on the firm portals. Disclosures and updates to disclosures are also available by ticker on the firm's public website. With that, I am very pleased to start today's call here. We are pleased to have both Dr. Lynn Seely, who is President and CEO of Lyell, as well as Dr. Alexander Boardman, Associate Physician, Division of Hematology/Oncology at Mass General Brigham Cancer Institute, and Faculty of Medicine at Harvard Medical School. I am joined by my colleague, Mark Aleynick. To start here, Lynn, could you provide us a high-level overview of where your lead program stands, the autologous CD19/CD20 CAR-T, ronde-cel, across the studies in B-cell lymphoma? Maybe start by touching upon the data that was released yesterday via the ASH abstracts as well.
Sure. Salveen, thanks for having Lyell here today. For those who are not as familiar with Lyell, we are a late-stage clinical cell therapy company. We are developing next-generation CAR-T cell therapies for patients both with hematologic malignancies and solid tumors, cancers. Today, we are here to talk about ronde-cel, which is our lead program. As Salveen alluded to, it is a CD19/CD20 dual-targeting CAR-T cell therapy, which is very specifically designed to be full potency at either CD19 or CD20. It is manufactured very specifically to have a predominance of naive T-cells in the cell product through a very special process called CD62L enrichment. The goal of this is really to drive more complete responses, longer duration of response, better CAR-T cell persistence, all with a softer safety profile. That was sort of really the design of the product.
I am pleased to say, as Salveen just mentioned, yesterday, ASH abstracts were released, and ronde-cel will be presented in two presentations at ASH. Our ongoing pivotal PiNACLE trial, which I will speak about in a moment, will have a significant data update where we are showing again these high durable complete response rates, exactly as the product profile was designed to achieve. That will be in an oral presentation. We will also be having a poster presentation on a second-line cohort that we are running, and this is from a phase I/II multi-cohort trial. At this point in time, ronde-cel is in evaluation in two pivotal trials. We are completing enrollment in the PiNACLE trial, which is a third or later line single-arm trial, which is designed to gain us approval. We will be having the full pivotal data set mid-next year with a BLA submission to follow soon thereafter.
This is a very exciting trial for us, and we believe will lead us to be the first approved CD19/CD20 CAR-T cell therapy program. We also have ongoing and enrolling right now the first of its kind, a randomized controlled phase III trial head-to-head, our CAR-T cell therapy, ronde-cel, versus investigator's choice of either axi-cel or liso-cel. This is a very exciting program that we have designed based on the very strong data that we are seeing in the clinic to date. I will look forward to diving in a little bit more detail. I would last just close my opening remarks with this, something that Lyell is really unique about, is we have our own manufacturing center, and we can make more than 3,000 CAR-T cell doses per year from that center at full capacity.
We are running our commercial manufacturing process as we speak. I am proud to say we have a 98% success rate delivering product to patient with a median vein-to-ship time, which is quite competitive at 16 days. We are really looking forward to commercializing ronde-cel if this product gets approved.
Great. Dr. Boardman, before we get into the data here, could you briefly discuss your background and clinical practice and how many lymphoma patients you see annually? How many receive CAR-T in the second line or third line plus settings?
Absolutely. Thank you so much for the introduction and for inviting me to speak. In brief, I did most of my early training in the Boston area. I did my internal medicine residency training at Brigham and Women's Hospital and Harvard Medical School. I then went down to New York City for my hematology oncology training at Memorial Sloan Kettering Cancer Center. As a fellow there, I led preclinical research that was aimed at understanding the molecular underpinnings of CAR- T cell toxicity, including cytokine release syndrome. I also took an early clinical interest in treating cell therapy patients. I went on to become an attending physician there, and I led early phase clinical trials in cell therapy, as well as translational research.
To get to your question, in terms of my clinical breakdown, I specialized in treating only lymphoma. Also, about 25% of my clinical time was treating patients with CAR- T cells. That amounted to treating about 20 patients per year with a CD19 CAR- T cell product. In total, I had amounted a panel of about 500 patients that probably translated to something like 1,500 visits per year. I would say about 20% or so of those patients were on active treatment. As you can tell from my introduction, I am transitioning my practice to Mass General Brigham as we speak, and I look forward to taking on a very similar clinical footprint in Boston.
Great. To start here on the data side, let's chat about the third line plus large B-cell lymphoma market. Updated phase I/II data for ronde-cel in both the second line and third line settings will be presented at ASH. Just looking at the emerging clinical profile in the third line setting or third line plus setting, ronde-cel achieved a 91% ORR and a 77% complete response rate, with 75% remaining at CR at 12 months. Dr. Boardman, can you contextualize these response rates against existing standard of care for the autologous CD19 CAR-Ts, and also the bispecifics in later line settings?
Yeah, absolutely. I always preface these comments by admitting to the caveats of comparing studies to each other. Obviously, these are studies that have differences in eligibility criteria and baseline characteristics. To speak about, firstly, about third line CAR-T in terms of the commercial products, I will really focus on BREYANZI and YESCARTA because those are really the products that are predominantly being prescribed by U.S. providers, relative to KYMRIAH, which really has, at the very least in real-world data, shown to be a less effective product. But in thinking about YESCARTA and BREYANZI in the third line, usually we are looking at overall response rates ranging from 70%-80%, something like that. Compared to the 91% we are seeing in the Lyell study, that is very impressive. CR rates tend to be 50%-60% or so. Again, these are very high response rates relative to those.
