BCMA/GPRC5D/FcRH5 – CARs/BsAbs – Clinical Update | Ajai Chari, MD, PhD | IMS 2024

Hi, my name is Ajay Chari. I am a professor of medicine and the director of the Myeloma program at the University of California, San Francisco. And at this year's IMS meeting in Brazil, I was invited by the organizers to give a talk on the T cell redirection therapy, meaning by specific CIN CARs targeting three important targets. Many of the audience will have been familiar with it, but BCMA, GPRC5D, and SCRH5. So obviously these therapies are revolutionary. And we say that historically for a new drug to be approved in myeloma, you needed a 20 to 30 percent response rate lasting three to four months. Now we're getting 60 to 100 percent response rates lasting from one to three years. So it's remarkable progress. And part of what I wanted to review is what are the unmet needs? What do we still need to do? Are we done? And I would say no, we're not done. So we're touring everybody. So where are the unmet needs? We have extramedullary disease, high risk disease, ISS3, meaning high stage, patients have a lot of bulky disease. Another one is what if you've already had a prior T cell redirection? What if you had a bispecific? What do we do then when it stops working? And then we also have to figure out how to minimize the toxicities. We don't want any deaths. In particular, it's tragic. A patient is in complete remission from their myeloma and having deaths or a serious side effect. So we need to work on side effect mitigation. And lastly, being a global conference, it's great to have all these therapies, but not as everybody in the world can't get them. And so access is another big one. So with that, what are the strategies to hit these unmet needs? And I would say you can divide them and there's this nice pictorial. You can divide them by targeting more than one protein. Why do we only do one at a time? We do combination therapy all the time with other drugs. Why not combinations with CARs and bispecifics? So that's one strategy to try to kill the myeloma with different targets. Second is to do a better job of activating the T cells, either by using different binding domains, different target cells, or maybe even moving it in earlier lines. Why wait for T cells to be exhausted and beaten up with multiple therapy? Why not do it earlier? And then lastly, combining those within two different targets together externally. So maybe putting two different bispecifics together, two different CARs together. So you can do it within one construct or you can do it across. So those are kind of like themes that I talked about. And we talked about individual drugs, investigational products, and then combinations. And so I think everybody in the audience is familiar with IDA cell and CIL2 cell, the CAR T's that have led to dramatic outcomes in patients. What are the exciting new things we're doing in CARs? We're doing alternative manufacturing, meaning new binding domains where maybe you don't see some of that neurologic toxicity we saw with CIL2 cell. Academic costs. So going to that cost issue. Why do we need to be paying $500,000 per CAR? Can you make it cheaper? And that's not to diss the industry. We need these drugs to be developed. But the reality is many countries can't pay that amount for CAR. And then also doing allogeneic CARs, right? Because currently you have to take a person's T cells, genetically modify them and put them back. That's like the process. Can we not just use CARs that are ready to go off the shelf? So those are some of the things that are being done. And then the other data, of course, that was important this year was with the approved CARs is what are the phase three studies? And why are those important? Up till now, almost all these T cell redirection therapy, which is the CARs and bispecifics, were approved on what we call accelerated approval, meaning you take a group of people that had very limited options and you gave them the product and you saw the efficacy. But what that doesn't tell you is how might this compare to other therapy, right? And that's what we really need, particularly understand the safety. You need a control arm. And so we had pivotal phase three studies read out, both CARMA 3 and CAR2T4. They tell us that both had market benefit, right? So IdaCell 50% improvement. CiltaCell had 75% improvement. And comparison to control arm. And what we heard at IMS is that with CiltaCell or CARDICTE, not only was there a 75% improvement, people lived longer by almost 15%. And that's, of course, what we all want. Yes, it's nice to have remissions, but we want to have people live longer. And what this means is that if you delay the myeloma relapse, you're going to have patients living longer. And that's great. And it also put into context some of those side effects, right? So one of the, I think, big messages from CAR2T4, yeah, it's safe. Yeah, there's CRS and ICANNs, but there are side effects. But those are generally quite manageable. And then we also have the neurologic toxicities that everybody's concerned about, like Parkinsonism. We have secondary cancers. And then we also have other rare combination things like GI toxicity. But the CAR2T4 told us that those toxicities were less, less heavily treated patients compared to the original six lines of therapy type of patients. So clearly, if you do treatments on very heavily treated patients, some of those side effects may have nothing to do with your treatment, just that these patients were really beaten up over the years with all the therapies that they needed. But what we did learn from CAR2T4 is even if you're doing it in one to three lines of therapy, not heavily treated patients, if the myeloma is not well controlled, these side effects are worse, right? You have more CRS, more ICANNs, more neurotoxicity. So I think one of the messages we learned this year is you've got to control the myeloma going into CAR. And there's also developed new CARs. We have CARs targeting GPRC5D. There's going to be CARs that are targeting CN70. We have combination CARs. Already we have clinical data. Really cool about CD19 and BCMA. One company from China has shown that the response rate, and this has been acquired by Grace Cell, that remission is 38 months over three years and preliminarily no neurologic toxicity, right? And so that's super exciting. Of course, the caveat is that we need diverse patient population, right? Some of the data that we're collecting at UCSF tells us that Parkinsonism may be more common in white men. So if you don't do a product testing in that population, you may not see the signal. So we're of course eager to see how these new constructs fare. And really cool is in vivo CARs, right? Why do we need to collect T cells? Can you not deliver the car using a virus directly into the patient? Forget