Podcast on the Emerging Role of PD-(L)1/VEGF Bispecific Antibodies in the Evolving Advanced Renal Cell Carcinoma Treatment Landscape

Abstract

Combinations of an immune checkpoint inhibitor (ICI) + anti-programmed cell death 1 protein (PD-1) or anti-programmed cell death ligand 1 (PD-L1) or an ICI + tyrosine kinase inhibitor (TKI; anti-vascular endothelial growth factor [VEGF]) are the current standard first-line treatments for advanced renal cell carcinoma (RCC). However, novel therapies are needed as treatments for RCC have relied on the same mechanisms for decades, with only modest advancements made in the field compared with other genitourinary diseases. Therefore, a considerable unmet need remains for additional treatment options with enhanced activity and minimal toxicity for patients with advanced RCC. Simultaneous bispecific targeting of PD-1 and VEGF may improve efficacy and safety compared with combination therapy of PD-1- and VEGF-targeting single agents. In this podcast, authors discuss the evolving treatment landscape for patients with RCC and describe how bispecific antibodies, as monotherapy or combination therapy, have the potential to transform the treatment of these patients. Preclinical evidence shows that bispecific co-targeting of PD-(L)1 and VEGF may result in cooperative binding, which can enhance both PD-1 binding affinity and anti-angiogenic activity. Bispecific targeting can also potentially confer safety advantages owing to a reduction in immune-related adverse events. PD-(L)1/VEGF bispecifics under development include PF-08634404, ivonescimab, and BNT327, all of which have distinct structural configurations and mechanistic differences. These bispecific antibodies, among others, are being evaluated for the treatment of patients with advanced RCC. The authors discuss existing clinical evidence with bispecific antibodies in other cancers and explore the rationale for evaluating the antitumor activity of PD-(L)1/VEGF bispecifics, either as monotherapy or in conjunction with other treatments in patients with RCC.

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Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1007/s40487-026-00450-x.

Key Summary Points

Novel treatments are needed for patients with advanced renal cell carcinoma (RCC).

Simultaneous bispecific targeting of programmed cell death 1 protein (PD-1) and vascular endothelial growth factor (VEGF) may improve efficacy and safety compared with combining PD-1- and VEGF-targeting single agents.

Preclinical evidence shows that a bispecific antibody co-targeting PD-1/programmed cell death ligand 1 (PD-L1) and VEGF may result in cooperative binding, which can enhance both PD-(L)1 binding affinity and anti-angiogenic activity. It can also potentially confer safety advantages owing to a reduction in immune-related adverse events.

A range of PD-(L)1/VEGF bispecifics with distinct structural configurations and mechanistic differences are under development, and some are currently being evaluated for the treatment of patients with advanced RCC.

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This podcast article is also accompanied by digital features, including an infographic, to enhance understanding. The podcast video and infographic are available to view and download on the article’s Figshare page: https://doi.org/10.6084/m9.figshare.32408241.

Transcript

Brian Rini

This podcast is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the speakers.

Everybody, welcome to a podcast on the emerging role of PD-1 (programmed cell death 1 protein), PD-L1 (programmed cell death ligand 1), and VEGF (vascular endothelial growth factor) bispecific antibodies in an evolving kidney cancer landscape. My name is Brian Rini. I’m a Professor of Medicine at Vanderbilt-Ingram Cancer Center, and I’m pleased to be joined today by Ben Garmezy from Sarah Cannon. Ben, if you want to just introduce yourself quickly.

Ben Garmezy

Yeah, hi, I’m Ben Garmezy; I’m the Associate Director of Genitourinary Cancer Research for SCRI’s (Sarah Cannon Research Institute’s) network, and I’m also the Associate Director of Drug Development for SCRI Oncology Partners, where I practice in Nashville, Tennessee. And again, also very excited to be talking about this novel immunotherapy that we have coming to kidney cancer.

Brian Rini

Thanks, Ben. So yeah, you and I, we’re going to cover a variety of topics here. I’m going to start by just talking about the kidney cancer landscape to sort of orient the audience. We’ll talk about bispecifics in general. We’ll talk about some of the data for bispecifics in other diseases, I think primarily lung cancer, where there’s the most data. Talk a little bit about the kidney cancer data that exists, and then about some ongoing trials or upcoming trials in kidney cancer. So this is, I agree, it’s an exciting topic. Kidney cancer has been in need of novel therapy, honestly, for a while. And this is a big class of drugs that are being explored widely.