In thinking about third line bispecifics, on the basis of the fact that bispecifics are coming to the market later than CAR-T, the way in which they were studied has to be taken in that context, right? Over 10% of patients in the pivotal studies leading to approvals of glofitamab and epcoritamab were CD19 CAR-T cell exposed patients, and they were heavily pre-treated. But with that in mind, the overall response rates were about 10%-20% lower in those pivotal studies. For instance, glofitamab and epcoritamab, we typically see somewhere in the range of 50%-60% overall response, and then CR rates in the range of 40% or so. Certainly lower than we were seeing in the pivotal phase III CD19 CAR-T cell studies, and substantially lower than what we are observing with the Lyell data.
In terms of speaking to the percent remaining in CR, I think you have to take that in the context of, first of all, how many patients are getting into CR, right? We are seeing almost 80% of patients getting into CR, and three-quarters of those remain in CR at 12 months. To compare that to the third line commercial CD19 CAR-T cell products, with the lower CR rates, generally about 65%-70% or so, a bit lower remaining in CR at that 12-month mark. This is very impressive, and I think that will bear watching as the follow-up matures.
Right. Maybe we can talk about that maturity with regard to durability here, but median PFS was not reached, noting an estimated 54% 24-month PFS rate. In your practice, what threshold of durability will represent a truly differentiated clinical outcome rather than an incremental benefit?
Yeah. To put this into context a little bit, we know that the vast majority of relapses are occurring in the first six months for these patients. When I have a patient who comes to clinic who's in a CR at one year, I usually tell them they have a less than 10% chance of relapsing. At two years, it's even lower, so probably less than 5%. In the CAR-T cell studies with the longest follow-up, we have seen relapses from large cell lymphoma as late as five years, but it's exceedingly uncommon.
What we're looking at for the benchmark for something like a 24-month PFS, which is a reasonable surrogate for patients that we're curing, is about 30%-40%, which is, in the third line, is typically what we expect, what we generally quote as probably the percent of patients that we're curing in the third line or greater with CAR-T cells in terms of large cell lymphoma. What I would say is that anything exceeding 30%-40% at that benchmark is impressive, and I think is more than incremental. I think it's a differentiated clinical benefit.
Did anything stand out to you on the safety profile?
Yeah. Safety, I imagine we're going to be speaking more about, and I think we see the numbers in the ASH abstract that are very promising. First of all, and I don't know how much background the audience has on cytokine release syndrome and ICANS, or immune effector cell-associated neurotoxicity, but these are cytokine-mediated toxicity events that occur in a substantial portion of our CAR-T cell treated patients. Notably, the third line plus data suggests that there were no high-grade or severe cytokine release syndrome events, which is very encouraging. To give that some context, patients treated with YESCARTA, about 5% or so will have a severe cytokine release syndrome event. So, certainly that's highly encouraging. BREYANZI has a better safety profile, and severe events are a little bit more rare than that. But again, that's certainly promising.
There was also reported a relatively low incidence of ICANS events, which I think is also quite reassuring. In terms of ICANS seen after axi-cel and, or excuse me, YESCARTA and BREYANZI, about 60% of patients who get axi-cel or YESCARTA are going to experience a neurotoxicity event, whereas BREYANZI is closer to 10% or so. These numbers are certainly very favorable, somewhere in between the two commercially available products, but definitely closer to liso-cel in my mind.
Got it. Lyell employs a dexamethasone prophylaxis protocol here. What is your perspective on these routine steroid prophylaxis and whether there's a clear clinical benefit for these patients, or any concerns regarding the steroid exposure dynamic?
Yeah. Steroid prophylaxis has a precedent. This was implemented actually back in the first pivotal phase II study, the ZUMA-1 study. Specifically, there was a cohort of patients that were treated on the study, cohort six, that basically had the identical approach, which was to treat patients with sort of moderate dose dexamethasone on the day of infusion and two days after that as well. We've seen the clinical data from cohort six. Notably, the incidence of high-grade CRS was reduced relative to the cohort that did not get dexamethasone prophylaxis. Again, ZUMA-1 was from the YESCARTA-treated patients. So importantly, those grade 3 or higher events seemed to sort of go away, which was encouraging. The incidence also of higher grade neurotoxicity as well was reduced.
Now, the clinical outcomes, the disease-related outcomes, did appear to be on par with the other cohorts, which was certainly encouraging. I will tell you as a field, there is mixed data in terms of the impact of steroids on CAR-T cell efficacy. We have data from Art, well, from MSK, we published on this, and when we looked at it, overall, whether or not patients got steroids did not seem to have a significant impact on disease-related outcomes or on infectious risk. However, when we stratified according to the amount of steroid exposure over time, over the sort of pre and post-CAR-T cell timeline, having higher than median doses of steroids actually did seem to impact the progression-free survival, not the overall survival. That being said, those median exposure doses were much higher than what is implemented in this particular prophylaxis regimen.
I would say that in general, as a field, we do feel comfortable giving steroid prophylaxis. We think that the benefit outweighs the risk, in particular in higher-risk patients. There probably is a limit to that. Giving high doses of steroids is probably a bad thing, but in the context of this sort of lower dose or moderate dose prophylaxis regimen, we think it's likely okay to do.