the collection, forget the manufacturing. Have the virus make the car in the patient themselves. And then also doing CRISPR CAR, right? A lot of people are excited about CRISPR technology. Why do we want a virus to randomly put in the car? Why can't we genetically target the car exactly where we want to go? So really exciting developments in CAR-Ts. And I think we also saw preliminary data with GPRC CARs that are looking very active. I think challenging their durability. We have some limited data of throwing things after CAR, like IMIDs or checkpoint inhibitors or gamma-secretase, still not ready for primetime. We need more studies for those. So that was kind of part one of my talk. And then part two was the non-CARS, right? The bispecific. And bispecific in some ways is already old. We've moved on to trispecific. And maybe not just T cell, right? So we're looking at ways to make these better. And there's a lot of different compounds that are in their development. Some make the T cell binding less strong, called T cell affinity. And you might think, well, is that a good idea? Well, preliminarily, maybe less CRS, less ICANs. And you don't need to step up those. It might be more convenient. We have trispecific. Why do you have to do two different proteins? Why can't you put them in one? So there's a trispecific that's already gone into patients where you target GPRC from BCMA. And then the double-sided tape of CD3 is always there. So you're bringing T cells to both proteins, GPRC and BCMA. So we're looking for that data. I think everybody here probably knows about the two approved products, TEC and ELRA from BCMA, Teclistumab or Tecvilli, Elvrananumab from Pfizer. These two have been approved in heavily treated patients. And we have preliminary data combining those with other drugs, which, of course, would be the next thing. And those data are encouraging in terms of responses. But I think there's also more neutropenia, more deaths. And so we need to get these side effects trolled. And that may be by giving IVIG, preventative antibiotics, maybe not doing as intensive dosing schedule. So I think that's what's kind of on the horizon for the BCMA by specifics. Of course, there's also GPRC, FcrH5. GPRC, many immunotalacetamab or TalV, which is now approved for heavily treated patients. And we have Foremtumig, which is also targeting GPRC, which is in development. And we have Sevastimab. And many have been wondering about this product because it targets the only one targeting FcrH5. We haven't heard any, not a peep about this drug for many years. Why is that? Well, if you look under the hood a little bit, the response rate was good, but the duration of response was more modest than the other by specifics, which probably means that the single agent activity may not meet the muster, right? It's a competitive landscape. You need to be, as we said, 60 to 100 is the new 20 to 30. And the remission has to last probably around a year or beyond to really have meaningful traction. And so while SIBO may not be hitting that benchmark, preliminary data with combination with pomalidomide showed 100% response rate. So small group, small numbers of patients, we still need longer follow up, of course, in larger numbers. But the challenge with that data is that if you don't have single agent activity and you need to do combination, it means it won't come to a store near you without the phase three study, right? Because the FDA will not give approval for a combination because they want to know what is the new drug doing. So you've got to compare that combination to a different combination and show that this is better. So it's going to delay the approval of that drug. Some of the other interesting developments with bispecifics are actually making it more practical and convenient. Prophylactic tocilizumab. Tocilizumab blocks IL-6, which is the chemical that causes fever and CRS. And what we now know is that across multiple datasets, CRS rates, which is at cytokine release when the T cells activate, probably can range anywhere from 70 to 80% for bispecific. If you give prophylactic TOSI, that can drop to like 10 to 20%, which is great. But the higher grade CRS doesn't seem to be reduced as much. What I mean by that is fever is one thing, and that's quite easy to manage, but low blood pressure, low oxygen, those are what we consider high grade. Those don't seem to be mitigated as much with the preventative TOSI, right? So we still have work to do, but it's encouraging, right? I think people forget, myeloma bispecifics, we have three, but bispecifics are here to stay in oncology. There's at least 11 bispecifics now approved across cancer, and not all of those bispecifics have these REMS programs, which the FDA has put in place because there's this risk of CRS. Myeloma ones have that label. Our hope is that we can make this more widely available because community patients who really need it aren't the ones coming to academic medical centers. A lot of those patients are really healthy. They could probably go to CARS, right? These are the bispecifics that can be given to anybody and ideally should be given in the community. We also have combination data with TAL. TAL has been combined with garotumumab, it's been combined with pomalidomide, it's even been combined with ticlostumab. And why is that important? These remissions are lasting 19 to 20 months, which is quite impressive, right? For an off-the-shelf product, that's great. And what we heard at IMS is that that really elusive extramedullary disease when the myeloma comes out of the bone marrow, TEC plus TAL remissions look just as good in EMD patients as non-EMD, which is I think paradigm shifting because we've never been able to really hit that. And what's also interesting about TAL is, yes, it has these target off tumor on target side effects like taste, skin, and nails, but it's one of the only products I'm aware of where the progression-free survival of high risk sits right on top of standard risk. And that's why in combinations it may be even more appealing and maybe we don't need to use as much of the drug so we can back off on some of those side effects. So we have a lot of phase three studies going on for bispecific, but keep in mind again, these are only approved as a single arm study so far. So we need to again put these drugs into contact with other agents and see how the combinations work. And so we're looking forward to that data. But what I would say the take home message is it's a really exciting time to be in myeloma. You're having patients who are having unprecedented responses despite having more treatments than ever before. And before that, they get these drugs and these deep durable remissions are translating into longer living and better quality of life. And that's really what we're all here to do.