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Alicia Morgans: Hi, I am so excited to be here today with Professor Jonathan Rosenberg, who is joining me from Memorial Sloan Kettering after a fantastic discussion at ESMO 2024, where he talked about some novel therapies in GU cancers. Thank you so much for joining me today, Jonathan. Why don't you take it away?

Jonathan Rosenberg: It's my pleasure to be here. Today I'm going to discuss two abstracts, focusing on first bladder cancer and then urothelial cancer. The first abstract that I discussed was focusing on a novel bispecific antibody-drug conjugate targeting EGFR and HER3 in advanced urothelial cancer. This ADC BL-B01D1 is derived from cetuximab, interestingly. The high-affinity antibody for EGFR is a cetuximab-derived antibody, and conjugated to two HER3 single-chain fragments (scFv's) that have a little lower affinity. So a high affinity for EGFR, lower affinity for HER3. And then these are then linked to a cytotoxic called Ed-04, which is a highly potent topoisomerase inhibitor, with a high drug-to-antibody ratio of eight. And it looks like this ADC is more active than either of the EGFR or HER3 ADCs alone in model systems. And so this was taken forward into phase I/II studies and now in urothelial cancer. And it was recently published in Lancet Oncology, the original phase I study.

So just to refresh people's memory who don't think about this pathway as much in urothelial cancer, EGFR and HER3 are in the same family, and they can heterodimerize or homodimerize. And the binding of this ADC can occur to either EGFR or HER3 or both. And so most of the signaling and most of the internalization is probably from EGFR, but certainly HER3 is modulating this. And so the initial phase I study in mostly lung cancer showed a high rate of activity in this patient population. And at ESMO, they reported the results of 34 patients treated at a slightly lower dose level, and most patients received prior checkpoint inhibitors and chemotherapy. Very few people received a prior antibody-drug conjugate. So maybe not the same population that we see in the United States right now, but certainly in many areas of the world, EV Pembro has not yet penetrated the markets there.

So a good effort out of China, showing that, in fact, at the dose level that they're taking forward, 40% of patients had responses. And in the second-line setting—only 12 patients, three-quarters of the patients had objective responses. But remember, these are relatively small sample sizes, but certainly interesting and promising data. I think we need to see where this agent goes. We do know that the IHC staining does not seem to matter in terms of intensity, and most tumors expressed EGFR or HER3. The PFS for this agent seems promising, and we need to see longer follow-up. What I think is really interesting is that the skin toxicity that you might see with cetuximab doesn't seem to be present, at least not in high grade and high frequency, and it's primarily hematologic toxicity from the cytotoxic.

So really promising, really interesting. We need to see where this goes, but it opens up a whole other set of targets for us in advanced urothelial cancer. And with the recent lack of success of Sacituzumab, I think we need to be exploring different ADCs. Moving on to renal cell carcinoma, our colleagues from a multi-institutional trial presented data of NKT2152. This is a HIF2a inhibitor. HIF2a is a transcription factor that regulates expression of multiple genes involved in RCC growth and metastasis. And currently in the United States, belzutifan is approved as a HIF2a inhibitor in previously treated renal cell carcinoma. And we saw results from the LITESPARK-005 data compared to everolimus with final analysis improved PFS without an OS benefit. Here we see the results of this agent in a dose escalation and expansion, and this drug is very similar in terms of its biological function, inhibiting the same genes you might expect from HIF2a inhibition.

They used a loading and maintenance strategy here to determine the recommended phase II dose, and then a phase II expansion for dose selection and optimization, as you see on the right side of the slide. They looked at pharmacodynamic and pharmacokinetic markers. The PD marker on the right shows suppression of erythropoietin, which is what you might expect. And on the left, you can see the PK levels. There were dramatically different dose exposures depending on the PK and depending on the dose level. And in fact, there was a fourfold variation between the two dose levels they chose—one at a very lower dose level, the other much higher dose level—and so they chose those two as a way to really see the benefit. One thing very different for this drug is it has a very long half-life, 38 days, compared to a much shorter half-life for something like belzutifan, which is on the order of about 16 hours, I believe.

