Healthcare Unfiltered Express
Healthcare Unfiltered Express curates quick-hit conversations between Dr. Chadi Nabhan and his guests on hot-button topics in the healthcare world today.
Healthcare Unfiltered Express
Episode 60: The SUCCESSOR-2 Trial in Myeloma
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I am joined by the amazing Dr. Paul Richardson from the Dana-Farber Cancer Institute to discuss the SUCCESSOR trial that was presented at EHA. This trial discusses CELMoDs by highlighting a landmark randomized Phase 3 clinical study evaluating the oral medication mezigdomide combined with carfilzomib and dexamethasone (MeziKd) versus carfilzomib and dexamethasone alone (Kd) in patients with relapsed or refractory multiple myeloma. Results show the regimen significantly improves progression-free survival.
Dr. Richardson puts this data into perspective. A must-watch on YouTube and listen here
Welcome to the Healthcare Unfiltered Express, where I conduct short video interviews connect with relevant and timely information that you cannot miss. So sit back and enjoy the show. Dr. Paul Richardson, welcome to Healthcare and Filtered Express. It's your first time on the show, but you promised me it won't be the last time.
SPEAKER_00Charlie, it's a pleasure. I mean, again, uh Marhaba. And uh I mean, really, it's we we had challenging time to schedule this, but we did it. And Charlie, I would say mashallah. Yeah.
SPEAKER_01So uh we are taping actually on the day Argentina is playing England. Are you gonna watch?
SPEAKER_00Well, I'll be in clinic. Um kickoff is at three o'clock. I I'm actually an old rugby player, but I have loved the soccer. And one of my my two of my favorite players are Harry Kane and Jude Bellingham. So we'll see. But I also really like Pickford the goalie. He's terrific. He's excellent. Um, so we'll we'll see, we'll see what happens. But uh, you know, as you know, I'm a big fan of Mesi.
SPEAKER_01No, no, you cannot. You cannot. He gets too many calls in his favor. I mean, he's a great player, he's one of the best in the world, but you know, at some point, like he cannot get every call. I feel like he goes in the other direction.
SPEAKER_00I I think Charlie, you're missing my pun, right? Mesi, as in mazigdomide. I totally missed it. No, no, no, no, it's fine, it's a fine, no, no, no. It's actually one of the reasons when we have Mazygdomide, and it was called Mazigdomide, we all chill, you know, as we all sort of said on the investigator call that when we were told it'd be, you know, 480cc92480 would become uh, you know, would we become Mazigdomite, we went Mesi. And everyone said, Great, you know. So anyway, that's where it started. Yeah.
SPEAKER_01And that's the reason I have you on the show to discuss the an excellent trial that you led alongside your co-investigators and so on with mesigtomite. So, what is Mesigtomite?
SPEAKER_00Well, thank you, Charlie. Above all, thank you for your interest, as we say, Shukranilah. Um, because quite seriously, um, Mesi has kind of been in development now since 2017. And it's a real privilege to have worked with the whole team. I want to especially acknowledge the phase one, two program, which is led by Michael Porterhad, actually, uh from BMS CellGene and the Discovery team, and all the way through to now the phase two, three program, Jessica Katz, Teresa Peluso, uh all the members of the study leadership who've just been phenomenal to work with uh across the board. I think the uh important point about Messi as a cell mod is uh just to share with your audience, it it is it is distinct um from uh uh the the imit class. I've obviously had the privilege of working with lenolidomide and pomylidomide for 20 plus years, but the bottom, in fact, 25 when it comes to lenolidomide. But the the fact is, in my opinion, my humble opinion, they are different. Um they obviously all broadly fall into the degrader class, they engage the cerebral E3 Lie gase complex, many other molecules do. I think the distinction, and whilst they do share this thalamido ring as a as a as a point of entry, um, the cell modes are different. They have this much bigger molecular structure, they have this entamomeric ability to engage the complex. What that means is it goes into the pocket and shuts into it. You don't get any of the R-isomer, which is very important from the point of view of off-target effects. It's all S-isomer engagement. And because it's a big molecule and sits in there and slots in, um, you know, at a very sort of simple level of thinking about it, you know, you don't get this off-target stuff, and you don't. And I think what's really interesting is that the closure of the complex by mesigdomite is 100%. Closure by ibertemide, which I think is a great molecule as well, is 50%. So it's not as potent as Mesi, but it's it's it's it's darn good, and it's also very safe. Um, POM and Len by comparison closed the complex by about 15 to 20%. So there's a quantum difference, and the results in terms of degradation coefficients for Icaros and Aelos are dramatic. What's also really interesting is this targeting of the cerebral E3 ligase complex. I like to use the analogy, it's like Star Wars, and it's you know, the return of the Jedi, and you're going into the Death Star, punching a hole in the middle of it, right? You know, Darth Vader and the Evil Emperor are gone. Um, and then you're bringing in the rebellion starships, right? The immune system. Uh, and I think that's kind of what Mesi does in spades, as does IBA. But but Mesi, which is the molecule I've I've worked on predominantly, um, is really uh um being the game changer in the relapse refractory space. I think IBA's got some real promise in early relapse and in and up in the upfront and maintenance space, love it actually. But the fact of the matter is, in the relapse refractory space, you know, that's that's where I've primarily worked with Mesi. And it's been a privilege to work with the IBA team led on the BMS Sology side by people like Paula McCague, but also on the investigator side, led by Saga Lonial and others, where really that's the up, that's the early relapse and upfront space. And obviously the Excalibur trial um results preliminary announced, you know, for a positive outcome. Um you'll hear much more about that, Charlie.
