Lyell Immunopharma Inc Aktie

Great. Thank you all for taking the time to join us for another session at the Baird Healthcare Conference today. My name is Jack Allen, for those who I haven't met in the audience, and I cover the biotech space. And for this session, I'm joined by the CEO of Lyell Therapeutics, Lynn Seely. Lynn, thank you so much for taking the time to join us.

Thanks. Well, I'm delighted to be here and have a chance to tell you about Lyell Immunopharma. For those of you who are not as familiar with Lyell, we are a cell therapy company focused on next...

Lynn, thank you again for taking the time to join us.

Well, thank you. I'm delighted to have a chance to tell you about Lyell Immunopharma. For those of you who are not as familiar, Lyell is a cell therapy company focused on next-generation CAR T-cell therapies for patients with cancer, specifically hematologic malignancies as well as solid tumors. We have 2 programs in the clinic. Our lead program is ronde-cel, which is a next-generation CD19/CD20 CAR T-cell therapy in 2 pivotal trials for large B-cell lymphoma. We have a single-arm study, the PiNACLE study, which is going to have a significant data update this year, and we expect our first BLA submission next year. So Lyell is on its way to hopefully becoming a commercial company.

We also have a first-of-its-kind head-to-head CAR T-cell therapy company of our product, ronde-cel versus investigators' choice of what are the approved CD19 CARs, axi-cel or liso-cel. And then we have a second program in the clinic, we call LYL273, which is a GCC-targeted CAR T-cell therapy for patients with metastatic colorectal cancer. So it's a full lineup. And I'm pleased to report we also have our own manufacturing facility, which gives us a lot of control over our destiny because that's a very important component of cell therapy.

Great. Thanks so much for the overview. I know we got a lot of ground to cover today, but maybe we can start with ronde-cel and step back and take a 50,000-foot view of ronde-cel and the design of the product. So this is a CD19/CD20 OR-gated CAR T. What does that really mean? Does it mean you can hit either antigen? And how does hitting both antigens change the safety and efficacy profile compared to CD19 autologous CAR Ts?

Sure. So just to back up a little bit, I think many people are aware that CD19 CARs have really transformed the treatment for patients with large B-cell lymphoma, which is -- was really a very deadly disease in the past, and they've made great benefit. But what became quite apparent is there's still significant room to improve upon outcomes, particularly driving more patients to complete remission or complete response as well as driving longer duration of response because what patients are really looking for is this treatment-free, disease-free interval.

And the beautiful thing about CAR T-cell therapy is it's a onetime treatment, which really is designed to bring those sorts of meaningful responses. And so the inventor of ronde-cel is an engineer-turned-biologist, really brilliant scientist, Yvonne Chen at UCLA, who really rationally designed this CAR T-cell therapy. And what she did is she wanted to design a CAR that was full potency at either CD19 or CD20. And this is really important because some malignant B cells have no CD19. And so therefore, CD19 CAR T-cell therapy won't benefit the patients at all. In this case, if the patient has either CD19 or CD20, we can benefit them, and that's expected to drive more complete responses.

In addition, we know that one of the main causes of escape from CD19 CARs is that the malignant B cells can drop the CD19 antigen itself as sort of this evolution to avoid therapy. Well, it's very difficult for these malignant B cells to drop 2 antigens. And so by having a dual-targeted CAR, we can drive more complete responses and longer duration of responses.

But then she did one more thing, which was really quite special is the field has really learned that if your CAR T-cell therapy product includes naive or central memory T cells, these are the -- think of it as the more fit and healthy younger T cells that actually those are the cells that are associated with longer overall survival, for example, in the ZUMA trials of axi-cel. And so we -- she really designed this product to specifically have a high percentage of naive T cells. So we think it's this combination of the dual targeting plus this very novel manufacturing process that is helping with the benefits that we're seeing.

Yes. And to that end, the manufacturing process, while it does select, I believe, CD62 is the marker that you select for, it's in line with CD19 autologous manufacturing process as it relates to timing from vein-to-vein. How do you think about that?