So, just real quick on kidney cancer. I think one of the reasons that this particular bispecific class is exciting is quite obviously that immune therapy and anti-VEGF pathway-targeted therapy are the two main pillars [1]. And when I’m talking to patients, that’s exactly how I explain it, whether I’m going to give them two immune drugs or one immune drug and one VEGF pathway-targeting, so an IO-TKI (immuno-oncology-tyrosine kinase inhibitor) regimen. That’s really the standard of care is this doublet, a doublet, an immune-based doublet in frontline clear-cell kidney cancer [1]. This is based on the biology of kidney cancer. So, VEGF-targeting agents came along first, gosh, probably over 20 years ago now, 25 years ago [2], based on the biology of von Hippel-Lindau gene inactivation, HIF (hypoxia-inducible factor) accumulation, and VEGF expression [2]. It was really the first time there had been active tumor shrinking drugs in kidney cancer [3]. About 10 years ago then, immune checkpoint inhibitors came along, largely directed against PD-1 [4]. There are PD-L1 inhibitors, I think we’ll talk about a little bit, not quite as effective. And then the CTLA4 (cytotoxic T-lymphocyte associated protein 4) antibody ipilimumab, which is part of an approved combination with nivolumab [5]. But this has really taken over the landscape of kidney cancer. Most patients will respond. The primary progression rate is really only about 5% or 10% with the IO-TKI regimens, maybe up to 20% with immune therapy [6]. Progression-free survival now measured in the year-and-a-half, 2-year range, including patients who can be cured of their disease, who can be out on that tail of the curve [6]. So, it’s a much different era than it was, you know, when I started doing drug development in kidney cancer, and it’s really set the landscape of kidney cancer again over the last decade or so.

Having said that, you know, as I mentioned at the outset, we really need novel therapies. So, we’ve been sort of adding drugs to the same, you know, bucket of mechanisms, so to speak, for a while, and so as we’re thinking about making advances for patients and curing more patients, quite obviously, we want novel ways to hit these targets and/or novel drugs, and that’s where I think bispecifics come in. So, Ben, with that, I’m going to turn it over to you to talk a little bit about bispecifics in general.

Ben Garmezy

Yeah, I think bispecific antibodies, I think to level set mean different things, right? So of course, when we talk about bispecific antibody, we could talk about PD-1, PD-L1, VEGF antibodies with two basically dual targeting, but we can also talk about some of the T cell engagers as well. Obviously, T cell engagers have started to make their way out of malignant hematology into solid-tumor oncology, and we actually have some US FDA (US Food and Drug Administration) approvals in small-cell lung cancer [7] and uveal melanoma [8] for this mechanism of action. We’ve seen data presented in kidney cancer with ENPP3 (ectonucleotide pyrophosphatase/phosphodiesterase 3) × CD3 (cluster of differentiation 3) T cell engagers [9]. So what we think about as a T cell engager is, unlike the PD-1, PD-L1, CTLA4 checkpoint inhibitors, these are molecules that actually grab onto the tumor microenvironment through an antigen on that tumor, as well as grabbing onto CD3 or CD28 on, actually, white blood cells within the patient and redirecting those white blood cells into the tumor microenvironment to directly engage and, you know, perform hopefully cytotoxic cell death via immune mechanisms [10]. Now, it’s obviously complex, and it’s a whole different side-effect profile than traditional checkpoint inhibition or, of course, VEGF inhibition, like we’re going to talk more about today. You know, you have issues such as cytokine release syndrome and other issues based on the target that you’re also going after. For instance, ENPP3 comes with some mast cell issues and rash [11], but again, those are different types of bispecifics that are also moving in. We have CD70 targeting as well [12]. But going back to what the focus of this podcast is, which is PD-1 or PD-L1 and VEGF, where these are bispecifics that are not T cell engagers. These are dual-targeting antibodies, and the goal is to basically augment the power of checkpoint inhibition and make it even stronger. And the reason that this works is because of the fact that we’re hitting two. We’re actually using VEGF to hone these antibodies into the tumor microenvironment in a more precise way, stabilize the neovasculature in the microenvironment, and also lead to a linking, where we basically get this daisy-chaining effect, where all these PD-1/VEGFs actually can circle up around the tumor cell of interest to hopefully provide an even stronger immunotherapy attack [13]. Now, Brian, did I miss anything on that? Or is there anything you want to add in that space about how maybe a PD-1/VEGF might be more unique from an immunogenic standpoint than a traditional anti-PD-1 molecule?

