Emerging role of PD-(L)1/VEGF bispecific antibodies for advanced renal cell carcinoma treatment

00:00:00: You are listening to an ADIS Journal podcast.

00:00:05: 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 through a podcast On The Emerging Role Of PD-One PdL One Embedget By Specific Antibodies In An Involving Kidney Cancer Landscape.

00:00:24: My Name Is Brian Reedy.

00:00:25: I'm A Professor Medicine at Vanderbilt's Ingram Cancer Center and I'm pleased to be joined today by Ben Garmsi from Sierra Kennen.

00:00:32: Ben, if you want just introduce yourself quickly?

00:00:35: Yeah hi i am ben garmsi the associate director of general urinary cancer research for scri's network ,and i'm also the associate Director of Drug Development For SCRI Oncology Partners where i practice in Nashville Tennessee .

00:00:47: And again also very excited to be talking about this novel immunotherapy that we have coming to kidney cancer.

00:00:54: Thanks Ben.

00:00:55: So yeah, you know we're going to cover a variety of topics here.

00:00:58: I'm gonna start by just talking about the kidney cancer landscape to sort orient the audience will talk about by specifics.

00:01:04: in general.

00:01:05: We'll talk about some of the data for buy specifics.

00:01:08: um In other diseases and primarily lung cancer where there's the most data Talked a little bit About uh The kidney cancer data that exists And then about Some ongoing trials or upcoming Trials Uh in kidney Cancer.

00:01:20: so This is, I agree it's an exciting topic.

00:01:24: Kidney cancer has been in need of novel therapy honestly for a while and this is uh big class of drugs that are being explored widely.

00:01:31: so just real quick on kidney cancer.

00:01:34: i think one of the reasons that Immune therapy and anti-vegev, a vegev pathway targeted therapy are the two main pillars.

00:01:46: 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 in one vegep pathway targeting.

00:01:54: so an IoTKI regimen That's really the standard of care is this doublet A-doublet An immune based doublet In front line clear cell kidney cancer.

00:02:03: This is based on the biology of kidney cancer.

00:02:06: So VEGF targeting agents came along first, gosh probably over twenty years ago now and twenty-five years ago, um... Based on the Biology of Von Hubbel Lindau gene inactivation, HIF accumulation and VEGEF expression it was really the first time there'd been active tumor shrinking drugs in Kidney Cancer about ten years ago.

00:02:23: then immune checkpoint inhibitors came along largely directed against PD one.

00:02:28: Um, there are PDL one inhibitors.

00:02:30: I think we'll talk about a little bit not quite as effective.

00:02:32: and then the CTLA for antibody if the Luma Mab which is part of an approved combination with Nivola Mab but this has really taken over their landscape.

00:02:40: uh of kidney cancer most patients will respond.

00:02:44: The primary progression rate is only about five or ten percent With the iotk regimens maybe up to twenty percent.

00:02:49: with immune therapy progression free survival now measured in the year and a half, two-year range including patients who can be cured of their disease.

00:02:57: Who could get out on that tail to curve?

00:02:59: So it's really... It was much different era than when I started doing drug development and kidney cancer And its set the landscape over the last decade or so.

00:03:12: Having said that As i mentioned at outside we need novel therapies adding drugs to the same bucket of mechanisms, so-to speak for a while.

00:03:23: And as we're thinking about making advances in curing more patients quite obviously we want novel ways to hit these targets and or novel drugs.

00:03:32: and that's where I think bispecifics come in.

00:03:35: but with that i'm gonna turn it over you to talk a little bit about bispecifics in general.

00:03:40: yeah I think biospecific antibodies can level set mean different things right?

00:03:45: Of course, when we talk about bispecific antibody.

00:03:47: We could talked about PD-I PdL I VEGF antibodies with two basically dual targeting But we can also talk about some of the T cell engagers as well.

00:03:55: Obviously T cell Engagers have started to make their way out of malignant hematology in this solid tumor oncology And we actually have some FDA approvals and small cell lung cancer and uveal melanoma for these mechanisms of action.