Yes. We just, in early summer, presented data where we, on the first 100 patients that we've treated, we had a 97% success rate in delivering product to patient and the median vein-to-site time is 16 days. So very much in line with axi-cel and better than what liso-cel and Breyanzi brings.

Yes. It seems like it could be a real innovation as it relates to autologous CAR T where you already have these CD19s, but you could displace them with this dual antigen approach. You touched on the safety and efficacy profile, but maybe can you dive a little bit more deeply into what you've seen so far in the clinical results with ronde-cel? And what has you excited about the 2 ongoing pivotal studies?

Sure. So very much so. So, this product was designed with a specific outcome and intent. And in fact, that's exactly what we're seeing in the data. We're seeing this in translational data that we presented at ASH last year, really showing very nice cell expansion, long persistence and duration of response. But most importantly, when we presented data at ASH last year, we had a 76% complete response rate in patients with third or later line disease, patients who have been failed by 2 prior lines of chemotherapy.

That's important because if you look at the CD19 CARs, they have in that line of therapy, about a 50% complete response rate. So a substantial improvement. And then what really got us a lot of attention is the median progression-free survival that we presented last year was 18 months. And that, again, compares very favorably with what has been presented for the CD19 CARs, which is 6 to 7 months of median progression-free survival. So again, it's pulling through this longer duration of response and more complete responses.

And maybe very briefly on the safety side of things, too. I think you've seen an improvement on the tolerability profile by hitting the dual antigen approach.

Yes. And maybe also because of the CD62L selection, we're seeing almost what we call a softer -- or I should say the investigators have told us is a softer safety profile. We've had no Grade 3 or higher CRS, cytokine release syndrome, which is a classic CAR T-cell associated adverse event. And then neurotoxicity or ICANS is also something which is seen with other CAR T-cell therapies. Our incidence is quite low at less than 10%.

And potentially a more frail patient population, too, that could be more susceptible to those. I know we go back and forth with the existing data all day, but let's talk about PiNACLE, and then we can move into the second-line study. Just to level set for those in the audience, can you describe the third line plus setting that you have -- or study that you have ongoing in the PiNACLE trial?

Yes. So we have a really thoughtful clinical development plan where we have what we call our fast-to-approval strategy. We want to be first CD19/20 on the market. It's called PiNACLE. It's a single-arm study, which is really a seamless expansion from the third-line cohort in the Phase I study. So it's just continuing on. The patients that we presented in the third line last year are part of that pivotal trial, which will continue on until we complete enrollment of about 100 patients. So that's really our fast-to-approval study. We're presenting an update in the second half of this year.

And then we're going to complete enrollment and expect to have the BLA submission next year with the data -- the pivotal data being available mid next year. So we're in a really great place to have this fast-to-approval strategy. The FDA has given us Regenerative Medicine Advanced Therapy for that third-line-plus indication. But in addition, we also have a pivotal trial ongoing in the second line, this head-to-head CAR T-cell therapy trial. And so we've positioned ourselves in a very positive way. But PiNACLE is our lead program, which is, we think, going to establish us as a first-in-class CD19/20.

Yes. And as it relates to PiNACLE, you mentioned you're going to have an updated data set in the later part of this year. There is a big medical meeting that focuses on hematology called ASH. We'll see if it's there or not. I'm not going to ask you to answer that question. But when we get that updated data, what are the key metrics that you'd point investor attention to as it relates to continued confidence in the profile as you move into the final data set from PiNACLE in the middle part of 2027?

Sure. So last year, we presented about 1/3 of the patients. As I said, this pivotal trial is continuing to enroll. And so this year, we expect to present data in more than 50% of the patients, so well on our way to the pivotal data set. And what you're looking for here is, of course, consistency. Where is the complete response rate? What is the median progression-free survival? How is this product performing over time? And I think the hallmark of a great product is it performs consistently over time. So that's what we're looking for.

Is there a specific bar as it relates to overall response rate or median PFS that you're looking at internally as the critical outcome...