Brian Rini

I think, I mean, going back now many years: so when VEGF agents first came in the clinic and immune agents, there’s been this…oh, inquisitiveness about, does VEGF inhibition make immune therapy work better? And I thought it really did, and then I thought it didn’t, and then I thought it did again, and now I’m not sure. And so, there’s been a lot of data back and forth about the effects of VEGF inhibition in the microenvironment on immune cells. I think for IO-TKI combinations, I think they’re largely additive. You know, I think, if you look at the numbers, they’re largely additive. I don’t think there’s evidence of synergy. I think for the bispecifics, I don’t know, right? We don’t know yet. They’ve not been tested enough. But I think it’s a—I think one of the main questions for the field is, are there going to be significant mechanistic differences when you inhibit these targets separately, as we’re doing now with FDA-approved drugs or with a bispecific for some of the reasons that you mentioned? I think that, to me, is the fascinating possibility for, you know, PD-1/VEGF bispecifics.

Ben Garmezy

Yeah, and when you think about it from a drug development standpoint, and you look at the entire field and where it’s moving, I think it really started with, you know, at least in the USA, we’re hearing data ex-USA from ivonescimab, which is a different PD-1/VEGF that’s being developed. And in lung cancer, it does show an increase compared with pembrolizumab in progression-free survival, though we haven’t necessarily seen that increase in overall survival yet [14]. But because of that data set, as well as other data sets, we’ve seen an explosion in the field of what I would call these PD-1 or PD-L1/VEGF bispecifics. We have numerous, numerous, numerous drugs in this space being developed by different companies to try to do exactly that [15–19]. How do we improve upon traditional checkpoint inhibition? And now specifically here, we’re going to talk about PF-08634404, which targets PD-1, so not PD-L1, but PD-1 and VEGF [20]. And I do think there’s some nuances that we might want to get into about PD-1 and PD-L1 and kidney cancer that I think has been quite controversial for some time. But this drug, which I think we can call now 4404 (PF-08634404), is being developed and coming into kidney cancer now [21]. So, is there anything specifically about maybe this drug that you get excited about in kidney cancer when we think about PD-1/VEGF? Perhaps do we need to think about that any differently than maybe the PD-L1/VEGFs?

Brian Rini

Yeah, I mean, over the years, to me, the clinical data is pretty clear that PD-1 inhibition is more clinically effective than PD-L1 inhibition in kidney cancer [22]. This is not true in other diseases, but confining my comments to kidney cancer: why exactly is that the case? I don’t think we know, but the trials with PD-L1 inhibitors have largely either been negative or shown just PFS (progression-free survival), while the PD-1 inhibitors have shown OS (overall survival) [23–26]. So, I think if it would stand to reason that in a bispecific you would want to inhibit PD-1—again, we don’t know. That’s speculation, and again there’s going to be some different mechanisms at play, but that’s, you know, a priori going into this. That’s what I would think.

Ben Garmezy

Yeah, and I agree, but also I think with you, I think we should be hesitant and cautious about that statement, right? I mean, we know that maybe PD-1 inhibitors work better than PD-L1 inhibitors when given alone in isolation, right, in RCC (renal cell carcinoma). We don’t know whether or not that applies to patients with a VEGF bispecific, right? Obviously, this is a slightly different MOA (mechanism of action). And perhaps there will be no differential effect between a PD-1 or a PD-L1-targeted molecule. Of course, there’s PD-L1/VEGFs out there that are going to be explored in kidney cancer, such as BNT327, and some of these other studies. And perhaps that will be equally efficacious as a PD-1/VEGF. I guess in the spirit of really not knowing, it—it’s possible that those could be more efficacious too. I just don’t think we know. And I think we just need all this research to get out there so that we can start getting this into patients so that we can really see how do we move the field forward and start to improve immunotherapy to ultimately, as you mentioned earlier, raise that tail of the curve, because that’s what the promise of immune therapy can do.