Okay. Given the totality of the data here, how would you prescribe ronde-cel to third-line plus patients over approved CAR-Ts? Is there any additional data that you are really looking to understand or outcomes in specific high-risk subgroups that you would want to see?
Yeah. Well, as I said before, these data are highly encouraging, and I do think that if ronde-cel does receive an approval, it will be very attractive for a number of reasons. First of all, the safety profile, which I already alluded to, I think is encouraging and would certainly give us a reason perhaps to prescribe it over one of the currently commercially available CD19 products. I will also say that there is emerging, and this is going back to what Lynn was saying before, emerging data on the impact of the heterogeneity of these targets on the lymphoma cell. We recently published data from MSK that seemed to show that patients who have either no CD19 or low CD19 levels on their tumor cells just don't tend to respond as well to these CD19 commercial products.
This is a substantial number of patients, and we frequently at our tumor board meetings will discuss patients who are CD19 negative or CD19 low, meaning you are not seeing a lot of that target on the outside of the lymphoma cell. We will discuss whether it still makes sense to give patients that product. I think that is really where the Lyell product has a distinct advantage. We call it the OR-gate. It does not rely just on CD19. It can also be activated by CD20, which we rarely see as dim or low in the second and third line context. I think that that is also a very important distinction. Lynn also alluded to the fact that the manufacturing success rate is very high, getting toward 100%, high 90%.
I will say that the most competitive product at the moment, I think that Kite/Gilead still has a slight advantage of the market, but that is changing rapidly. We are seeing actually that the numbers of BREYANZI, the amount of BREYANZI that is being prescribed to patients in the U.S., I think we are going to see probably this year will exceed YESCARTA. With that in mind, although Bristol Myers Squibb has made strides in improving their manufacturing process, it really still is not at that high 90s level. It is really closer to high 80s, low 90s. When you are comparing two products that have good safety profiles, and one of which has very promising high overall response rates and high CR rates, we are going to have to really significantly consider this Lyell product in that context.
Lynn, to bring you in here. Pivotal data from the single-arm third-line plus PiNACLE trial is expected in mid-2027, with the BLA submission planned by year-end 2027. Two questions. One, from both a regulatory and commercial standpoint, what do you view as the minimum bar for success in this registrational cohort? Then two, you have previously noted that the third-line plus market is larger than appreciated, about 6,000 to 7,000 patients. Can you walk us through the data supporting this estimate and your confidence here in commercial uptake, which Dr. Boardman just spoke to?
Yeah. Maybe starting with approval, we are, as we said, barreling forward. We are completing enrollment in this PiNACLE pivotal trial. Our last patient will be treated by the end of the year. We will then have the full pivotal data set by mid-next year with the BLA submission to follow. The primary endpoint for this trial is overall response rate. That is the best overall response a patient achieves, which is either complete responses, which we have talked about are 77% in the data set to date, and partial responses. Those two things together make up the overall response rate. Of course, the agency will also look at duration of response. Commercially, as we talked about, the comparator, what we are looking for is to switch out the CD19 CAR. It is around that 70% overall response rate that Dr. Boardman mentioned.
Actually, for the regulators, the bar is even lower because the majority of patients still get chemoimmunotherapy as the standard of care across the U.S. patients. The bar for them is even lower than that, lower than 70%. We think with this 90%+ overall response rate, we are in a very strong position to get approval. As we have talked about, the safety profile is appropriate for outpatient administration, so it is also not expected to be a problem. For us, our goal is to just continue and complete the execution, get this BLA submission in. We are really excited about this third-line launch, and we think it is bigger than people are expecting. I would say there are lots of third-line patients out there in total, but let us just focus on the patients who are getting CAR-T cell therapy today.
We know that market is for the approved CD19 CAR-T cell therapies is a $3 billion market today, expected to grow to $5 billion by 2030. We know from data, a retrospective analysis that was presented out of Memorial Sloan Kettering Cancer Center, that about 50% of their patients who go to CAR-T cell therapy have had two prior regimens of chemotherapy before they get their cells collected. That would be a patient population who would be considered third or later line. That was very interesting data that we saw. It also mirrors our experience in the field as we are recruiting for both second and third-line patients.
What we did is we confirmed this in a Medicare fee-for-service claims analysis, and we looked specifically at patients with large B-cell lymphoma, and we said, "How many prior regimens of chemotherapy have they had before they get their cells collected for CAR-T cell therapy manufacturing?" There, it was 57%. There is a large market there for patients who would be on-label for a third-line approval if you needed to count regimens. Today, doctors do not count regimens because the CAR-T cell therapies are approved in both lines. If you needed to, there is a substantial number of patients who would be on-label for that profile. When we think about commercial launch, there are a lot of patients out there. Goal number one is to switch out the CD19 CAR-T cell therapies. That is what this product has been designed to be, a next-generation product.
We know from, let us say, from CARVYKTI that the physicians who prescribe CAR, and Dr. Boardman can speak to this better than I can, but they are very data-driven, and they will switch CAR-T cell therapies if the data warrant that. In the case of CARVYKTI, it was efficacy which really drove the rapid uptake of that product. We are talking about BREYANZI taking over YESCARTA because of its improved safety profile. ronde-cel is bringing both improved efficacy, assuming these data hold and the product gets approved, along with that safety profile and that manufacturing capability. We believe, taken together, this is a very promising commercial launch. Then I will say one third thing is, still today, most patients who are eligible for CAR-T cell therapy do not get it. Part of it is people think, "Oh, these are older patients.