Well, what's really interesting is the bar is, of course, I mean, the approved CD19 CARs, and I told you their response rate in this line of therapy is about 50%. So we want something 60% or north. And I told you what we had last year was 76%. So that puts us in a good position. And for median progression-free survival, they're at 6 to 7 months, we had 18 last year. So we're well above any bar that one might set or quite frankly, that would be required for approval in this space.

Yes. I think consistency is a great way to put it in that you'll have greater maturation of the data set, too. So you have greater confidence in the numbers as you move through this readout as compared to the less mature existing data set, which is always naturally the case as drugs are developed.

Yes. And this will be really the last look at the data before the pivotal data come out mid next year. So it's going to be a really important data outcome.

And you alluded to, I think it's a '27 -- second half of '27 potential BLA and an approval in 2028. This is in the third-line plus setting. A lot of people will think that in second line, autologous CAR T is now kind of the standard of care. But is that necessarily the case? Are some people getting bridging therapy? And how do you think of the commercial opportunity within the PiNACLE setting?

Yes. So many people think that the third and later line is a smaller indication and second line is really where most of the patients are because, in fact, CAR T-cell therapy is recommended in the second line, and that's where most patients are intended to be treated. But in reality, what happens is we know from data that 50% of patients who hit the apheresis chair, the leukapheresis where they collect cells for CAR T-cell therapy, 50% of patients who receive CAR T-cell therapy today have had 2 regimens of chemotherapy.

So that means they would be third-line patients and on label. So 50% of the lymphoma market today, which is about $3 billion, would be third or later line based upon having received 2 prior regimens of chemotherapy. We've confirmed this actually in the Medicare -- this was retrospective data from Memorial Sloan Kettering, but we've confirmed it in the Medicare fee-for-service claims analysis, which showed very similar results. So we believe this third or later-line population is actually quite large, and we're very excited about it. And then about 50%.

And then maybe just to round it out as it relates to the PiNACLE setting, are you also pursuing it in a broader swath of patients and that you have older patients in the trial as well, and that maybe isn't an area where the autologous CD19s have gone into quite yet? How do you think about breadth of the label in the third-line-plus setting on a relative basis?

Yes. It's always really important to compare patient populations, but this -- our product, we are -- have no upper age limit. So we successfully treated patients who are 75 and older. I think that, that's something that when you look at the randomized controlled trials for Breyanzi, for example, they didn't include any patients over the age of 75. And so that's something that we're able to do.

Great. And so the other trial that you alluded to was the PiNACLE head-to-head trial, which is quite an innovative design. Maybe just to level set, could you give a little bit more context around the design of that trial in the second line and what you're looking to achieve with that study?

Yes. Well, we call this our leave no doubt strategy because it is a superiority trial that is -- the way we believe this market is going to evolve is that our CD19/20 ronde-cel is going to displace the currently approved CD19s. And so we wanted to provide the data to ensure and leave no doubt that, that was the right decision for physicians and for patients. And it's important to note that in this marketplace, the physicians who prescribe CAR T-cell therapy are, of course, very data-driven. They are loyal to CAR, but they will switch CAR T-cell therapy based upon data. And we know this from the lymphoma marketplace where Yescarta or axi-cel used to be the market leader, but they have lost substantial market share to Breyanzi or liso-cel as Breyanzi has a better safety profile.

So based on that better safety profile, physicians are changing. We know in myeloma -- multiple myeloma, for example, that Abecma was the market leader, but when Carvykti came on the market with a much better efficacy profile, physicians switched. Well, now we intend to bring ronde-cel to the market with better efficacy and better safety. And so this is a place where we believe that with the third-line data set and then the randomized controlled head-to-head trial, we'll be able to switch out the CD19 CARs. And when you think about it, once ronde-cel gets into place in these centers, we've got a 76% complete response rate, assuming that data holds with this very long duration of response and no Grade 3 or higher CRS, it's going to be very hard to displace us. And so that's why the fact that we're first-in-class is so important.

