Oncology Momentum: Tracking the Early Pipeline from AACR to ASCO – Transcript

Welcome everyone. So, I'm Regina Cheung. I'm the Director of Operations here at Oncology Resource Group. We're here to help your team stay ahead of what's happening across the oncology clinical landscape. AACR just wrapped, and as always, there was a lot to process: clinical trial data readouts, program updates, all amongst a sea of scientific data. So, we thought it would be useful to get together and talk about it to share with you. With us today, I've got our MOA leads. We have Amanda Koch, who's our leader for cell therapies, Carla Cabrera, who's our leader for antibody drug conjugates, Amanda Lanser, who is our director of the IO group, and I also lead our Emerging Clinical Signals coverage, which tracks early phase assets across all of the other MOAs. Together we have an eye across all of the early stage oncology development. So, we'll start with some shared questions first, some things that we're thinking about regardless of the mechanism that we're following, and then we'll dig in a bit deeper to look at what's happening in each of our specific areas. So let's dig in, and we'll start with our biggest takeaways from AACR. Amanda Koch, anything that happened that confirmed your expectations, anything that surprised you?

Yeah, so the cell therapy development is really still very popular, but it definitely does seem like things are starting to shift around between different subclasses. All that being said, autologous CAR-Ts are still the most popular, so that really hasn't shifted much in the last couple years, which is a little bit surprising. It does seem like companies are trying to really figure out what targets they want to go after for solid tumors, and then they're also trying to figure out new targets in heme, besides the well-established CD19 and BCMA targets, but I am seeing a lot more readouts, clinical and preclinical readouts for subclasses like TILs, CAR NK cells, and TCR T-cell therapies, and so data is starting to emerge for those subclasses, especially in solid tumors, which is has been interesting to see over the last couple years, and especially at AACR this year, and then something that surprised me specifically at AACR, with all this excitement that's happening around in vivo cell therapies, specifically, I didn't see a whole lot of clinical or preclinical data at AACR. That being said, there are clinical data readouts that are expected at ASCO, so we're excited to see what those look like.

Great. So, how about you, Carla? Anything that was surprising to you at AACR for antibody drug conjugates?

Yeah, so we reviewed close to 400 ADC abstracts and posters, and the majority of which were preclinical. So, I'll give you a few numbers first to start with. We had over 100 new ADCs that were reported information at AACR, about half of them were bispecific ADCs, and then a bit more than 30 were dual payload ADCs, including something that we hadn't seen before, which is a triple payload ADC that is a Nectin-4 ADC by Araris, that's using an MMAE, a Topo1, and a Topo1 derivative payload.

Wow, all three at once

Yes, that was interesting to see, and so I think my surprise was just the sheer volume of the dual payload and multifunctional ADCs, and the field is clearly evolving beyond just first generation optimization, like it was a few years ago, where the focus was largely on identifying new targets or improving link or stability, and this year there was much more emphasis on the multifunctional ABC architectures, and again these dual payload functionalities.

That's really interesting, Carla. Thanks for sharing those numbers,

Amanda L, anything in the IO field that confirmed your expectations or surprised you in the IO field?

We've seen continuous momentum around innovating around PD-1/PD-L1s, and that includes bispecific antibodies that target both PD-1/PD-L1 and VEGF, and we continue to see continued development and investment around that area at AACR. A new and surprising group of data that evolved at AACR was the amount of data around T reg depleters. What really came out of AACR is that while efficacy remains modest, the agents are really differentiated by their toxicity profile. So, for the CCR8 monoclonal antibodies, which are expected to deplete Tregs in the tumor specifically, there was a big difference between Gilead's agent, which had high rates of rash, versus Amgen's agents, which had a very clean safety profile. On top of that, Novartis had a very unique agent that is a degrader of Helios and was associated with neuropathy. So all of three of these agents really differentiated with the safety and AEs that they emerged with, so the question for T regs has evolved from, can we deplete T regs, to, how does the way we deplete them affect the outcomes and ability to combine with PD-1/PD-L1s in the future. So there's more data coming out of ASCO, including first data for BeOne's CCR8 monoclonal antibody that I'm looking forward to understanding how this fits into the body of work that we saw come out of AACR.