Maybe they're not eligible." From day one, we have allowed patients of all ages to be in our trials, and that's important because these are older patients. We successfully treated the elderly patients 85 and beyond. These are patients who were excluded from some of the earlier trials of the CD19 CARs. We think this ability to treat all comers is a real advantage. In the community oncologist's office, today, they can offer bispecifics, which maybe are not quite as good as CD19 CARs, but not that much worse. It's kind of okay to keep the patient. They're older, they don't want to be a bother, they want to stay with their local doctor.
But with the kind of data that ronde-cel brings, should this be approved, it is going to be very hard not to offer the patients the opportunity to have these durable remissions, and I think patients and their families are going to respond well to that. We're really looking forward to an opportunity to growing the market overall as well. Switching, important. We're going to be the first to market. We believe we can switch out the CD19 CARs. When you think about it, there's not much headroom left. How is the second or the next product going to switch ronde-cel out?
Yeah. No, that's a fair point, when you're getting response rates in the 90%. Pivoting to the second-line data. We saw the ASH abstract yesterday. The second-line data will be presented in the poster at ASH, and the abstract show that ronde-cel achieved a 95% ORR and 76% CR rate in the second line, noting that 92% of the patients remained in CR at six months. Dr. Boardman, how compelling are these response rates in the second-line lymphoma setting, and does the data signal that ronde-cel can overcome the aggressive biology associated with primary refractory disease?
Yeah, absolutely. I think just to say, I think these are very compelling. I will say that as a general principle in oncology, earlier lines of therapy patients tend to do better. When we look at these data from the pivotal phase III studies that led to approvals of YESCARTA and BREYANZI in second line in large cell lymphoma, these numbers are a bit better than the ones I quoted you before for the third line. Overall response rates exceeding 80%, 85+% CR rates, certainly in the 70s, high 60s, low 70s. These certainly compare quite favorably, and again, a substantial proportion of patients still remaining in CR, which is what we tend to see. In thinking about second-line bispecifics, it's a complicated landscape now with the advent of these bispecific combination regimens, which have shown great efficacy results in second line.
But these are studies that were done in transplant-ineligible patients, so it has to be taken with a grain of salt. I think the most mature data from a bispecific combination regimen in the second line would be the STARGLO study, which in transplant-ineligible patients compared glofitamab plus GemOx to GemOx alone. The response rates were certainly not quite as high as the ones that I quoted before, but the durability did seem to be there, so those are certainly encouraging. But overall, these response rates exceed those of bispecific combination regimens as well as second-line CAR-T products. You mentioned the challenging-to-treat population, and I think the most notable thing looking at the baseline characteristics from the second-line data was the very high proportion of patients that were primary refractory. This is a high unmet clinical need.
These patients, we know, tend to do not as well after CAR-T cell therapy. In fact, we are presenting an abstract at ASH looking specifically at this population and kind of characterizing some of the particularly high-risk features. But to just get back to the Lyell data, these numbers are in the mid-80s and certainly exceed the sort of low 70s of patients who are primary refractory in the pivotal phase III studies. So, I think knowing that the baseline characteristics are a bit different really also helps to contextualize these very impressive high overall response rates and CR rates.
Got it. Thank you. Yeah, we'll discuss the baseline characteristics in a second. But Lynn, I want to ask, Lyell is running the phase III PiNACLE-H2H study evaluating superiority of ronde-cel against investigator's choice CD19 CAR-Ts, YESCARTA or BREYANZI. Could you walk us through the strategic rationale for pursuing a head-to-head superiority design over an alternate control arm?
Absolutely. We obviously are presenting data at ASH in more than 80 patients, both in the third line and the second line, as we just talked about. So, we know what this product was designed to do. We now have clear data that it is really pulling through and doing exactly what we had hoped it would do. We wanted to design a study to gain approval in the second line. The FDA does require a randomized controlled trial, unlike the third line, where a single-arm trial is sufficient. When we considered the randomized controlled trial, there's an obvious choice. We wanted to give physicians and patients the data that they need to make the decision to choose the next generation over the approved CD19 CAR. So, it just made the most sense to run this randomized controlled trial.
In lymphoma, in particular, as we just were talking a little bit about, the patient population matters. It is very hard to do cross-trial comparisons. It is very important that you are comparing an apples-to-apples patient population. By running a randomized controlled trial against the approved CD19 CARs, we get to balance the treatment group. As patients are randomized, they are also stratified based upon risk factors so that we ensure the risk factors are comparable between the two groups. This data will then allow doctors and their patients to make the best decision. It is designed as a superiority trial. We absolutely are confident in the ability of ronde-cel to be superior, just for the reasons we have talked about. It has got two targets, so that should drive more complete responses. It has got these naive T cells to bring better persistence of response.
The primary endpoint of this trial is event-free survival. That plays specifically to ronde-cel's strength, which is that durability of response. We are not seeing the substantial drop-off in patients' benefit in the first six months. They are going well beyond that. As we have talked about, the durability data clearly are the strength of this product, in addition to the high number of complete responses. That is why that is our strategy. Let us play to win, and let us design the right trial for patients and physicians.