You're potentially consuming all of the headroom. You're really moving the standard of care forward and standard of care has progressed meaningfully with these cell therapies over the last 5, 10 years. As it relates to PiNACLE head-to-head, you say it's the leave no doubt strategy. What do you expect the comparator arm to be comprised of? I know you mentioned that the market is shifting towards Breyanzi from axi-cel, do you have any thoughts on the early composition of Breyanzi versus Yescarta?

Yes. It's a little bit hard to say definitively because, of course, as we said, market share is shifting. So we expect to see more Breyanzi use. Our footprint is largely in the U.S. We also have sites in Canada and Australia. We think the majority of the patients will be Breyanzi, but with a substantial share from Yescarta because we do have U.S. sites that are very much Yescarta users as well as Canada and Australia. So we think it will be a mix, but with a little bit of preponderance with Breyanzi, which is great. And I think this is a real-world study where physicians were going to be studying this product to bring physicians meaningful data, which represents what they're doing in practice today because most centers use both products and they select the product that they're going to use based upon the patient that's in front of them.

Yes. And one of the questions I get on the PiNACLE head-to-head study is that it's a very innovative trial, but it's a lot of cell therapy and cell therapy costs a lot to produce and that you have a cell therapy control arm and the cell therapy active arm. It's very innovative in that way. Can you talk a little bit about the measures you put in place to mitigate cost of the trial and some of the insurance preauthorization that you have and enrollment criteria here?

Sure. So we have designed this trial to be very much as we were just talking about, according to standard practice. The comparator arm, Yescarta or Breyanzi, depending upon what the investigator chooses, is on label for the product. And so that arm is reimbursable, the product, the administration. In fact, in many cases, the adverse events are reimbursable under Medicare or even commercial insurers because it's a well-designed clinical trial using product on label. And so that's been a substantial help to us. Of course, we're paying for study infrastructure for both arms, but this really helps defray the cost of the trial.

Great. And we're expecting an update from the study later this year. It's framed as a broad update. Any more context you want to provide around what we should expect as you provide an update?

Yes. I think we're really just looking to demonstrate the momentum in the trial. I think we've heard repeatedly from sites and investigators how pleased they are with our study design and particularly that it gives them the data they want for their patients and for themselves to make the switching decision. And so it will be largely to give investors some signs of the momentum in the trial and the progress that we're making.

Great. Well, we'll look forward to that and also the data update from PiNACLE as it relates to ronde-cel. At this point, I'd like to transition the conversation to LYL273, if that's okay with you.

Sure. Sure.

To level set, LYL273 is your GCC-targeted CAR in metastatic colorectal cancer. This is a really high unmet need. Maybe you could talk broadly about what you've seen from this asset so far to date in this high unmet need.

Yes. Well, let's back up and talk a little bit about it. So this is a very special and novel CAR T-cell therapy for patients with metastatic colorectal cancer. As you spoke about, the unmet need here is tremendous. There is actually a surge in metastatic colorectal cancer, very specifically in younger patients and patients we're talking younger than the age of 50. And so this is a place where not only are the patients younger and the population increasing, the treatment options, as they progress on their journey, are very limited.

And so when you look at the approved products in the third or later-line metastatic colorectal cancer for those patients, which is where we're studying our CAR, they have response rates of 6% or less. They have 6 months median progression-free survival or less and the overall survival is less than a year. So the outcomes for these patients are very not good. And having a CAR T-cell therapy that could give them a onetime treatment to give them some relief from the progression of this disease would be really, really important so they can get back to their lives, to their kids, to their work.

And so we have been tracking this very particular target for our CAR T-cell therapy, GCC, guanylyl cyclase C. It's a really important solid tumor marker in colorectal cancer because it's expressed in more than 95% of colorectal cancers and their metastases. So it's a great target. We came across a paper in JAMA Oncology from a company in China that had developed a really novel CAR where they had GCC as a target, but they were coupling it with CD19, which is a B-cell target, a heme malignancy target. But these -- the CD19 CARs release cytokines or express these supportive hormones when the CAR T cell is activated.