That's really interesting, since I recall that the T reg depleters really started coming onto the scene in terms of preclinical development back in 2020, when we really started seeing a lot of them show up. It's great to finally start seeing more clinical data for them come out and understand how they differentiate from each other. All right, in terms of the data that I took a look at, I would say that the excitement about RAS and KRAS was really palpable at this conference, and that was something that got talked about at quite a few of the the early stage sessions that I sat in on. Another thing that we continue to see is a really strong interest in protein degraders and molecular glues. So now I think we'll go into a little bit more detail for each of the MOAs, so we'll start with Amanda K for cell therapies, so CAR-T really has dominated the conversation for years, and it's really interesting to hear you talk a bit about the allogeneic CAR-Ts. Do you think they're finally ready to be taken seriously?

Yeah, that's an interesting question. I've definitely seen the development around allogeneic CAR-Ts slow in the last few years, and especially in the solid tumor space. At AACR, I saw no clinical readouts for allogeneic CAR-Ts, and there were very few preclinical disclosures, which is interesting, and that's not something that I've seen in past conferences, so definitely slowing down

Specific to this year and specific in solid tumors. So there are allogeneic CAR-Ts that are in development in heme, and quite a few of those are in pivotal trials, so it definitely seems like there's still some momentum in heme, but that just hasn't translated into the solid tumor space, unfortunately.

Do you think that the field in general is just waiting on those pivotal trials?

It could be. So the most recent bit of data that we've seen for an allogeneic CAR-T is from Allogene's cema-cel, which is in CD19 allogeneic CAR-T, and that's being developed in NHL. So they just had a readout, and numbers were still kind of small, so it's hard to really compare that data to those already approved autologous CAR-T's in the space, but the efficacy data does seem to be pretty promising. Interestingly, with allogeneic CAR-T's, kind of a theme that I've noticed is that the safety data is a little bit more promising compared to autologous CAR-T, so where efficacy lacks, safety is a little bit more promising. So it could reignite the field and move allogeneic CAR-Ts a little bit forward. I'd be interested to see if that translates to solid tumors, though. 

I would imagine that the combination of better safety with so much less complication for manufacturing would really help with an allogeneic CAR-T being taken up if it were to make it to market.

Definitely. Yeah, I think that, fortunately or unfortunately for autologous CAR-Ts, as new generations are coming out, they are figuring out quicker ways to manufacture and better ways to handle the adverse events that are associated with CAR-T such as anemia primarily from the lymphodepletion. It does seem like they are kind of mitigating a lot of those issues that we've seen in the past for autologous CAR-T, so it might, might be like squishing that space for allogeneic CAR-Ts to move into.

Okay, so you've talked a little bit about solid tumors, I mean, obviously that's still really the, the white whale, so to speak, for cell therapy, did anything at AACR shift your confidence that cell therapy is going to get there?

Yeah, well, definitely there are some autologous CAR-Ts that are reading out data that look pretty promising in solid tumors, so I'm going to just kind of briefly mention a couple, but really what the development focus has been around for CAR-Ts specifically for autologous CAR-Ts and solid tumors, is trying to make the CAR-T more persistent and harder hitting in that really difficult solid tumor microenvironment. And there have been a couple ways that have been popping up, different technologies that I've been seeing to do this. One of them is on off switches, so that turns off the CAR-T unless it's actively engaged in the tumor antigen, and so that is high to decrease T-cell exhaustion and keep that CAR-T more active for a longer period of time. Then the other way that companies are trying to really amp up the CAR-T efficacy in solid tumors is by testing multiple doses. So both of those were presented at AACR, and interestingly, both were targeting mesothelin. Yeah, so that's seems to be a target that companies are going after for solid tumors right now. Both of those assets, so both those technologies were presented, both of them elicited responses, and so that's good news. And it seems like specifically for that target, the indication that seems to have the most responses was mesothelioma. So it's encouraging that we're seeing anti-tumor activity for both of those approaches, but data from the asset that was testing the multiple doses did have some safety concerns, and we saw some DLTs. So I'm not sure if multiple rounds of a CAR-T is the way to go, necessarily.

That's really interesting for the on off switches, were those flipped on or off during treatment, or was it something that is an on off that is inherent to the CAR-T, and how its target?

Yeah, for this particular asset, it was specific for the target, so as soon as the CAR-T engaged in the target, it would turn on, and then turn off if it wasn't engaged.

Interesting.

but those other types of switches are being developed as well, where you induce the the on state with some kind of other drug.

Are there any other cell therapy technologies that are emerging, especially for the solid tumors that you wanted to discuss?