00:04:10: We've seen data presented in kidney cancer with EMPP three CD-III T cell engagers.

00:04:16: So what we think about it as a t cell engager is unlike the PD-I, PD-L I CTA IV checkpoint inhibitors these are molecules that actually grab on to the tumor micro environment through an antigen on that tumor, as well as grabbing onto CD-III or CD-IIIII on actually white blood cells within the patient and redirecting those white blood cell into the tumor microenvironment to directly engage and perform hopefully cytotoxic cell death via immune mechanisms.

00:04:43: Now... It's obviously complex, 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.

00:04:53: You know you have issues like cytokine release syndrome and other issues based on the target that you are also going after.

00:04:58: for instance EMTP-III comes with some mass cell issues in rash but again those were different types of bispecifics that are all so moving in.

00:05:06: We have CD-seventy targeting as well But going back podcast is, which is PD-One or PDL One and VEGF where these are by specifics that are not T cell engagers.

00:05:17: These were dual targeting antibodies And the goal this to basically augment The power of checkpoint inhibition and make it even stronger?

00:05:26: And the reason for this works Is because of the fact that we're hitting two.

00:05:29: We're actually using VEJF To hone these antibodies into the tumor micro environment in a more precise way stabilize the neovascular chair In the microenvironment and also lead to a linking where we basically get this daisy chaining effect, were all these PD-One VegFs actually can circle up around the tumor cell of interest to hopefully provide an even stronger immunotherapy attack.

00:05:51: Now Brian did I miss anything on that or any thing you want add in that space about how maybe a PD One VegF might be more unique from an immunogenic standpoint than traditional anti-PD one molecule?

00:06:09: VEGF agents first came in the clinic and immune agents, there's been this inquisitiveness about.

00:06:15: does VEJF inhibition make immune therapy work better?

00:06:18: And I've thought it really did.

00:06:20: Then I thought it didn't.

00:06:21: then I thought again now i'm not sure.

00:06:24: so There has a lot of data back-and forth About the effects of VEGEF inhibitions in microenvironment on immune cells.

00:06:32: For IoTKI combinations they are largely additive.

00:06:37: You know, I think if you look at the numbers they're largely additive.

00:06:39: I don't think there's energy evidence of synergy.

00:06:42: Um i think for the by specifics...I don't know right?

00:06:45: We don't Know yet They've not been tested enough but I think it's a-.

00:06:48: I Think one Of The main questions For the field is 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 buy specific for some of the reasons that you mentioned and I think That To me is the fascinating possibility.

00:07:05: you know, PD-I VEGF by specifics.

00:07:08: Yeah and when you think about it from a drug development standpoint... And you look at the entire field in where its moving I think that really started with You Know At least In The US With hearing data XUS From Ivan Esimab Which is A different PD-iVeGF That's Being Developed And in lung cancer Does Show An Increase Compared to Pembrolizumab In progression Pre-Survival Though We Haven't Necessarily Seen That Increase In Overall Survival Yet.

00:07:33: But because of that data set, as well as other datasets we've seen an explosion in the field.

00:07:39: Of what I would call these PD one or PDL One VEGF by specifics.

00:07:42: We have numerous numerous numerous drugs In this space being developed By different companies to try To do exactly That.

00:07:50: how Do we improve upon traditional checkpoint inhibition?

00:07:53: and now specifically here?

00:07:55: We're going to talk about PF dash zero eight six three four four zero Four which targets PD-one, so not PD-O one.

00:08:01: PD-One and VEGF... And I do think there's some nuances that we might want to get into about PD- One in PD-L one and kidney cancer.

00:08:08: that has been quite controversial for sometime.

00:08:11: but this drug which i can call now four-four-oh-four is being developed and coming into Kidney Cancer Now.

00:08:17: So Is There Anything Specifically About Maybe This Drug That You Get Excited About In Kidney Cancer?

00:08:24: When We Think About PD-ONE Veg F Perhaps?

00:08:26: Do we need to think about that any differently than maybe the PDL-I VEGFs?

00:08:31: Yeah, I mean over the years.

