Alicia Morgans: Hi. I am so thrilled to have here with me today Dr. Scott Tagawa, Professor of Medicine at Weill Cornell University, New York. Thank you so much for being here.

Scott Tagawa: Great to be here. Thanks for the invite.

Alicia Morgans: Course. I wanted to really pick your brain about some of the advances that you have been participating in over the last number of years; really have been a key player, advancing things both in bladder and in prostate cancer, and had the opportunity to present those at ESMO 2019, and I'd love to start with your work on antibody-drug conjugates in urothelial cancer. Can you tell us a little bit about that work?

Scott Tagawa: Sure. So just kind of broadly, I'm sure that you know, and most of the viewers will know, but beyond platinum-based therapy and immunotherapy with immune checkpoint inhibitors, a fit in there for that select subset, it's really an unmet need. And it's interesting that some of the lead drugs happen to be antibody-drug conjugates. I've been involved with a couple of them, but the one that we've been involved with for a long time is sacituzumab govitecan or IMMU-132. The antibody recognizes Trop-2, which has overexpressed a number of different epithelial tumor types, including urothelial. It's labeled with SN-38, which is the active metabolite of irinotecan.

And the original basket study, interestingly, amongst the Phase I dose-escalation, there were a subset of patients with urothelial cancer that, for someone in the field, I thought that would look really good. Approached the company, and we are able to expand that. That was presented earlier in 2019, and that led to a dedicated Phase II trial that's potentially pivotal for urothelial carcinoma called TROPHY U-01. That was designed as a two-stage trial, where the first stage had a futility stopping rule, and we presented the results of that first phase of the study.

Alicia Morgans: Great. So just to clarify for everyone and make very clear; it's interesting, in urothelial cancer, that we are approaching that treatment both from a very targeted standpoint, but also from a "who can we treat as an all-comers population?". And what's so important about IMMU-132, I think, is that you're not screening for a biomarker to identify a population to treat these patients. This can be an all-comers population, which is really, really important because we also have erdafitinib, which we're really excited about, but that is going to be a select group of patients, and all of those kind of targeted agents are that. But, tell us a little bit about this first phase that you presented at ESMO for this.

Scott Tagawa: So it was 35 subjects that had cancer progression despite platinum-based chemotherapy and immune checkpoint inhibitors, without any restrictions on lines of therapy. So most patients, in fact, actually had more than three lines of therapy, so it was an average of fourth-line therapy with a primary endpoint of overall response rate by RECIST. And basically, it was a heavily pretreated patient population. A large number of them had visceral metastasis, including about a quarter with liver metastasis. And basically, the bottom line is, it met the pre-specified futility rule, surpassed that, where approximately 30% had an objective response rate. And that compares well compared to historical controls of somewhere between 8 and 14%.

Alicia Morgans: Absolutely. I think in a population with visceral metastases, particularly liver mets, this is a population that we know is imminently going to decline and is not necessarily always so responsive to other agents that we have like checkpoint inhibitors, although, of course, we certainly try in that population. So really exciting. And how was this drug tolerated?

Scott Tagawa: So the majority of patients had some AEs of all grade. Luckily, the main long lab AE was diarrhea. So that did happen to the majority, about two-thirds. But generally, it's Grade 1 and generally, it's temporary, meaning following the dose, there's a few days of Grade 1 typically, but occasionally Grade 3, but typically Grade 1 diarrhea that gets better. So I don't think that it affects their overall quality of life on a constant basis. It's an intermittent basis, kind of like chemo-related fatigue that we'd normally see with platinum, for instance. Neutropenia is the dose-limiting toxicity that's been seen across all tumor types. There was Grade 4 neutropenia, as well as some cases of febrile neutropenia, about 1 in 10, that looks like it can be ameliorated with the use of prophylactic growth factors.

Alicia Morgans: Okay. Wonderful. So when do you expect to enroll in the next phase of this trial and when can we start looking for those results?

Scott Tagawa: So there are two cohorts in this TROPHY study. The pivotal cohorts is what I discussed, which is post-platinum/post-immune checkpoint inhibitor. That has now fully enrolled. So I would expect that in the next six months or so, we're going to get the major signal, whether that is positive or negative. There's a second cohort that continues to enroll, and that is for cisplatin unfit, post-immune checkpoint inhibitors.

Alicia Morgans: Great. Well I really look forward to hearing more about that, and I think you mentioned just before we started recording that you're also looking at this agent in other populations that are relevant to GU oncology, so particularly the prostate cancer population.