And so this could lead to some issues down the road, particularly around hypoxia. And the median duration of hypoxia for patients who had significant hypoxia was about two weeks. And so this might cause some problems. The toxicity profile otherwise was no different. The response rate was actually interesting: 20% in the phase I study, I think, is worthy of further follow-up. And the longer they followed patients, the better activity it seemed to have. So perhaps some of these responses are delayed, with a response rate of 26%. It's very hard to interpret PFS in the phase I trial, but a PFS of 9.2 months is actually quite good. So where is this going to fit? Belzutifan clearly has a role in advanced renal cell carcinoma. The different PK properties might lead to more steady inhibition of HIF2a target genes that perhaps allow this to be used after belzutifan, but the long half-life might pose some challenges in patients who do develop hypoxia. And so I think this is a very interesting and active agent, and further evaluation is worthwhile, but toxicity management and where to place it in the kidney cancer landscape remain questions without clear answers right now.

Alicia Morgans: Fantastic, Jonathan. It's really amazing, especially since you had to discuss two very unrelated topics and put that into a cohesive conversation. But I think that the really underlying theme here is that we have, not necessarily new targets in terms of the renal cell carcinoma approach, but really new approaches and new ways to potentially modify the landscape in both of these disease states. Now, I know you've worked actually for a long time in urothelial carcinoma, especially on HER2 as a target. Can you tell me from your perspective, is this a new opportunity, a new way to get at these receptors and perhaps find an opportunity to have a treatment that's more effective than some of the things that we looked at before like lapatinib and urothelial carcinoma?

Jonathan Rosenberg: It's a very good question. So in urothelial cancer, HER2 is overexpressed in anywhere from 25% to 40% of patients, and it does limit the utility of HER2-directed therapies, whereas at least this very preliminary early data suggests that EGFR and HER3 expression may not really need to be assessed as this drug is developed, the bispecific antibody-drug conjugate. Whether these drugs might have sequential activity in HER2-expressing patients is a great question that we don't have an answer to. And you could think of reasons why it might, and you can think of reasons why it might not, and so it's very hard to know. We are seeing the development of disitamab vedotin, which has a different cytotoxic, which targets HER2. So one can conceive of cocktails potentially, even in the future, of ADCs that might have different targets and different payloads that would allow very efficient and highly active and highly effective targeting of these tumors.

Alicia Morgans: It's exciting, and I feel like I can see the wheels turning and you're coming up with new approaches and new studies even as we talk to target these because it's really been, I feel like, a career-long foe of yours and one that I look forward to seeing you overcome. So when it comes to the kidney cancer work, I think it's interesting that we're continuing on this pathway and that we may find ongoing ways to address this pathway and still benefit patients. I would love to hear your thoughts more. The hypoxia is certainly something that we have to think about when we think about the currently approved agent here and something that can be limiting for the population. It sounds like this is something that you think may still be actually potentially even a larger issue with a longer half-life here. Is that something that you think might be limiting for patients in the long run?

Jonathan Rosenberg: It's possible. And I do think there's a lot of discussion within the kidney cancer community about how to manage these sort of toxicities, and particularly as we bring it earlier in the course of the disease. And then certainly with a drug with a 38-day half-life, you really are waiting quite a while before this agent gets out of their system. And so whether this will be viable as far as development down the road goes, I think more research needs to be done. It's interesting in that apparently this long half-life was not predicted from the preclinical work and that it really only was evident in humans. And so where this goes and what is the metabolism of this drug may pose some challenges, but maybe there's different opportunities. And maybe the opportunity really is in belzutifan-refractory disease, where you might be willing to accept more toxicity in patients who may not have any other options. And while that may not be the preferred place for a new drug in kidney cancer, it may actually be a very useful tool for our clinicians.

Alicia Morgans: I think that makes a lot of sense. And what I think is ultimately clear from both of these abstracts, and certainly your discussion, is that the pipeline is really strong in GU cancer development, and we really look forward to seeing where these drugs and so many others go over time. Thank you so much for taking the time to discuss with us today and certainly for your efforts at ESMO.

Jonathan Rosenberg: Thank you very much.