this treatment?

Scott T. Tagawa: It's a good question. So it's the vast majority. It's 90% plus. That being said, those historical studies were on the primary tumor and archived and sent to companies. We are ... So there is a validation, potentially pivotal Phase 2 study with this drug in a refractory urothelial carcinoma population, where we are prospectively collecting samples and will use a CLIA approved test to look at that. We're also internally looking at resistant biopsies, looking for a number of different mechanisms, but potentially, one of them could be loss of Trop-2. So we're examining that. 

There's also a non-urothelial study, so non-breast and urothelial, those are the two diseases that are most developed with this drug. There are other diseases. There's a new basket study that's being started specifically for patients that have overexpression by IHC of Trop-2.

So in answering your question, I think it's the majority of urothelial carcinoma patients. We will explore how much the response is related to the level of expression. So I think almost all tumors express it. We'll see how much the level of expression matters.

Alicia Morgans: Great. You know, one of the final things I wanna think about because we know that this landscape is becoming more and more populated, which is a fascinating and fantastic thing for the metastatic urothelial population. But as we get more and more treatments, the landscape starts to become more complicated. Where do you see this treatment fitting into that landscape?

Scott T. Tagawa: So right now, like with most new drugs, it's post the normal, so that's post-platinum-based chemotherapy for the most part and immune checkpoint inhibitors. The follow-up study is enrolling patients, a subset of exploratory patients that are platinum unfit, that have received an immune checkpoint inhibitor. So it'll be nice to explore that in kind of a second-line setting.

But overall, if all the kind of near-term drugs get approved, I think that will have some molecular-selected patient populations, namely FGFR3 patients. The rest, the leading antibody-drug conjugates, as I see it, with nectin-4 and Trop-2 as targets, those targets are pretty ubiquitously expressed, so I think that it'll likely be that we will use those drugs post-platinum, post-IO, and pick one versus the other based upon whatever disease characteristics we see that read out in the current trials, and may be based on toxicity profiles. So someone that comes in with neuropathy, maybe we're gonna pick IMMU-132. Someone that has pre-existing diarrhea or other problems, maybe we're gonna go with the nectin-4.

Alicia Morgans: Sure.

Scott T. Tagawa: But the best thing, for me, as a practicing clinician, I think for our patients, is having a number of options out there.

Alicia Morgans: Absolutely, which is certainly different than it was a few years ago.

So thank you so much for sharing this update and really enlightening us on some of the work that you've been doing. And I expect that we'll hear more about this in the future, and I really appreciate your time.

Scott T. Tagawa: Thank you very much.