00:08:33: To me The clinical data is pretty clear That pd one inhibition Is more clinically effective then Pdl One addition in kidney cancer This is not true and other diseases.

00:08:42: but confining my comments to kidney cancer Why exactly is there?

00:08:46: that's a case i don't Think We know.

00:08:48: um But The trials with PDL one inhibitors have largely either been negative or shown just PFS while the PD-one inhibitors I've shown OAS.

00:08:55: So, i think if it would stand to reason that in a by specific.

00:09:00: you'd want to inhibit PD-One again.

00:09:01: we don't know... That's speculation and there are going be some different mechanisms at play but that is a priori going into this.

00:09:08: so thats what I would think.

00:09:10: Yeah!

00:09:11: And I agree.

00:09:12: But also..I think with you We should be hesitant and cautious about that statement right?

00:09:17: We know that maybe PD-one inhibitors work better than PDL one inhibitors when given a loan in isolation, right?

00:09:24: In RCC.

00:09:24: we don't know whether or not that applies to patients with a VEGF by specific Right.

00:09:30: obviously this is a slightly different MOA and perhaps there will be no differential effect between a PD-One or Pdl One targeted molecule.

00:09:38: of course PD-L I VEGFs out there that are going to be explored in kidney cancer like BNT, three two seven and some of these other studies.

00:09:46: And perhaps that will be equally efficacious as a PD-I VEJF.

00:09:50: In the spirit of really not knowing it's possible those could more efficacious too?

00:09:55: We just need all this research so we can start getting into patients.

00:10:02: how do you move them forward As you mentioned earlier, raise that tail of the curve because that's what the promise of immune therapy can do.

00:10:13: And yeah I guess so would say again thinking back about when the first VEGF inhibitors came out.

00:10:19: we kind of assumed they were all going to be the same sort of a naive assumption and then it became pretty clear over time that differences in potency and selectivity etc.

00:10:31: really created some you know, VEGF receptor inhibitors or multi-target inhibitors broadly speaking.

00:10:38: And I think if you look at the spectrum of bispecifics...you In the binding arms, there's mechanistic structural maybe a better term.

00:10:55: Structural differences in these and it stands to reason that very well could result in clinical difference is again we don't know.

00:11:01: but if there's not enough clinical data certainly an RCC to know this.

00:11:04: But I think It'll be an interesting story too.

00:11:06: keep track of moving forward.

00:11:10: Yeah

00:11:11: Let me cover.

00:11:12: um i wanted to cut...I covered some Of This in The Opening but I just want To reiterate A little bit around specific rationale in kidney cancer.

00:11:22: Again, we've been targeting VEGF and targeting PD-I largely or PDL I in Kidney Cancer for a while based on biology.

00:11:29: And you mentioned some of this about... I think it's this cooperative binding and this multimer forming to increase the affinity against PD- I one hundred fold in a preclinical setting.

00:11:42: This is not only true for four four oh four but Ivan Esmab of Ivan Nesimab and BNT, three two seven have shown this as well.

00:11:50: basically that you're getting superior blockade.

00:11:53: As opposed to individual PD-one PdL one or individual VEGF targeting.

00:11:58: um And again how clinically relevant?

00:12:00: That'll be I don't know.

00:12:02: One area where it could be relevant also is toxicity.

00:12:05: right i mean we struggle.

00:12:06: Uh doublets.

00:12:08: We've done a pretty good job of managing toxicity.

00:12:10: the trials of triplets haven't borne out yet in part because Of toxicity.

00:12:14: so again whether there's Um, reduce toxicity from this kind of approach.

00:12:19: I don't think.

00:12:19: again in my opinion there's enough clinical data to know.

00:12:21: but i think it's important to understand Again mechanistic differences not only within the class But between the class uh and our established agents.

00:12:30: And again It makes all the sense in the world To target both of these targets In kidney cancer that's Not going anywhere.

00:12:35: Kidney Cancer will always be a vegev-driven disease.

00:12:38: so um i'm A fan Of vegeV targeting.

00:12:40: i'm less than less of a fan of vege VKIs over time If you, see enough patients over time and this well done is that TKI's just wear people out.

