Thomas Powles, MD, PhD, and Jonathan E. Rosenberg, MD, on Urothelial Carcinoma: The DESTINY-Pan Tumor02 Study and New Findings on Sacituzumab Govitecan

Powles: So Jonathan, we are here again. We were here two years ago. It was such a roaring success. Jonathan: Yes. Powles: So they must have asked us back. I've not seen the video. I don't know if you have, but they did skip last year, so it might be they've forgot [inaudible 00:00:20]. Jonathan: Right, exactly. Powles: And that's also possible. I don't know the detail, but we are here at ASCO 2024. And one of the things I wanted to talk about was sequencing of ADCs. And I know you at Memorial, have done some really interesting work on SG after EV. Do you want to talk a little bit about what you showed? Jonathan: Yeah. So we looked at our experience in treating patients. We have a very large volume of urothelial cancer patients, both have protracted bladder. And so over the course of several years we accumulated about 82 patients who received EV followed by sacituzumab. This is all EV monotherapy followed by sacituzumab. And a couple of things that came out of that. First of all, that top line information is that sacituzumab after enfortumab, in our hands, had an 11% [inaudible 00:01:01] response rate. We actually had radiologists review the scans of any patient who had tumor reduction and only about one in 10 patients, one in nine patients showed major regression of tumor. Their PFS was a little over two months, and the overall survival was only six months in that patient population. Now, if we think about the data that we have from the Sacituzumab Phase 2 Study in the second and third line setting, we know that those patients, very few of them received enfortumab. And so there really hasn't been any prospective data and very limited retrospective data. So this is one large single-center experience that really suggests that the activity of sacituzumab is relatively limited. We did need substantial growth factor support in these patients. And this has been highlighted recently in the press release from the TROPiCS-04 Study showing that that trial was negative, perhaps in part, due to early deaths. Also, it didn't hit the mark in terms of overall survival in general. And so the toxicity profile of the drug can be difficult. And there may be something in the sequencing of sacituzumab after enfortumab that may blunt its ability to be effective. And we don't have biomarker data at this point. We don't have any other data other than the clinical story. Powles: A gap between EV and SG, if you sequence them directly after each other, was the outcome worse there? Jonathan: It probably was, although we have not looked at that in detail at this point. I think the patients who were coming off EV for progression are the ones who ended up going on sacituzumab rather than getting re-challenged with enfortumab, perhaps. So those patients are really the ones who are in need of subsequent therapy and they're the ones who were primarily included in the analysis. Powles: How important is GCSF support in this population? Jonathan: I think it's quite important. I think there is a real risk of significant toxicity in the early cycles of treatment. The patients, about I believe 2/3, maybe even 70% of patients received growth factor support as primary prophylaxis and many, many patients received it as secondary. It was manageable though with GCSF support. Powles: Jonathan, I nearly fell off my seat a few days ago when I saw TDXD got FDA approval in urothelial cancer in HER3 3+. Jonathan: HER2 3+? Powles: Yeah, sorry. HER2 3+ patients, of a basket study. And what I thought was striking was it was of 16 patients, and we in Europe don't tend to get super... Now, don't get me wrong, it's a bigger study, and there are lots of different patients. And I think I actually quite like the idea. I'm really supportive of that because I think it's progressive. I'd like to see more data in the future. And of course, we can do that. Now, you've got FDA approval, which is great. Jonathan: Great. Powles: There's a poster here as well which looked at that [inaudible 00:03:42] that population, and also the high population, 2+ and 3+. Do you want to talk a little bit about what that shows? Jonathan: Yeah. So overall, the 3+ patients had a very high response rate, over 50%, whereas the entire cohort was about 39%. Which is very respectable, actually, in an ADC and a refractory patient population, in the 1+ and above, effectively, although, mostly 2+. The local review and the central review was discordant in many patients. And in fact the local review, 3+, was actually a much larger group. So it does raise the question, is there heterogeneity, are there problems with the assay, that it's not as standardized as we think? That the samples sent in locally versus sent into the central review come back even zero in some cases, in very few of them as opposed to 3+. So I think it probably reflects the underlying heterogeneity of HER2 expression in urothelial cancer. What we did see in this very small group of bladder cancer patients is regardless of the expression level, the time-to-event data looked promising and very similar actually between 1+, 2+, and 3+. About six months PFS and 12 months OS, which again is about what we're seeing in all the antibody-drug conjugates in this scenario. I think it is a different toxicity profile than the other TOP1 inhibitor, sacituzumab, so less cytopenias, small risk of pneumonitis which can be life-threatening or fatal, but generally, a reasonably well-tolerated treatment overall. And I know from personal experience, participating in that study and putting patients on it, that some patients with HER2 3+ can do extraordinarily well. Powles: What do you want to see next? I mean, this can't be enough, I guess? Jonathan: Correct. Powles: Do you want to see a prospective trial? Does it have to be randomized? Jonathan: I don't know that it has to be randomized in this population. I think that we know the spectrum of activity of this drug in breast cancer with HER2 overexpression, as well as in gastric cancer where it's approved. I think the pan tumor approvals that the FDA have done have been very judicious and well-thought-out. And have shown that dramatic responses can occur in a subset of patients with durability. And that the clinical benefit, I think, follows from that. I do think we have to change our thinking a little bit sometimes, around relying on phase three trials for very rare patient populations when we can truly show that there are patients who benefit across disease types. Powles: How confident are you in the biomarker, this one, 2+ versus 3+? Are you 100% confident? Jonathan: I am not 100% confident. Powles: Why? Jonathan: Mostly because I think the 2+ patients actually have substantial benefit and maybe 1+ as well. Powles: Why? Jonathan: So I think the FDA, in its own way, was being conservative at saying 3+ only based on their data. So we can't have it both ways. Powles: No. Jonathan: We can't have them approve it on a single-arm, small study with a biomarker that's not performing well. Powles: Yes. Jonathan: They [inaudible 00:06:39] and that makes sense for now. Powles: Yes. I'm not sure the EMA would see it in the same conservative way. Jonathan: I agree with you. Powles: I think they would say, "Ambitious." Jonathan, this has been even better than last time. Jonathan: Thank you very much. Powles: It's lovely to see you. Jonathan: You as well.