Brian Rini

And yeah, I guess I would say, you know, again, thinking back about when the first VEGF inhibitors came out, we kind of assumed they were all going to be the same, you know—it was sort of a naive assumption. And then it became pretty clear over time that differences in potency and selectivity and et cetera, et cetera, really created some differences among the, you know, VEGF receptor inhibitors or multitarget inhibitors, broadly speaking. And I think if you look at the spectrum of bispecifics, you know, some of which you’ve mentioned, there are differences in either IgG4 (immunoglobulin G4), which is 4404 (PF-08634404) [20], or IgG1 in the binding arms. There’s mechanistic, structural—maybe a better term—structural differences in these. And it stands to reason that it very well could result in clinical differences. Again, we don’t know, but there’s not enough clinical data, certainly in RCC to know this, but I think it’ll be an interesting story to keep track of moving forward.

Ben Garmezy

Yeah.

Brian Rini

Let me cover—I wanted to, I covered some of this in the opening, but I just want to reiterate a little bit around the specific rationale in kidney cancer. Again, we’ve been targeting VEGF and targeting PD-1 largely or PD-L1 in kidney cancer for a while based on biology, and you mentioned some of this, about—I think it’s this cooperative binding and this multimer forming to increase the affinity, you know, against PD-1 100-fold in a preclinical setting [27]. This is not only true for 4404 (PF-08634404), but ivonescimab [28] and BNT327 [29] have shown this as well, basically, that you’re getting superior blockade as opposed to individual PD-1, PD-L1, or individual VEGF targeting. And again, how clinically relevant that’ll be, I don’t know. One area where it could be relevant also is toxicity, right? I mean, we struggle. Doublets…We’ve done a pretty good job of managing toxicity. The trials of triplets haven’t borne out yet, in part because of toxicity [30]. And so again, whether there’s reduced toxicity from this kind of approach: I don’t think, again, in my opinion, there’s enough clinical data to know. But I think it’s important to understand, again, mechanistic differences, not only within the class, but between the class and our established agents. And again, it makes all the sense in the world to target both of these targets in kidney cancer. That’s not going anywhere. Kidney cancer will always be a VEGF-driven disease [31]. So I’m a fan of VEGF targeting. I’m less and less of a fan of VEGF-TKIs over time. If you, you know, see enough patients over time—and you know this well, Ben—is that TKIs just wear people out. They just wear people out. And the happiest patients I have are patients I’ve taken off TKIs or given a break to. Sometimes patients don’t even realize how worn out they are. So, I think for me, one potential advantage here is that you get, you know, TKI-like activity—or at least bevacizumab-like activity—with these bispecifics, but without the added toxicity. And again, we have to see how this plays out, you know, in the clinic. But I think if we could, even if they’re exactly the same, you know, level of activity as IO-TKI, but less toxic…to me, that would be a major advance. It’s a difficult regulatory pathway, but it would be a major advance for patients.

Ben Garmezy

Yeah, I completely agree. And when we start to think about the toxicity, the adverse-event profile, I think there’s clear potential benefits here and clear potential risks as well, right? So when we think about the benefits, right…So drugs such as 4404 (PF-08634404) or ivonescimab or some of these other ones are designed to actually interact with the vasculature and modulate VEGF-related immune pathways. And the reason we think that this could be even more effective without additional toxicity is that we’re going to try to accumulate these molecules into the malignant tissue that will hopefully reduce some of the—what we would say—you know, adverse events related to IO toxicities that we can better hone these molecules in. Now, all that being said—and I think we’ve seen this risk on prior data sets in RCC—is when you have two targets on the same molecule, and we do run into side effects, right? And now all of a sudden we think we have an immune-related side effect, or maybe we have a VEGF-related side effect, we can’t stop one of these molecules in a combination. We actually have to stop the entire molecule. So, while we might see these benefits in better immune targeted, which might lead to less IRAEs (immune-related adverse events), right, immune-related adverse events, or maybe better targeting, you know, our VEGF as it’s not a TKI. So, it’s as if it’s more of a monoclonal antibody with a more bevacizumab-based toxicity profile. Those are two clear wins, but I do also think there’s a clear risk here in the sense that I can’t stop only one, right? So, thinking about how do you develop these drugs and thinking about, well, if I have clear VEGF-related side effects, I need to switch into a traditional monotherapy PD-1 inhibitor or something…I think it becomes a challenge because we have seen a couple of phase 3 trials [32] when we add on MOAs, leading to confusing side-effect profiles, leading to more steroid use, et cetera, that perhaps those phase 3 trials don’t always look as good as those phase 1 and phase 2 trials [33].