00:12:51: They're happy as patients I have or patients who've taken off TKIs are given a break too.

00:12:57: Sometimes patients don't even realize how worn-out they are.

00:13:00: so for me one potential advantage here Is to get TKI like activity Or at least bevacism ablike with these by specifics but without the added toxicity.

00:13:12: And again we need to know you know, in the clinic.

00:13:15: But I think if we could even...if they're exactly the same level of activity as iotkii but less toxic to me that would be a major advance.

00:13:24: it's difficult regulatory pathway but

00:13:28: Yeah, I completely agree.

00:13:30: And when we start to think about the toxicity of the adverse event profile... ...I think there's clear potential benefits here and clear potential risks as well right?

00:13:38: So if you're thinking about the benefits so drugs like four-four-or-four or IVanS and Mav or some these other ones are designed actually interact with a vasculature moderate modulate VEGF related immune pathways.

00:13:49: And the reason we think that this could be even more effective without additional toxicity is, that we're going to try and accumulate these molecules into the malignant tissue.

00:13:57: That will hopefully reduce some of what would say adverse events related to IO toxicities if we can better hone those molecules in.

00:14:07: Now all that being said...and I've seen risk on prior data sets at RCC when you have two targets and we do run into side effects, right?

00:14:20: And now all of a sudden we think that we have an immune-related side effect or maybe we have a VEGF related side effect.

00:14:25: We can't stop one of these molecules in combination—we actually need to stop the entire molecule!

00:14:31: So while you might see benefits in better immune targeted which may lead less I.R.A.Es —immune-related adverse events—or of, you know our VEGF as it's not a TKI so its more monoclonal antibody with a more bevacizumab based toxicity profile.

00:14:49: Those are two clear wins.

00:14:51: but I do also think there is a clear risk here in the sense that i can't stop only one right?

00:14:57: So thinking about how to develop these drugs and thinking well if I have clear VEGEF related side effects monotherapy PD-one inhibitor or something, I think becomes a challenge because we have seen.

00:15:08: A couple phase three trials when we add on MOAs leading to confusing side effect profiles leading too more steroid use et cetera that perhaps those Phase Three Charles don't always look as good as this Phase One and Phase Two trials?

00:15:21: Yeah no i totally agree!

00:15:22: I think it's great point.

00:15:23: is you combine more mechanisms into single moiety That it's sort of all or nothing, right?

00:15:31: You're you are all in and not.

00:15:32: And so I think we're going to learn about what is that toxicity profile?

00:15:38: how do we modulate?

00:15:39: when should we hold?

00:15:40: there was always a learning curve of new drugs.

00:15:42: i find It takes me many patients to really get.

00:15:45: Get it down When it's appropriate to hold her nodding.

00:15:47: I Think that's gonna be true for our class as well.

00:15:51: Let's touch on the lung data.

00:15:52: you mentioned The harmony trial before.

00:15:54: if he could just take us through A little bit of that.

00:15:57: That was sort of when, at least for me as a kidney cancer doc by specifics broke on the scene.

00:16:01: is you saw these curves coming out of China from this for the Ivan Estimate by specific?

00:16:07: Yeah I agree and i think the harmony trials kind show some of The fact we can improve PFS compared to pembrolizumab.

00:16:15: so Harmony was based in non small cell lung cancer Trials conducted in china.

00:16:20: there were numerous you know harmony two harmony six etc.

00:16:23: And what it shows compared to PD-I inhibitors that IvanSMAB is an improved PFS.

00:16:29: And again, the safety profiles are manageable with no new increase in adverse events or a safety profile that was not expected.

00:16:36: there were little bit of VEGF based adverse event as we would expect given molecule.

00:16:42: The Global Phase III harmony trial really splashed and presented at the World Conference on Lumb Cancer.

00:16:49: Now, while it failed to meet its dual endpoint overall survival that hazard ratio was zero point seven nine.

00:16:56: And the confidence interval with zero point six two to one point oh One.

00:17:02: so I would say That's a true trend in overall survival even if It didn't quite hit The overall survival.