Yeah, just a couple real quick. So I wanted to point out that TILs are really emerging in popularity. I saw quite a few preclinical disclosures that we have, and then also some clinical data readouts that were at AACR, and it definitely seems like TILs are going after melanoma. So we already have an approval for TILs in melanoma, and I think really what the next step is is engineering them and making them more effective and safe in that specific indication.

Thanks for that roundup, Amanda. All right, so let's move on to Amanda L and the IO space. So the PD1/PD-L1s have really saturated the marketplace. Are there other targets that are having momentum?

That is absolutely correct. We've seen PD-1/PD-L1s as main states for quite some time now, and there was previously a lot of energy put into developing novel targets for monotherapy, but that has a bit shifted, as I mentioned previously, to rather than developing novel targets as monotherapy towards enhancing the efficacy we've already seen with PD-1/PD-L1, and one of the ways that that's being done is by combinations as well as the bispecific dual targeting agents, and at AACR we saw both of these have promising efficacy in terms of combinations. There is intriguing data using vaccines as a partner for PD-1s in the melanoma space. Moderna's mRNA vaccine targeting IDO and PD-L1 had very promising efficacy in PD-1 relapsed refractory melanoma, which is still an area of unmet need, but I'm the field is a bit cautious about interpreting these data since we recently had a phase three failure for an agent with the same targets in terms of the PD-1/PD-L1 x VEGF bispecifics. There has been an emerging trend that we've seen combining those with ADCs, which is a very intriguing combination. It's thought there's an anticipated synergy between combining these two classes of agents because the VEGF inhibitors will allow for better tumor access, and then the ADCs will increase antigen exposure and tumor immune specific targeting of the tumor. We saw an early readout for Convolive PD-1/PD-L1 x VEGF bispecific with a TROP-1 ADC, and that showed early promising efficacy and good safety. The caveat with this combination is that a lot of the programs are still in China only, and so we're waiting to see if this trend moves west as it has for development of PD-1/PD-L1 x VEGF bispecifics in general.

Have there been any of these PD-1/PD-L1 x VEGFs with ADCs that are being tested in later stage trials, or it's all still really early, early phase?

It's all still really early, and this was one of the first readouts we've seen for that combination, so it's an area of excitement, and it's intriguing as well, because both of these therapies and subclasses have the potential to replace standard of care, so as well as the combination of typical PD-1 and chemotherapy could not potentially be replaced with PD-1/PD-L1 x VEGF bispecifics, and ADCs, so the potential there is really high, but it's definitely still early.

early days still

and we're already seeing some of that trend move over into solid tumors, where we've had approvals recently in breast cancer and in bladder cancer of an ADC that is replacing the chemo, the standard of care chemo, plus a checkpoint inhibitor, so a PD-L1 or PD-1 inhibitor. So I think that is going to continue to shift, like Amanda said, with with the bispecific antibodies being combined with with ADCs as well.

Yeah, that does seem like a logical building block to tack that right on to the combination of an ADC with a checkpoint, Amanda. Amanda L, is there anything else that you wanted to share in regards to the T reg depleters? Certainly sounded like it was a fascinating conference AACR for that space.

It was certainly fascinating. The additional information or context that I'd add is that there's still a good amount of investment going into T reg depleters, so there's there's still some hope and optimism around it. Although the efficacy has been low, there's a number of agents still in development, and we're seeing a trend towards those moving into later phases of development. I think the focus now has really been on using it as a combination partner, and so we'll see how that data pans out. There's also a lot of debate around the technology. Do we have the right technology? Is it possible that we need to hit multiple nodes of T reg depleters in order for this to be effective and so there's a lot of unanswered questions and a lot of ongoing investigation in that area

for the T reg depleters that have read out how confident are you that they are actually depleting T regs

it's an important question, and because of that, most groups are showing T reg depleting data that is showing T reg depletion itself. So that's a major aspect of these presentations that folks are actually showing that T reg depletion, it's happening in both the tumor and the periphery, and so I am fairly confident that that's actually happening. 

The mechanism is actually working by the way it's been designed. Yeah,

yeah, but there are certainly nuances around the target and the way these molecules are designed. As we've seen with the adverse events, so a lot of tweaking that that could be explored still in that area.

Thanks, Amanda. That was a really interesting overview. Carla, let's move to you and the antibody drug conjugates. What novel technologies are you seeing in this space right now?