Brian Rini

Yeah, no, I totally agree. I think it’s a great point, is that as you combine more mechanisms into a single, you know, moiety, that it’s sort of all or nothing, right? You’re all in or not. And so, I think we’re all going to learn about: What is that toxicity profile? How do we modulate it? When should we hold? There’s always a learning curve of new drugs. I find it takes me, you know, many, many patients to sort of really get it down when it’s appropriate to hold or not. And I think that’s going to be true for a class as well.

Let’s touch on the lung data. You mentioned the HARMONi trial before. If you could just take us through a little bit of that. That was sort of when, at least for me, as a kidney cancer doc, bispecifics broke on the scene is that you saw these curves coming out of China for this, for the ivonescimab bispecific.

Ben Garmezy

Yeah, I agree. And I think the HARMONi trials kind of show some of the fact that we can improve PFS, right, compared with pembrolizumab. So, HARMONi was based in nonsmall cell lung cancer trials conducted in China. There were numerous, you know, HARMONi, HARMONi-2, HARMONi-6, et cetera [14, 34, 35]. And what it shows is that compared with PD-1 inhibitors, that ivonescimab is an improved PFS. And again, the safety profiles are manageable with no new increase in adverse events or in safety profile that was not expected. There was a little bit of VEGF-based adverse events, as we would expect given the molecule.

The global phase 3 HARMONi trial that really, you know, splashed was presented at the 2025 World Conference on Lung Cancer [36]. Now, while it failed to meet its dual endpoint in overall survival, that hazard ratio was 0.79, and the confidence interval was 0.62 to 1.01—so, it was close; the p-value was 0.057 [36]. So, I would say that that’s a true trend in overall survival, even if it didn’t quite hit the overall survival where it did hit PFS, and that was versus placebo in addition to chemotherapy, right? So, this is adding on to chemotherapy in this post-third-generation EGFR (epidermal growth factor receptor)-TKI setting in nonsmall cell lung cancer. So again, this is exciting. It does not necessarily apply to kidney cancer, but it shows that this molecule has data. Now, there’s other Chinese studies in nonsmall cell lung cancer with ivonescimab that are compared with more traditional immunotherapy approaches.

And then moving on into HARMONi-2 [14]. You know, this was a phase 3 study in frontline PD-L1-positive nonsmall cell lung cancer done in China. The overall response rate with ivonescimab, 10 mg per kilogram monotherapy, was 64.7%, right? 39%, though, with pembrolizumab. So, we did have an increase in objective response rate in this—in this study. So, that’s a phase 2 study. It’s showing that you have the potential for a PD-1/VEGF to overcome and increase the efficacy compared with pembrolizumab. Now, remember, though: we have two targets versus one target. We have PD-1 and VEGF here versus pembrolizumab, which is a PD-1 alone. So, I think this is all exciting. You know, we have other data sets as well. There’s no data in other solid tumors. There’s a phase 2 study with, not ivonescimab, but with 4404 (PF-08634404) and chemotherapy showing objective response rates of nearly 60% and 57.5% in combination with XELOX (oxaliplatin and capecitabine) or modified FOLFOX6 (modified oxaliplatin, leucovorin, and 5-fluorouracil) [37]. So, that looks exciting in a phase 2 setting in colorectal cancer. That’s not with ivonescimab. Remember, that’s with 4404 (PF-08634404). And there’s also data from BNT327 in combination with chemotherapy—that’s a different PD-L1/VEGF—which was 41.5% objective response rate in second-line small-cell lung cancer [38] and 73.8% in frontline triple-negative breast cancer [39]. So I think, overall, this is exciting. If we go back to the initial—like all the way back into the initial first-in-human phase 1a ivonescimab studies, they did a pan-solid-tumor cohort, and the objective response rate was 25.5% [40]. So, what you’re seeing is, there’s a role for this type of drug in many solid tumors as we take a step back before we go back in and think about more kidney cancer specific.