00:17:08: where did hit PFS?

00:17:09: and that Was versus placebo In addition to chemotherapy right?

00:17:14: So this is adding on to chemotherapy in This post third generation EGFR, TKI setting non-small cell lung cancer.

00:17:21: So again this is exciting.

00:17:24: it does not necessarily apply to kidney cancer but it shows that this molecule has data.

00:17:31: now there's other Chinese studies in non-small cell lung cancer with Ivanesimab that are compared to more traditional immunotherapy approaches.

00:17:39: And then moving on into harmony too, you know this was a phase three study in front line PDL one positive nonsmall cell long cancer done in China.

00:17:47: the overall response rate Thirty-nine percent, though with pembrolizumab.

00:17:57: So we did have an increase in objective response rate in this study.

00:18:02: so that's a phase two study.

00:18:03: it's showing that you have the potential for PD one VEGF to overcome and Increase.

00:18:10: the effect is efficacy compared to Pembrolism.

00:18:13: now remember Though We Have Two Targets versus One Target We have PD-one and VEGF here versus Pembrolyzma, which is a PD one alone.

00:18:22: So I think this all exciting.

00:18:23: you know we've other datasets as well.

00:18:24: there's no data in Other solid tumors.

00:18:27: There's a phase two study with not Ivan Esimab but with four for oh four in chemotherapy showing objective response rates of nearly sixty percent at fifty seven point five percent In combination or modified Paul Fox six.

00:18:41: So, so that looks exciting in a phase two setting colorectal That's not with Ivan Esmaev remember?

00:18:45: That's with four four oh four.

00:18:46: and there's also data from BNT three to seven In combination with chemotherapy.

00:18:51: That's the different PDL.

00:18:52: one VEGF which was forty-one point five percent objective response rate And second line small cell lung cancer and seventy three point eight percent in frontline triple negative breast cancer.

00:19:02: I think overall this is exciting.

00:19:04: If we go back to the initial, like all the way back into the initial first in human phase one AI and SMF studies they did a pen solid tumor cohort.

00:19:12: And the objective response rate was twenty-five point five percent.

00:19:15: 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.

00:19:27: Yeah I think What's interesting also Is You know I don't see these other diseases.

00:19:33: I just see GU largely RCC, but they're not really hugely VEGF-responsive diseases right?

00:19:37: They are immune therapy responsive diseases.

00:19:40: so you would hope that in a disease like kidney cancer which is clearly VEGA for responsive then it's even greater activity again to be determined.

00:19:49: the data you've cited may largely be due enhancement of an immune activity and

00:19:56: I think that's the goal, right?

00:19:58: If these drugs are gonna do what they're promised to do it can't just be the fact we're tacking on a VEGF inhibitor.

00:20:07: It truly has to be that multimer or daisy chaining effect of better honing PD-one inhibition into the tumor microenvironment if its really going.

00:20:15: have this foundational change where seeing numerous trials launch across many solid tumors.

00:20:21: so thats initial proof And that has to be the thought, and I hope that's true when we see what these early signals are showing as you move into later phases of development across solid tumor oncology.

00:20:34: Yes so let's maybe we'll wrap up all describe sort of what's going on in kidney cancer bringing us back to your my favorite disease.

00:20:41: So for four or four is gonna be studying a phase one B two study in frontline advanced Kidney Cancer.

00:20:49: so no prior systemic therapy although prior adjuvant immune therapy.

00:20:55: There's a small monotherapy lead-in, and then some combination cohorts.

00:21:01: And I think that's going to be really interesting combining a TKI exitnib with this right?

00:21:08: When we tried back in the day to combine sugnitinibidivisism and GOEL with some vascular toxicity whether it'll be the same here obviously will find out sort of carefully dose escalate also.

00:21:20: a combination was CTA IV mentioned at.

00:21:23: We've been great at developing doublets in RCC.

00:21:26: In fact, recent data in the adjuvant and refractory setting with HIF-based doublits triplets have been a challenge until we haven't quite been able to take that next leap.