I think you know I'm going to sound like a broken record just repeating about these dual payload ADCs and triple payload ADCs. So I think what we're also seeing is differentiation for ADCs that is becoming a primary competitive difference, so I think historically we've seen ADCs being engineered and modified based on target selection, and now we're seeing differentiation based on the payload class, optimizing the release kinetics, spatial selectivity of these agents, for example, there was a number of dual payload agents at AACR that showed that the field is trying to engineer around known resistance mechanisms with a single payload exposure, so we're seeing that. I think I've also seen that bispecific ADCs are evolving from targeting just novelty targets, shifting into the meaningful biology. So, for example, the PD-L1 bispecific programs, they're trying to use this bispecificity to address spatial biology, like I mentioned before, and tumor microenvironment interactions, not just increasing antigen density, and, like Amanda mentioned, that you know, combining these bispecific, these bispecific agents with ADCs. I'm also seeing a little bit more sophistication around immune biology, so constructs combining checkpoint inhibitors or microenvironment targeting with payload delivery and immune engaging ADCs, so a lot of engineering going on, which is exciting to see.

It's really interesting to hear about the contrast between where the development is happening between the IO and ADCs, where I think IO is still definitely thinking a lot about targets, and ADCs are thinking much more about the payload that they're bringing.

Yeah, absolutely. Regina, what about you? What early phase data did you see at AACR that was particularly interesting?

So, really, most, most of the basket trial readouts that I looked at were pretty firmly in dose escalation. So, the primary takeaways were about safety of the drug, but there were a few that are starting to show some signals that are leading those companies to move forward with tumor-specific plans, so those would include D3 Bio. They presented quite a few presentations on their KRAS G12C inhibitor, elisrasib, and their ERK1/2 inhibitor D3S-002. Essentially, they're teeing them up for combination testing in NSCLC and I know that the IND had been cleared earlier this year. Then there is Nested, they have a MEK/RAF molecular glue that is now being tested at the recommended expansion dose in melanoma. They presented their dose escalation data that supported that dose expansion. Then there is Debiopharm. They have a combination of WEE1 inhibitor, zedoresertib, with their PKMYT1 inhibitor, lunresertib. Those are now in dose optimization in ovarian cancer. Then there was a Acerand's presentation on their PARP1 specific inhibitor, ACE 106 and that is setting them up for a planned Phase 2 trial of ACE 106 with enzalutamide in prostate cancer. So, with those last two, I just wanted to point out that the DDR space, where that WEE1 inhibitor is playing, the PARP1 inhibitor, that's not new. We've consistently seen these basket trial readouts over the years at AACR, ESMO, and ASCO, but I did want to point out that we also are still seeing a lot of preclinical interest in this DDR space at AACR in more specific PARP inhibitors, WEE1, PARG, Werner Helicase, Pol Theta, and ATR/ATM, so to me it's really interesting to continue to see DDR be a place of high interest in this basket space.

Is there anything else you wanted to talk about regarding the first early signals, or did that cover

that covers the early phase data that was of particular interest, yeah.

What about additional mechanisms or targets? Is there anything interesting that you're seeing that's been new?

So, a really interesting trend that we've been noticing that really reared its head, specifically at AACR, is the uptick in antibody conjugates that are including other payloads, other than the classic chemo type payload, I mean, Carla, you were already talking about seeing some dual payloads and triple payloads, but we're also seeing completely different payloads being tacked on as well, things like kinase inhibitors, such as PI3k/PIKK, a whole bunch of various degraders like IKZF, GSPT1, BRD4, even KRAS targeting molecular glues. So some of these really novel antibody conjugates have entered first in human trials recently, and quite a few of those designs were presented at AACR, so that is a space that we're going to be continuing to watch for the next few years, I think. So with that, I'll move on to some shared questions to wrap up our discussion of AACR and look forward a little bit to what we expect at ASCO. I'll start with you, Amanda K. Are there any big momentum shifts that you are looking forward to seeing more about at ASCO,