SPEAKER_01Saga, Saga will be on the show. He is an RGB.
SPEAKER_00Oh, good. Well, you'll hear much more about it from him. But but the important point is that Ibera is there, well tolerated, as Saga likes to say, lots of zeros in the toxicity table, which is very true. Um, Mesi is that much more powerful. I mean, twice as much. And the reality is, in terms of the closure of the complex. And so, in terms of its position across the very challenging relapse refractory space that we now face, I think Mesi's uh to again use the football analogy, it's kind of oh soccer, I should say, it's it's it's a sweeper. You know, it's there cleaning up the relapse refractory space um across all across all settings, actually. And this is what we can come to with successor two. Um, and obviously IBA is in early relapse number one, one to through two prior lines based on Excalibur, and then up front and maintenance. That's where I really see it playing well.
SPEAKER_01So the successor to trial, which uh you led, uh tell us about uh the successor to trial. What was it comparing one, you know, what are the comparatives?
SPEAKER_00Sure, sure. Well, Successor2 is a privilege actually to lead it with Thanos Dumopoulos, who was the European lead and I was the US lead. Um, I I think obviously, and I just want to acknowledge all the Successor2 team. There's also a great Successor 1 team as well. Uh it's wonderful, actually. It's a very good soccer analogy, finding off. But anyway, the the bottom line is the first across the goal line, as it were, has been Successor2. And it's the first randomized phase three to report its findings for any of the Cell mods uh in detail. Um, and so what what was Successor 2? Well, Successor II was built on the success of, excuse the pun again, but the success of the phase one, two program, where just with Mesidex alone, we were able to engender a response rate of 41% in triple class refractory disease, just with oral therapy, about a 30% response rate with the extramodullary disease, which just for a pill was remarkable, particularly as these patients were so heavily pre-treated and BCMA exposed. And then very interestingly, Charlie, in the BCMA exposed cohort of that trial, um, which we published in Union Journal in 2023, actually, um, we saw a 50% response rate, which is really interesting because, you know, these were CAR T bi-specifics and antibody drug conjugate patients. Uh, and so it's almost as if the BCMA was kind of resetting things. I mean, if that doesn't sound too sort of uh pejorative, but at the end of the day, that was a nice response rate to see in that cohort, around 50%. And it's not dissimilar to what Saga saw at a lower overall response rate with IBA in the BCMA exposed population. You may say, well, why do you say that? Only because it raises the question that immunotherapy might be a very good dance partner with the cell mods. And I think we're seeing that, and we we can touch on that perhaps a bit later. In any event, with the success of the uh Mesi-DEX program, its safety and the efficacy even in the most sick patients. Um, we then moved into the space where we combined Mesi with bortesimib, we combined Mesi with carfilzamib, we then also combined it with both Dara tumimab and elotusimab. Um the mesidara data, very, very, very encouraging, over 75% response rate, mesi-elo, about 50%, even in Dara refractory patients. So the antibody space is very interesting. What was struck us, though, was that with the Mesi KD and Mesi VD, we saw response rates between 80 and 90%, even in patients who had been heavily pre-treated and had prior proteosome exposure and/or refractoriness. So that signal was very striking. And so hence successor one and successor two were launched, because essentially there's clear synergy with the PIs, um, preclinically and clinically. Uh, and to us, it made great sense from a real-world point of view. You've got an oral therapy, we've got an outpatient-based strategy, and whilst all credit to CAR T and Bispecifics, you know, revolutionary platforms, but I think, Charlie, as you know from your world in lymphoma, you know, these things come with challenges, uh, logistics, expense, but also most importantly from my perspective, you know, they can go very well some, you know, majority of the time, but we obviously see significant complications. And so the simplicity of oral therapy, the simplicity of outpatient distribution, et cetera, really matter. With that, obviously, Successor 1 and Successor 2 launched. What's about Successor 2? Well, Successor 2 was basically Mesi KD, which was very active in phase two, uh response rate over 85%. Um, and then the comparator arm, and this is a slightly controversial point, but we chose KD as the as the as the as the comparator. You may say why. It is actually