Got it. Could you speak to the phase III design and powering assumptions? What EFS hazard ratio is the trial powered to detect? Also, when you are speaking of balancing characteristics, how does investigator's choice between YESCARTA or BREYANZI factor into the trial design and modeling here?
So maybe I will start with that last question at the beginning, because the patients are randomized, and you are right, they either get ronde-cel, or we let the investigators choose, just as they would do in normal practice, do you want to put this patient on label for either axi-cel or liso-cel? So it is real world. They are doing exactly what they do. Those two products will be pooled in terms of the analysis. Ultimately, we will need to show superiority over axi-cel plus liso-cel, that pooled population. I think the endpoint, as we talked about, is event-free survival. That is largely progression events, so progression, death, or, for example, starting a new chemotherapy for their disease. We are enrolling 400 patients, so 200 per arm.
The trial is well-powered at 90%, and we have an interim analysis, so we've given ourselves an opportunity to get out early, which we fully believe ronde-cel has a great chance of achieving, and then also a final analysis, which is conservatively powered. When you think about effect size or what is clinically meaningful, this is a hazard ratio, so you're looking at a reduction in risk of having a bad event, a progression event. Typically, what's clinically meaningful is anything below 0.8, so a 20% reduction in risk of having a bad outcome. You might imagine that a conservatively powered trial would use that threshold. Something a little bit more aggressive would be lower than that.
We feel like we're in You've seen the types of differences that we're showing in our data set to date, that we're very confident in the design of this trial.
Got it. How is site activation and patient accrual tracking relative to your expectations? If you could provide any additional guidance on timelines for those analyses.
Sure. We have the majority of our centers open. Key part of our strategy, quite frankly, is think about this. We're enrolling this head-to-head study that will be ongoing at a large number of centers, about 60 centers, largely in the U.S., at the time of this third-line launch. These centers were selected for their commercial capability and, of course, their ability to run clinical trials. They will be using ronde-cel head-to-head in an open-label way with the approved CD19 CARs. They're going to know exactly how ronde-cel performs at the time of this third-line launch. That's a very important part of our strategy, and we think, again, will lift up this third-line launch because they're going to see to use ronde-cel is to love ronde-cel in many ways. The site activation is going well.
Recruitment is actually exceeding our expectations as sites are getting up and going. They're consenting and screening and enrolling patients. Oftentimes in studies, a few centers will drive the vast bulk of the enrollment, but some centers sort of get up and going, but then never really put patients on, but we're just not seeing that. There's really high enthusiasm for the design of this trial.
Amazing. That's really good to hear. So kind of on the second-line opportunity, Dr. Boardman, if you can frame the current real-world treatment algorithm for second-line large B-cell lymphoma. When a patient relapses, what considerations dictate the decision to prescribe either YESCARTA or BREYANZI or something else?
Yeah, absolutely. The way that we think about second-line diffuse large B-cell lymphoma patients really depends on a few things, including how fit that patient is, which is an assessment of medical comorbidities, what other medical issues do they have, how functional are they in their day-to-day life, but also very importantly, how long has it been since the completion of their first-line chemoimmunotherapy regimen that they received for their first-line therapy, right?
On the basis of two positive large phase III randomized controlled trials that compared CAR-T cell therapy and the two positive studies, which the experimental arms were YESCARTA or BREYANZI in two separate studies, being ZUMA-7 and TRANSFORM, those groups were compared to patients receiving what was previously considered the standard of care in that setting, which is a platinum-based chemotherapy, what we call salvage regimen, and followed by an autologous stem cell transplant, or as we sometimes say, stem cell rescue, which basically means the patient's stem cells are removed prior to conditioning chemotherapy, and then they receive them back to enable immune reconstitution.
These two studies that I just alluded to really challenged that and have since changed the standard of care since 2022, which really now we consider patients relapsing within one year of their first line of therapy, we consider CD19 CAR-T cell therapy to be the standard practice there. The two options you got there are YESCARTA and BREYANZI, as you alluded to. If you relapse greater than 12 months after the completion of first-line chemoimmunotherapy, and this is really guided on the data that we saw from those studies, we still consider those patients for the strategy that I mentioned before, which is more chemotherapy and a stem cell rescue. However, given that a substantial proportion of these patients are 70 years or older, many of these patients will not be able to receive a transplant.
Generally, for a transplant, we prefer not to transplant patients in their 70s whenever possible, and we certainly err away from transplant in patients who have significant other medical problems, which, of course, in the U.S. is quite common. In that setting, we do have access to still CAR-T cell therapy, and really only BREYANZI in this setting do we have access to. This is based on the results of a phase II study called the PILOT study, which asked the very question, "Is it feasible, is it safe, and does it look effective for patients who aren't eligible for bone marrow transplant who relapse whenever, greater than a year or less?" We often consider CAR-T for those patients. I will say that what we consider transplant-eligible definitely varies center to center.
You specifically asked about I guess one other thing to add to that is if you deem a patient ineligible to receive CAR-T, which I will say, in particular at large academic medical centers, CAR-T ineligibility is a very slim fraction of patients, certainly in my view. I will tell you, I have treated patients with BREYANZI who are almost 90 years old and have done quite well. I think we're really starting to understand as we get more and more follow-up that patients even with significant medical comorbidities, unlike transplant, can tolerate CAR-T cells. I would be remiss if I didn't at least mention that for those patients, sometimes we are considering bispecific combination regimens, one of which I alluded to before, the STARGLO regimen, including the CD3/CD20 bispecific glofitamab in conjunction with chemotherapy.