Brian Rini

Yeah, I think what’s interesting also is, you know, I don’t see these other diseases. I just see GU (genitourinary), largely RCC, but they’re not really hugely VEGF-responsive diseases, right? I mean, they’re immune-therapy-responsive diseases. So, you would hope that in a disease, such as kidney cancer, which is clearly VEGF responsive [41], that you would see even greater activity—again, to be determined—but the data you just cited may largely be owing to enhancement of immune activity and not so much a VEGF effect.

Ben Garmezy

I agree. I think that’s the goal, right? I mean, if these drugs are going to do what they’re promised to do, it can’t just be the fact that we’re tacking on a VEGF inhibitor to the PD-1. It truly has to be that multimer, that daisy chaining, that effect of better honing the PD-1 inhibition into the tumor microenvironment if it’s really going to have this foundational change where we’re seeing numerous trials launch across many solid tumors [17–19, 21, 42, 43]. It has to be that. So that’s the initial proof of concept. And that has to be the thought. And I hope that’s true when we see what these early signals are showing, as we move into later phases of development across solid-tumor oncology.

Brian Rini

Yes, so let’s—maybe we’ll wrap up. I’ll describe sort of what’s going on in kidney cancer, bringing us back to, you know, my favorite disease. So, 4404 (PF-08634404) is going to be studied in a phase 1b/2 study in frontline advanced kidney cancer [21]. So, no prior systemic therapy, although prior adjuvant immune therapy is allowed, as you might imagine, as that’s a standard. There’s a small monotherapy lead-in. There’s—and then, some combination cohorts. And I think that’s going to be really interesting, combining a TKI, axitinib, with this, right? I mean, when we tried back in the day to combine sunitinib and bevacizumab, it didn’t go well, with some vascular toxicity [44]. Whether it’ll be the same here, obviously we’ll find out, and you know, sort of carefully dose escalate. Also, a combination with CTLA4—I mentioned at the outset that we’ve been great at developing doublets in RCC. In fact, you know, recent data in the adjuvant [45] and a refractory [46] setting with HIF-based doublets, triplets have been a challenge, and so we haven’t quite been able to take that next leap. And so, obviously, triplets will be evaluated here if you count the bispecific as two drugs or at least three different mechanisms across the regimen. So, we’ll see. Again, I think safety first, you know. If we can give it safely, then I think it opens up the door to potential increased efficacy.

There is a study of the BNT (BNT327) compound as monotherapy in kidney cancer [43]. There was some early results presented with a response rate of 25%, PFS of 10.9 months [16]. As you know, it’s hard to really to evaluate these small, sort of, phase 2 experiences in very select patients, but clearly active as you would expect. You’d be shocked if these drugs had no activity. And it looked like a manageable toxicity profile, and we’ve touched on the importance of that.

And then there’s a study at MD Anderson called IVORY, which is an ivonescimab, ivonescimab monotherapy in different cohorts [47]. I think one is just IO refractory, probably it be nivo (nivolumab) refractory, and one is IO-TKI refractory. So we’ll see—again, we’ll start to get some more data about these agents. I think in the next 12 to 18 months, that, you know, upcoming meetings, we’re going to start to see this sort of featured prominently. And there was some—again, I mentioned the data out of China, you know, it’s probably the biggest data set we have. It’s not that it’s not that big, right? So, we’re really just starting to get into the clinic, establish safety, and then hopefully efficacy, and then onward to bigger, bigger registrational trials.

But maybe we could just wrap up with—I’ll ask you first, and then I’ll go—about, what are you most excited about? Two-parter, one about the bispecifics in general, and then just maybe about kidney cancer in general.

Ben Garmezy

Yeah, I think, you know, these bispecifics, I think they’re exciting because we have not been able to effectively develop a triplet in RCC, right? We thought we were going to have it. Unfortunately, pembrolizumab and lenvatinib and belzutifan does not look like that’s going to be the combination that is going to move forward [48].

So, then, how do we get three targets or a better way to give two targets? You already talked about, maybe we can decrease toxicity burden by just a monotherapy here, and I think that’s worthy of exploration. But perhaps now we can get three targets as well by giving two drugs in a safer way. And it goes back to that BNT327 study that you mentioned [16]. The grade 3 immune-related adverse event rate in that study was only 3.8% [16]. So, if we have decreased IRAEs, we can potentially pair this better with ipilimumab than some of these other combinations. So, I think that’s really exciting. I agree with you, the combination with VEGF-TKI is potentially challenging, though worthy of exploration. I think Saby George presented some data with a TKI and bevacizumab, though it was alternating [49]. That was quite exciting, though small. So, I think that—that really excites me, that maybe we can better hit three targets with this type of combination, whether it’s with 4404 (PF-08634404) or with one of these other PD-1 or PD-L1/VEGFs.