the regulatory standard, it's one of the many regulatory standards that are used, PVD, DVD, and others in this space and have been used as the comparator arms for CADA 2-4, for Karma 3, you know, for the majestic studies. So these are legitimate comparators. But what we sought to do was to try and make this have equipoise. And so basically the randomization was three to two, not one to one. So three out of five patients would get uh mesi KD and two would get KD. Two, we maximized the KD. We made an arrow, which was 70 milligrams per meter squared once a week, or 56 twice a week. And in the triplet arm, to maximize safety, we did 56 at once a week. This bore fruit, actually, as we'll come to in a minute. But in any event, um, it was also very novel as a trial because it built in stage one and stage two. Stage one was dose optimization per FDA guidance from Project Optimus, stage two was classic phase three. And basically we landed at one milligram of Mesi, three weeks on, one week off, so daily, three weeks on, one week off. That we'd built carefully and fastidiously with a phase one program. And then essentially in the phase three comparator arm, it was Mesi KD versus KD, and we could carry over the patients in the stage one who had fallen into that category. We also had a randomization category in stage one as well, small number of patients, about 45, but it generated the real sort of operational equipoise that we needed. So this was carried on across 26 countries, no less. Uh and we enrolled obviously a really impressive number of patients, uh, over uh 600, about 660 all told. So, so you know, sort of very a big study. Um so basically, um with that in mind, we then rolled into um uh the efficacy output. The efficacy output was striking, the median PFS, well, but we'll just very quickly touch on the prior characteristics. We had a decent number of patients who are over the age of 75, about 25% of them. Um we had good American representation, very important, positive. Uh we had uh over 10% US participation, and we had a number of African American patients in that 10% of the whole study. Um so, and the actual percentage was was reasonable. Now I wish those always were higher, but we continuously work at that. But the most important thing was that the American representation wasn't sort of, you know, less than 5%, less than 1%. It was solidly up there at north of 10%. So that was good. Um the important from a regulatory point of view, huge, but 20, 26 countries. Um, and so in that space, um, we had uh, as I say, all relapse refractory. The most important thing is they had to be refractory to lenolidamide and they had to be refractory to CD38 monoclonal antibody and or exposed. So this is a unique population, and there are not many trials that have addressed this particularly vulnerable group, which is an important point about the study. So one to one to one or more prior lines. The median actually was two, but we went as far as nine. And as I mentioned uh earlier, we had a decent representation of older patients. And if you look at the study demographics, um, over 30% had four or more prior lines of therapy. So this really represented real-world relapse refractory disease. EMD was represented in about a quarter of patients, uh, and high risk cytogenetics by classical criteria, Chardi, about 35%. That's important.
SPEAKER_01That's important. EMD, examidullary, that's really important.
SPEAKER_00Well, well, especially after BCMA, right? Right. And and and I agree with you, and after CD38 antibody failure, absolutely. Um, and also, Chardi, we had when you use the expanded IMWG new criteria for high risk, which incorporates um gain of 1Q, deletion 1P, the number went over 50%. So we had a really you know high-risk, real-world practice population. Yeah. Uh and uh as I say, you had to be CD38 and lenolinamide exposed and all refractory. So this was a very vulnerable population. Um, so with that in mind, um, we basically had uh you know a tough group of patients to treat in terms of efficacy. Not surprisingly, the control arm performed as expected, um, with a uh, you know, a um a median progression-free survival of about eight and a half months. Actually, that's what's expected from the other trials, such as CAD-2-4 and others. I mean, that's kind of where you would want to land or expect to land, which I think tells us that KD as a control arm in the future may have some important uh limitations, but it's certainly valid for this particular trial. Um, and then what was so striking is that we gained uh over 10 months for the uh Mesi KD. So the median PFS was 18 months um for uh for the control for the experimental arm for the Mesi KD. And in fact, in if you looked at patients in first relapse, we haven't reached the median, um, which is great.