Scott Tagawa: Trop-2 we know through work funded by the Prostate Cancer Foundation, we know that Trop-2 is an important cell surface target, particularly in patients post-AR-targeted therapies and is especially present with AR splice variants. So that's just a fact that we know that the target is there. There was a small number of patients treated with prostate cancer in the basket study and they had some stabilization of Zs, more than we'd expect past a number of lines of therapy. So those two bits of information together led to a trial that is supply of drug and some funding through the company, but also through a Prostate Cancer Foundation Challenge Award, a multi-institutional award where there's now a three institution, Phase II study assessing the efficacy and safety of sacituzumab govitecan in castration-resistant prostate cancer post one line of AR-pathway inhibitor therapy. So that'll be very interesting. And there's a number of interesting circulating tumor cell biomarkers in collaboration with Josh Lang that will look at a number of different things including Trop-2 expression as well as AR splice variants.

Alicia Morgans: Well wonderful. I think we're always very eager to have things that are going to be a different mechanism of action to really add into that armamentarium that we have. So I look forward to hearing more about that. And then to stay in the prostate cancer realm, you also presented some information on lutetium at ESMO this year. Can you share a little bit of that?

Scott Tagawa: Sure. So I think that PSMA, in general, is becoming hotter, if you will. I'm saying that partly in jest, with Israeli labeled drugs, both in imaging side as well as in the therapeutic side. And we've now actually completed accrual on two separate randomized trials, and that'll be exciting to see probably next year. With the small molecule lutetium PSMA-617, there was never really a dose-escalation study ever done. So we did one extrapolating from our antibody results, and that was presented at ESMO 2018, where we essentially showed safety, despite going up to where we plan, we practically stopped escalating. And then what we presented and updated this year was the addition of essentially an expansion Phase II cohort at the recommended Phase II dose. It was 600 millicurie or 22.2 gigabecquerel in a single cycle. To put that in perspective, that is around the same as three to four cycles of, kind of, the traditional dosing. It is essentially a dose-intense regimen. And the bottom line is, we showed safety.

One thing that was slightly different with this patient population is that we didn't select for PSMA. So they had baseline PSMA PETs, we ignored them to assess that as a biomarker, and treated everyone. And despite not selecting for PSMA, 82%, or so, had a PSA decline, and at the recommended Phase II dose 67% had at least a 50% PSA decline. So that looks very good compared to historical controls in this heavily pretreated patient population.

Alicia Morgans: Absolutely. And, you know, particularly important because it wasn't a selected population. How did they fare in terms of adverse events, cytopenias, and anything that you think might be a longer-term issue?

Scott Tagawa: So there were very few cytopenias, single-digit numbers for Grade 3 thrombocytopenia or anemia. The most common, actually, and this is interesting cause I wasn't expecting it, was a pain flare that happened within one or two weeks. Unclear if that was a true pain flare because many patients, as their cancer is progressing, had increasing pain coming in, and their pain scores by BPI short form decreased. But in any case, that was the most common AE reported, generally Grade 1. The second most common is well known, which is xerostomia. So in the only, I'd say, bigger prospective trials, it's the majority of patients that do get Grade 1 xerostomia with lutetium. The nice thing about it is it tends to be Grade 1 and temporary. So it tends to get better and doesn't affect overall quite of life. We're analyzing our FACT-P scores and it looks like there's about a 10-point decline, which I think that's a good fit over a short course between pretreatment and in three months, despite the AEs that happen.

Alicia Morgans: Okay, well that's good and I do really look forward to seeing that data. And you know, we're working together on a project, hopefully in the hormone-sensitive patient population, and we can assess it there too, where those kinds of declines we hope are not going to be long-lasting and we can see that too. But I am just, I'm really encouraged by all the work that you're doing. Excited in both realms, bladder and in prostate, and would love to hear any, you know, final thoughts or words that you have to the audience.

Scott Tagawa: Well, overall I think you actually said this in prompting for questions. It's exciting that we have a number of different therapeutic drugs in development, actually in late-stage development. So I think that is quite possible that next year or maybe the year after, we're going to have many more drugs available for the patients in the general population with advanced urothelial and prostate cancer. And we're going to continue work to number one, develop even more drugs, and also optimize those drugs with biomarkers. I think that in the general population, there's overall results and overall tolerability, but I think we can even better select the patients.

Alicia Morgans: I completely agree and I really look forward to hearing those updated results, participating in the trials, and really helping our patients along the way. So thank you so much for your time today.

Scott Tagawa: Sure. Thanks.