That does still have a role here. You asked about how we determine BREYANZI versus YESCARTA for patients in this population. I will tell you, it's very center-specific. I think, as I also alluded to before, the market's changing a bit. I think the BREYANZI, people are seeing that BREYANZI is, time and time again, the data are suggesting both in real world and in clinical trials that BREYANZI is a safer product. I have yet to see compelling data that YESCARTA exceeds BREYANZI in any disease outcome at all whatsoever. For that reason, we tend to prescribe BREYANZI for the most part. The exception being perhaps a young and fit patient who has exceedingly aggressive disease, in which case you may want to have that product back a bit sooner.
Going back to what Lynn was describing in terms of vein-to-shipping time, the vein-to-shipping time of BREYANZI tends to be about a week longer than that of YESCARTA. YESCARTA is pretty close to what ronde-cel is, by the way. In that small proportion of patients who you think can tolerate that worse safety profile of YESCARTA, we do sometimes prescribe it in that context.
Got you. That is really interesting, actually. I did not realize that. That makes sense. As you guys alluded to earlier, sort of differences in the eligibility criteria between these studies, bridging therapy, inclusion of higher-risk patients, they complicate cross-trial comparisons when looking at ronde-cel against YESCARTA or BREYANZI in the second line. Dr. Boardman, what are your expectations for the control arm performance in the head-to-head phase III ronde-cel study? Just to expand on that, how would you interpret a hazard ratio of 0.7-0.8 in this setting versus YESCARTA and BREYANZI?
Yeah. I think first of all, historically, the YESCARTA study, the Kite/Gilead-run studies, really, the ZUMA trials, as we called them, or as they called them, there was sort of this selection bias inherent in these studies. They did not allow bridging therapy beyond corticosteroids in those studies. Whereas in the TRANSCEND and TRANSFORM studies led by BMS, studying BREYANZI, patients were allowed to receive bridging chemotherapy. To put that into context, I will tell you, I can think of maybe two patients in the last two years that I have encountered who did not require bridging therapy. I think the idea of running a study that does not allow bridging chemotherapy is a little bit artificial. I think all of the ZUMA studies have to be taken into that context. What would I expect from the control arm in this phase III study?
Well, first of all, as I have said a couple times now, I do think that probably more patients will be treated with BREYANZI in the control arm than YESCARTA. Which, by the way, was one of the reasons as a center we were more attracted to the Lyell study than to the Kite study, which mandated YESCARTA in the control arm. That being a major difference. I do think we could see slightly underperforming axi-cel-treated patients relative to ZUMA-7 for that reason. BREYANZI, I do not necessarily expect to underperform TRANSFORM. I think we will likely see relatively similar results. What will that calculate out to? I think we are looking at event-free survival. I am expecting the control arm to be somewhere in the 40%-50% range in terms of the two-year event-free survival.
I think if we are seeing a hazard ratio of 0.7, to give you context, for some of the pivotal phase III studies in frontline DLBCL, we considered hazard ratio of 0.7 to be practice-changing. That would certainly be a number that I would be excited to see. I am of course referring to the first study in first-line large cell lymphoma to indicate a benefit over R-CHOP in over 20 years, the POLARIX study, which indicated a hazard ratio of 0.7 for progression-free survival in patients treated with the pola-R-CHP regimen over R-CHOP. I would consider a hazard ratio of 0.7 to be quite exciting in this study.
Got it. Lynn, so we have spoken about this, but just to put a final point on it, what is the target efficacy delta, or required EFS improvement for ronde-cel, given the inclusion of these higher-risk patients? What profile are you looking for from the phase III head-to-head study? What internal benchmarks, including this ASH abstract data, give you confidence, positive head-to-head study superiority outcome?
Yeah. First, we are including all patients eligible for CAR, really, in this head-to-head trial. It is not limited to high risk. There will be high-risk patients because we allow older patients and have from the get-go with this product profile. I think getting back to that, we think that, as we say, the vast majority of patients can be eligible for ronde-cel. I think that is the first point. I think, as we said, this is a superiority trial. When that P-value comes out superior, that is going to be adequate for approval, and we believe will be clinically meaningful for sure. What the exact hazard ratio will be, time will tell. I think as we have talked about, we have an opportunity at an interim to get out early if the hazard ratio is on the lower side, the bigger delta, I should say.
Then, there is also a more conservative final analysis. We are highly confident. Why are we highly confident? Because we are showing data at this point at ASH in more than 80 patients. That is in the abstracts. There will be more patients coming to ASH with longer follow-up. What we consistently see is ronde-cel's strength is in durability, and that is exactly what event-free survival measures. This endpoint in this trial plays exactly to ronde-cel's strength. I think, in particular, the second-line primary refractory dataset that will be presented at ASH is very, very powerful because we know those patients do not respond well to CD19 CARs, and yet they are responding very well to ronde-cel. Recently, there was published real-world evidence data from an academic center, consortium, I should say.
Real-world evidence typically overestimates benefit because it is not nearly as rigorously conducted as a formal clinical trial, particularly a pivotal clinical trial. Even in spite of that, what we are seeing is, they broke out for the first time in the published literature, the primary refractory subset of a large number of patients. What they showed was that the median progression-free survival was met at about six months. We have shown you what our six-month estimated median progression-free survival is, not 50%, but 75%. So well above that. Their 12-month estimated progression-free survival was 38%. This is for liso-cel. Ours is well above that at 55% and still maturing. The data are not close, whether you are looking at complete response rates or durability of response.