SPEAKER_01And Paul, just because we only have a couple of more minutes uh before we wrap up, uh a bit about toxicities and managing those?
SPEAKER_00Sure. Well, if I may, quickies on on efficacy. Um so big PFS difference, hazard ratio of 0.49, response is strikingly different, MID data's coming, but we basically doubled and tripled response uh comparisons for VGPR and CR. Just to share that. One very important uh uh outcomes uh analysis, PFS2, there was a year difference in favor of uh Mesi KD. And OS, the hazard ratio is 0.79. There's no there's no overlap, there's no crossover of the curves. That's moving in the right direction. The medium follow-up, uh Chadi is only uh um uh 11 months, so it's still early. But I do think we'll see a survival benefit. Now, tolerability can be very quick here too. No weird stuff, very low rate of opportunistic infection, less than 2%. Infections were there, but not associated with neutropenia. Neutropenia is the on-target effect of Mesi, and you just have to plow through it with GCSF, and it's not a stem cell effect, it's an upstream effect, or rather downstream effect. So you're not hurting stem cells. And importantly, if that was proactively managed, you did very well. So we saw infections, but you know, around 30%, essentially half the rate of what you see with the bi-specifics and the more, I mean, very active platforms, but potentially very risky from an infection point of view. So, from my perspective as a clinician, very pleased with the tolerability and no off-target effects. We were pleased also by one thing which would be important for the audience: the rates of hypertension were lower with Mesi KD because we were fixed at 56, not at 70 or 56 bi a week. So we saw less cardiovascular toxicity with the Mesi KD compared to the KD control.
SPEAKER_01Well, congratulations. This is a great paper. I'm really uh very excited for you guys. And uh maybe in 60 seconds or less, what uh what's next for uh for Mesi? Where we go from here?
SPEAKER_00Well, where we go from here is successful. One's coming down barreling down the pike, Mesi VD, which will be very good for healthcare jurisdictions around the world where carfilzemid may not be so accessible. Uh, I think at the same time, great for us as clinicians in the US because you need both, right? And there's not every patient suitable for carfilzemid and and vice versa for Velcade. So good to have both options available. I think where Mesi is going to float all boats is it's gonna be very useful with immunotherapies. It's gonna help with on-ramping for CARTEs, it's gonna help potentially for salvage. Combining it with other small molecules is incredibly exciting. We've seen great responses with other small molecules like trimetinid, where we've got a 75% response rate in combination. This is work led by Luciano Kostram, we're part of that study team. So, really exciting stuff. I would emphasize other things. There's another study led by my colleague Cliff Moe, combining Mesi with Selli. Really interesting, well tolerated, exquisitely active. And this is the interesting thing, Charlie, immune rejuvenating. You basically reset uh uh immune exhaustion with Mesi. It basically activates T cells and it activates NK cells. So you can basically reverse the kind of immune exhaustion that comes with biospecifics and CAR T. I personally am very excited about the future combining Mesi with obviously PIs and antibodies, but very importantly, antibody drug conjugates. I think Mesi combined with something like Balantanab, and that's underway in Europe now, and we're hoping to get it open in the US, ASAP, that is a really exciting platform because essentially it's all outpatient, minimizing the TOX, the ocular stuff, as you know, with Bella is manageable now, very much so. And I'm very much hoping that we'll see those kind of combinations real, really bring benefit to patients in every setting, basically.
SPEAKER_01The one and only Dr. Paul Richardson, thank you so much for coming on Healthcare Unfiltered Express.
SPEAKER_00Charlie, it's an absolute pleasure. I would say Afuan. And I I you know, as as I I remember this term when I lived in the Middle East, I loved it. Bukhra, inshallah. Bukhar inshallah. And basically, um, you know, thank you. I really appreciate you having me on the show. And congratulations on a great show, by the way. Um, you know, it's really you do a great job, Charlie. Thank you.
SPEAKER_01Thank you for listening to this edition of the Healthcare Unfiltered Express. Until next time, take care.