00:21:34: so obviously triple it will be evaluated here if you count them by specific as two drugs or three different mechanisms across the regimen.

00:21:42: So again I think safety first.

00:21:44: If can give safely then opens up door for potential increased efficacy.

00:21:49: There is study of the BNT compound as monotherapy in kidney cancer.

00:21:56: There was some early results presented with a response rate of twenty-five percent, PFS at ten point nine months.

00:22:02: As you know.

00:22:02: it's hard to really evaluate these small sort of phase two experiences and very select patients.

00:22:07: but clearly active is...as you would expect be shocked if these drugs had no activity.

00:22:13: And they look like manageable toxicity profile.

00:22:15: we've touched on importance.

00:22:17: And then there's a study at MD Anderson called Ivory, which is an Ivanesimab monotherapy in different cohorts.

00:22:25: I think one is just IO refractory probably epinevore refractory and one is IoTKI refractory.

00:22:31: so we'll see.

00:22:32: again will start to get some more data about these age-I think in the next twelve or eighteen months that you know upcoming meetings were going to start to see this sort of featured prominently.

00:22:44: Again, I mentioned the data out of China.

00:22:46: You know it's probably the biggest data set we have is not that big right?

00:22:50: So really just starting to get into the clinic established safety and then hopefully efficacy in onward to bigger registration trials.

00:22:59: so maybe you could wrap up with...I'll ask first what are your most excited about two parter.

00:23:08: one about the bi-specifics.

00:23:13: Yeah, I think you know these by specifics.

00:23:16: I think they're exciting because we have not been able to effectively develop a triplet in RCC right?

00:23:23: We thought we were going to have it.

00:23:25: Unfortunately Pembrokes-Mabell and Vatnam & Belzutafan does not look like that's gonna be the combination That is gonna move forward.

00:23:32: so then how do we get three targets or A better way to give two targets You already talked about.

00:23:37: maybe we can decrease toxicity burdened by just a monotherapy here And i think That's worthy of exploration, but perhaps now we can get three targets as well.

00:23:45: by giving two drugs in a safer way.

00:23:48: And it goes back to that BNT-IIIII study you mentioned, the grade three immune related adverse event was only about .

00:23:56: So if we have decreased IRAEs ,we can potentially pair this better with epilimumab than some of these other combinations.

00:24:03: so I think thats really exciting and i agree with your combination with Begev.

00:24:07: TKI is potentially challenging the worthy of exploration.

00:24:14: Though it was alternating, that was quite exciting though small.

00:24:18: So, I think that really excites me.

00:24:20: That maybe we can better hit three targets with this type of combination whether it's with four-four-oh-four or if one of these other PD-one or PD-L One Veg Fs.

00:24:29: 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.

00:24:46: Hopefully we're only one or two years away from launching some, you know large phase three studies with drugs.

00:24:53: With different targets whether those be T cell engagers Or whether there's some of these other new smaller molecules currently in development.

00:25:00: I do think while we've been stuck within if inhibition checkpoint inhibitors and veg f inhibition for so long i Think were actually on the cusp of moving in with new drugs and kidney cancer, like we have the other two YouTubers that we also treat in prostate and bladder cancer.

00:25:16: So I'm getting excited about that And i think will just had to see over next few years if im proven right or wrong on it.

00:25:24: Yeah broadly agree for the by specifics its combined ability is key If non-RCC trials are any indication making immune therapy work better.

00:25:36: You know, kidney cancer should have the most activity.

00:25:38: Right?

00:25:38: That's the most immune response of all the disease we've talked about today.

00:25:41: so then you throw in any VEGF pathway inhibition activity and really should be onto something for both those reasons.

00:25:50: So will see I think exciting times when were going to find out because there is a lot different by specifics being tested in Kidney Cancer broadly And I agree, we still need even more novel mechanisms in RCC.

00:26:28: Anyway, Ben thanks for joining.

00:26:29: It's been a lot of fun.

00:26:30: I think the field is excited about by specifics.

00:26:32: as mentioned A lot of trials moving forward and we're all excited to hopefully see data that helps patients.

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