That is why we can go with great confidence into this head-to-head trial, because if you think about it, this product was designed specifically with the knowledges of the weaknesses of the CD19 CARs. The translational data beautifully support what we are seeing in terms of the design, the persistence of the product, and the activity of the product in the patient, then we are seeing it in space in the clinical data. When you see that sort of a dataset all start to come together, it gives you great confidence. We are doing the right study. It is bold, but we are very confident that this is the right product to take into that sort of a study.
Stepping back here to the broader competitive landscape, we are seeing rapid innovation across cell therapies. We are seeing in vivo platforms, we are seeing T-cell engagers. Dr. Boardman, how do you see the B-cell lymphoma treatment landscape evolving over the next three to five years?
Yeah. I could speak for an hour about this, but to just hit some of the high points, I think what I have been, I guess, alluding to a little bit and what I think we are really seeing as a field is that bispecific antibodies are moving earlier and earlier in lines of therapy, both in diffuse large B-cell lymphoma, but also in other types of lymphoma. I think that is the most obvious answer. I do also get a feeling that in our older and less fit patient population, there is a lot of interest in incorporating bispecific antibodies and reducing the amount of chemotherapy necessary. We are seeing that in sort of these chemo-light regimens, as well as sometimes chemo-free regimens, which has gained a lot of traction.
Other than that, we certainly are seeing other types of bispecific molecules coming into early phase study, including those targeting other molecules like CD19 instead of CD20, for instance. There are many small molecule drugs that are coming into study, including the BCL6 degrader class as well as the BTK degrader class.
Great. There's also, as you just talked about, there have been multiple positive readouts of these CD20/CD3 antibodies in frontline LBCL combinations. In your view, what is the efficacy benefit of frontline bispecifics, or is the efficacy benefit of frontline bispecifics worth the added immunological toxicity and the logistical burden? Maybe just to follow up there, do you expect broad community adoption here on this front? What potential impacts do you see to the addressable second and third line plus patient pool?
Yeah. There really are two major frontline bispecific studies that, and I believe you're referring to. The one that we recently heard was a positive study, was the phase III EPCORE DLBCL-2 trial, which compared epcoritamab, a CD3/CD20 bispecific antibody, in combination with R-CHOP versus R-CHOP alone. This was a study that met its primary endpoint and actually showed, they reported in press a 51% reduction in the risk of disease progression or death, which is quite substantial. I will mention, and the one thing to contextualize this particular study is the choice of the control arm, which is felt to be problematic in the field. The reason for that is, so this study, to give context and eligibility, this is enrolling higher-risk patients with an International Prognostic Index score of two or higher, which is sort of in matching the POLARIX study that I mentioned before.
On the basis of the POLARIX study, many of us consider these high-risk patients, we consider the standard of care to be not R-CHOP, but pola-R-CHP, which is now really the regimen that we're using more often in the front line, in particular for these high-risk patients. So that control arm is a little bit problematic, and the question is, how much better is epcoritamab plus R-CHOP than pola-R-CHP? With the caveats of cross inter-trial comparison, I mean, the hazard ratio was quite favorable, and I do expect it's likely that this regimen will be approved. However, I will mention that the study we're all really anxiously awaiting to hear the results from is the phase III SKYGLO study, which has that proper comparator of pola-R-CHP, relative to glofitamab, the Genentech drug, plus pola-R-CHP. So that we will be very much awaiting.
You mentioned the sort of the logistics, the onerous nature of these regimens. To give you a sense, we give pola-R-CHP or R-CHOP every three weeks to patients for six cycles with advanced-stage disease. But epcoritamab incorporation actually requires weekly infusions for the first couple cycles. This is definitely a more onerous regimen than R-CHOP or pola-CHP alone, and is potentially going to impact how broadly this is taken up. Furthermore, you mentioned the community. I mean, this is an important point, right? I still receive referrals from community doctors to take patients through those first few treatments of bispecific antibody therapy, which is when, by the way, those cytokine-mediated events tend to occur. So some of the toxicities we see with bispecifics overlap with those that we see with CAR-T cells, and in particular, cytokine release syndrome is the one we definitely see.
There are community doctors who understandably don't feel comfortable managing cytokine release syndrome. So the community uptake has been a little bit slow. I think it's getting better. I can imagine that with an approval, epcor R-CHOP or glofitamab plus pola-R-CHP may be used broadly at academic medical centers, but maybe not so much broadly in the community just yet. I think it's going to take some more time for that.
Got it. Just to follow up here mechanistically, there is concern that bispecific exposure may promote T-cell exhaustion. How do you think about sequencing therapies in this context, and could prior bispecific therapy compromise the CAR-T fitness over time and use in the follow-on settings?
Yeah. Well, I alluded to this before, just on the basis of when these products came to market, there's much more data for giving bispecifics after CAR-T cells than the opposite. We know that patients treated with bispecific antibodies immediately in the post-CAR-T cell setting tend not to do as well. That's also probably because you're selecting for the bad actor diseases, the really, really aggressive diseases. But we've seen in the data, but also I've seen anecdotally, I've cured patients with bispecific antibodies who relapse after CAR-T. I think the really important question, because of the things that I was discussing before, the possibility that we'll have bispecifics as standard practice prior to the second line, is does that impact your ability to make a fit CAR-T cell product, a good cell therapy product? In my mind, the data currently is insufficient to answer that question.