Yeah, definitely. So one thing that I wanted to point out, and like Carla said, I'm going to sound like a broken record here, but development for allogeneic CAR-Ts really seems to have slowed in solid tumors, specifically, and I wonder if that's going to continue with the excitement and push towards in vivo CAR-Ts, and so my big question really is, will the in vivo cell therapies take over the allogeneic CAR-T's and kind of really pinch that space. But kwith that being said, I can't imagine that in vivo CAR-T's are going to run into the same persistence obstacle that a lot of the autologous and allogeneic CAR-Ts have seen in solid tumors, specifically. So, really, right now I want to point out that the in vivo CAR-T development is not so firmly, but predominantly in heme right now, and that is something that we're seeing. We're seeing clinical readouts at ASCO for quite a few in vivo CAR-Ts, and those are in multiple myeloma, NHL, and ALL. So, again, kind of firmly in that heme space right now. So I'm excited to see some of the perhaps some of the in vivo cell therapies move over into the solid tumor space, and that's going to be exciting to see that coming out in the future. I think that's really the biggest momentum shift that I've noticed right now is that push towards in vivo cell therapy development. 

There were some in vivo acquisition news that happened while we were on the ground at AACR, that definitely people buzzing. So, it's exciting to see this in vivo space move forward.

And it's going to be exciting to see the data come out to kind of back up all of the money that's being put towards those acquisitions.

Yeah, very exciting. Carla, in terms of the antibody drug conjugates, are there other unanswered questions that you're hoping to see some answers for coming up?

Yeah, and I think looking forward to ASCO, we are seeing some reports of first in human data for bispecific ADCs, so that's going to be interesting and exciting. We already know that the combo of checkpoint inhibitors and ADCs has been efficacious across different tumor types, so we've seen approvals in bladder and breast, and some data being reported in non-small cell lung cancer from a Chinese trial, so we kind of already have an answer that those technologies and combinations are working well. I think an unanswered question for me that I'm still wondering about is whether some of these more complex architectures that I mentioned are actually going to translate into better therapeutic index clinically, because preclinically these contracts look very compelling, but we still need to see what the safety will look like with all these different payloads and whether it improves outcomes for patients.

Plenty to look forward to. There, how about you, Amanda L? For the IO space, are there unanswered questions you're looking to ask for, or generally what should folks be watching?

In terms of unanswered questions, there's still very much a need to understand how patients should be treated post checkpoint inhibitor, and as I mentioned, as we've discussed this combination of PD-1 x VEGF with ADCs, because it's such an aggressive therapy, I'm really curious where that might fit in the treatment algorithm, and that's going to be different for different tumor types. In addition, building on the data we have so far for T reg depleters, there'll be another readout for BeOne's CCR8 monoclonal antibody. So I'm looking forward to that, and seeing if that helps address some of the unanswered questions there. Looking forward for IO, and this builds on the trend of innovating around PD-1/PD-L1 is a group of abstracts that are going to be presenting molecules that are targeting both PD-1/PD-L1 and cytokines. So this is another wave of innovation that could potentially replace PD-1/PD-L1s by both improving efficacy of the PD-1/PD-L1 and safety of the cytokine target, as well as being more tumor specific, so that is what I am looking forward to in terms of the next wave of innovation for IO, and there'll be several abstracts related to that mechanism at ASCO.

Plenty of the other mechanisms that I'm tracking for the Emerging Clinical Signals Report, we've got a couple of KRAS G12D inhibitors with basket trial readouts, continued DDR development with a PARP1 inhibitor and a WEE1 inhibitor reading out, as well as a couple of PRMT5 inhibitors that will be reading out. So I think that's a great place to land. I really want to thank Amanda, Amanda, and Carla for really being honest about where they think the science is strong and where it's still a work in progress. This is exactly the kind of conversation we try to have internally every day at ONCrg. So, if anything we discuss today is relevant to the work you're doing, whether that's tracking early stage innovation, monitoring the broader oncology pipeline, or really focusing in on a specific tumor indication, we are here to help our MOA reports explore early stage innovation and track how those drugs are spreading across tumor types as they advance, while our tumor reports dive deep into the phase two and beyond. So, these really have comprehensive coverage of all drugs in development for a given indication to understand the competitive landscape and what's in the pipeline from a tumor specific point of view. So, as we head into ASCO, you can imagine our tumor coverage gets quite rich. So, you can learn more about our syndicated reports and advisory services at onc-rg.com or reach out directly to our team, we'd love to talk, and if you want a deeper dive into tumor-specific readouts, sign up for our ASCO Live event, which is happening on May 26th. So you can follow us on LinkedIn for more details, and there we'll review some of the most exciting readouts that are already shifting standard of care. So until then, thanks for watching.