And then when I think more broadly, what gets me excited in kidney cancer is probably, you know, I really do think moving into these refractory settings, we are starting to see finally some new MOAs gain some traction as we kind of start to get to this point where maybe, hopefully, we’re only 1 or 2 years away from launching some, you know, large phase 3 studies with drugs with different targets, whether those be T cell engagers or whether some of these other new smaller molecules currently in development. I do think while we’ve been stuck with HIF inhibition, checkpoint inhibitors, and VEGF inhibition for so long, I think we’re actually on the cusp of moving in with new drugs in kidney cancer, like we have in the other GU tumors that we also treat in prostate [50] and bladder cancer [51]. So, I’m getting excited about that, and I think we’ll just have to see over the next 2 years if I’m proven right or wrong on that.

Brian Rini

Yeah, I broadly agree. I mean, I think for the bispecifics, it’s—combinability is key. And if the non-RCC trials are any indication, I mean, making immune therapy work better, you know—kidney cancer should have the most activity, right? It’s the most immune responsive of all the diseases we’ve talked about today. So, then you throw in, you know, any VEGF pathway inhibition activity, right? And you really should be onto something, you know, for both of those reasons. So, we’ll see. I think exciting times, and when we’re about to find out because there’s a lot of different bispecifics being tested in kidney cancer and broadly. And I agree, I think we still need even more novel mechanisms in RCC. I am excited about the cell therapies, how they can roll out and how applicable they’ll be. And yeah, I think that’s going to be interesting to see. But if prostate cancer can do big phase 3 trials with, you know, T cell engagers, then we should be able to as well, right? I would have thought it would have been the opposite, but I think there’s a lot of room for cell therapy as potentially curative therapy, right? As we think about, you know, potent immune therapy, broadly speaking. So, anyway, Ben, thanks for joining. It’s been a lot of fun. I think the field is excited about bispecifics, as mentioned—a lot of trials moving forward, and we’re all excited to hopefully see data that helps patients.

Author Contributions

Brian I. Rini and Benjamin Garmezy contributed to conceptualization and writing (review and editing).

Funding

This podcast, and the rapid service fee, was sponsored by Pfizer.

Declarations

Conflict of Interest

Brian I. Rini reports participation in advisory boards for Merck, Pfizer, Eisai, Arcus Biosciences, and Aveo Pharmaceuticals; invited speaker (institutional) for Merck, Pfizer, AstraZeneca, Adela, Arcus Biosciences, Regeneron, and Arcus; and research funding (institutional) from Bristol Myers Squibb. Benjamin Garmezy reports consulting (institutional) for Amgen, AstraZeneca, Bayer, Bicycle Therapeutics, BioNTech, Bristol Myers Squibb, EMD Serono, Eisai, Exelixis, GlaxoSmithKline, Immunocore, Janssen, Merck, Monte Rosa Therapeutics, Novartis, Onviv, Pfizer, Roche-Genentech, Specialty Therapeutics, Takeda Pharmaceuticals, and Xencor; research grants (institutional) from AbbVie, Accutar Biotechnology, Adcentrx, Adicet Therapeutics, Amgen, Arcus Biosciences, Arvinas, AstraZeneca, Avenzo Therapeutics, Aveo Pharmaceuticals, Bicycle Therapeutics, Bristol Myers Squibb, CRISPR Therapeutics, Daiichi Sankyo, Eikon Therapeutics, Exelixis, Roche-Genentech, Flare Therapeutics, GlaxoSmithKline, Halda Therapeutics, Harbour BioMed, HiberCell, Ideaya Biosciences, Incyte, Janssen, Janux Therapeutics, Jubilant Therapeutics, Kinnate Biopharma, Lilly, Loxo Oncology, Merck, Mink Therapeutics, Novartis, Nuvation, Pizer, Profound Therapeutics, Rise Therapeutics, Rondo Therapeutics, Takeda, Teon Therapeutics, Tmunity Therapeutics, Xencor, and Zenshine.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.