This is actually an active area of research and one that I'm actually actively working on myself. In theory, and in preclinical modeling, we can see that bispecific antibodies can change the immunophenotype, the profile, the fitness, whatever you call it, of the circulating T-cell pool, which can certainly impact your ability to make CAR-T cell products. But again, this is still theoretical. There have been a few reportings at recent conferences. Last, in June at EHA, we did see a relatively large data set from a German group that also did some immune profiling on circulating CAR-T cells. They showed that there was an increase in what we call exhaustion or a particular phenotype that can be associated with poor outcomes in CAR-T cells. But the clinical data was very heterogeneous, and it was hard to draw any strong conclusions.
I would say that in terms of sequencing in that direction, the bispecific then CAR-T, there's still a lot of unknowns, including whether there's a washout period, whether, in other words, somebody could get first-line bispecific in chemoimmunotherapy, and then six months later, you collect them. Is that okay? We don't know. I think my suspicion is probably it is, but we still don't know, and more to come on that.
Got it. Lynn, in the last couple of minutes, on the autologous CAR-T competitive landscape, we know Gilead is advancing their bicistronic CD19/CD20 CAR-T, KITE-753. Could you speak to ronde-cel's differentiation and any differences in the clinical study design? I know they're running a phase III against YESCARTA only. Also just a quick follow-up, is your phase III ronde-cel study, does it have a cap on YESCARTA, BREYANZI?
Both KITE-753 and ronde-cel are dual targeting CD19/CD20s, but they're actually quite different in construct. The Kite product basically requires the cells to make two CARs, right? So they have to make CD19, which is basically YESCARTA, and then a CD20. Ronde-cel is a single CAR construct that includes both the CD19 or the CD20 at full potency. I think the concern is the neurotoxicity, quite frankly, of the CD19 of YESCARTA. The other thing that's different is we've talked about, we use the standard manufacturing process, but with the CD62L selection to enrich for naive T cells. What Kite/Gilead has chosen to do is to move to a rapid manufacturing process with the goal of achieving more naive T cells. Recently we learned they're on partial clinical hold because of an increased risk of grade 3/4 ICANS in some patients.
We do not know if that is because of the construct design or the rapid manufacturing design, but is quite differentiated on both from what we are experienced with ronde-cel. I think we have designed our phase III randomized controlled trial to be appropriate for what is real world, as we just heard as some criticism of an ongoing controlled trial, is when the data come out, you want it to represent what doctors are doing, so you are showing superiority over their practice. Their practice today is to pick BREYANZI or axi-cel. Different sites, as Dr. Boardman said, pick different ones. That is why we are pooling it. We think that is a strength of the design.
Just to confirm, there is no cap on YESCARTA and BREYANZI in your setting?
No.
Okay, got it. J&J recently discontinued their CD19/CD20 dual CAR-T product. Does that exit alter your view of the competitive field, and have you experienced any tailwinds as a result?
100%. I think the field is now wide open. We are first in class. We have the best in class data. We are presenting the most data. I think there were others, but I think Lyell continues to execute and ronde-cel continues to put up exactly the data that we hoped that it would. So I think we are in a great position, and I think others are having some difficulties, but ronde-cel is full steam ahead.
Got it. In the last minute, Dr. Boardman, Legend is going to show additional data from their in vivo CD19/CD20 CAR-T platform. Wanted to get your assessment of the in vivo CAR-T field and modality, and do you see this as additional validation for the CD19/CD20 dual targeting mechanism?
Yeah. I'll try to keep this one brief in the last minute here, but I think there's a lot of buzz about in vivo CAR-T right now. There's been a large investment in trying to make this modality, this strategy work. Why it's attractive is because it takes out the need for ex vivo manufacturing, and it brings cell therapy closer to bispecifics, which we call off the shelf, meaning you can give a patient the product the same day you deem them eligible to receive that product, as you would with a bispecific. It's very early in this particular aspect of the field, and there's very little mature data.
We have seen some abstracts for first-in-human data from various groups in this latest ASH, and the Legend's abstract that you're referring to, they presented some early data at EHA that seemed to suggest there was, their Dose Level 2 had exceedingly high overall response rate. I think it was every patient responded. Interestingly, their Dose Level 1, nobody responded. So there's clearly a very finicky aspect to this. I think that it still requires a lot of optimization. There are a lot of variables here. The mode of delivery, lipid nanoparticles, viral, where the actual, that moiety is actually binding to transduce the T cells is still a sort of variable product to product. I think one of the biggest challenges is the persistence of these products. We're really not seeing the product actually stick around within the patient's body for very long.
I think, interestingly, in their ASH abstract, they mentioned that the longest duration of response that they actually saw was five months, which is, and obviously we're going to want to see their oral presentation, but very concerning that so few, well, that that's the longest response. I think that really speaks to the fact that both efficacy and safety are very much understudied in this modality so far. But I think more to come on this in the coming years.
Great. With that, I want to thank you so much for your time today, Lynn. I really appreciate it, and Dr. Boardman as well. Thank you.
Thanks for having us.
Thank you for having us. Yeah.