And what the inventor thought of was this idea that we've got a great target, but in solid tumors, CAR T cells oftentimes don't expand enough. They get exhausted and die very quickly. And so by coupling the GCC CAR with the CD19 CAR that makes these special hormones, we could get great cell expansion, get an infiltration into the colorectal cancer. And more importantly, they presented data on 15 patients that showed a 50% -- excuse me, a 40% overall response rate. And that got our attention, liver metastases that improved in patients which are very difficult to treat.

And so they, this Chinese company, brought this product to the U.S., got the Dana-Farber Cancer Institute and University of California in San Francisco to participate in the clinical trial and presented data on 12 patients at 2 doses that replicated those results and showed a 40% across both doses -- excuse me, a 50% overall response rate across both doses.

So this is an active CAR, and we were super excited to bring it in at the end of last year. We are busy working to develop it. We're continuing dose escalation. We want to find the right dose for patients and to really manage the one safety sign that we've seen, which has been GI toxicity. It turns out normal bowel does express low levels of GCC. And so we have seen some diarrhea and some colitis, which we're working to manage. So this program is ongoing. In fact, we've expanded out the Phase I/II. We now have more sites participating. We've added more cohorts, including a second-line cohort, and we're busy getting ready for an end of Phase I meeting.

And you've added a new protocol to help mitigate against that GI toxicity. Maybe could you just talk through a little bit about the history there, what you did to mitigate it and where it sits as it relates to the more recent safety data that you presented in the first half of this year?

Sure. So there was a patient who had quite significant diarrhea, colitis and got treated with a lot of immune suppression. And so the patient actually got an infection and died, which was a really bad outcome. What's important to note about that patient is he had very widely metastatic colorectal cancer. And at autopsy after getting his GCC CAR infusion, there was no evidence of disease. So this is an active CAR. What has to happen is we obviously need to manage diarrhea, colitis.

And so we implemented a prophylactic safety regimen where we use 3 treatments, vedolizumab, infliximab and budesonide. These are treatments that are known to protect the gut from colitis in advance of symptoms. And we were able to show that we could decrease diarrhea -- Grade 2 or higher diarrhea and colitis from 55% down to 10%. So really helped with that. And again, we're continuing to optimize now the dose and also the safety management plan.

And then finally, I'm proud to say we just announced last week that we have successfully transferred our -- this manufacturing process to our LyFE manufacturing process. One of our critical success factors, as I sort of said early on, is that we own our own manufacturing center. And so this is a process which now we can bring in there. It's largely automated. We've improved some of the analytical methods and the process of that. And so we will now be gaining some additional data with that manufacturing process.

That's a huge accomplishment. Congratulations on bringing that manufacturing internally. As you continue to dose escalate, are you expected to see the similar potency with internally manufactured product as compared to the externally manufactured product? Or is there any potential improvements in potency that you could get with a new process...

Yes. I think it generally is comparable. I mean that's our goal. But I think what we have done is we have improved the cryopreservation step. We have sort of a Lyell-optimized cryopreservation step. And so, we just want to -- it can improve cell viability, for example, and decrease apoptotic cells. And so it gives which are -- cells, which are not as healthy. And so it could give us an opportunity to get even better benefit. And so we want to take a look at that.

Is that on the back end or the front end?

It's on the back end.

So the shipment of the cells could be more streamlined as you look at a commercial setting, having a better cryopreservation could allow for greater "shelf life."

Yes, it's always a better thing. Yes.

Yes. Great. And so you're continuing to enroll patients, and I believe you're going to have a data update in the first half of next year or early '27? You can correct me on that. But...

2027. We were not...

Anywhere in 2027.

Yes.

What should we -- what's the key factor to keep an eye on as we look towards that update? I know you've had some very encouraging early efficacy results. How should we think about that?

Yes. I think, again, what we're -- the work of Phase I really is to optimize dose. And what is the recommended Phase II dose, that's a really critical step we need to define before we take this program to the FDA for the end of Phase I meeting, which we are looking to do. And then that really defines our path forward. And as we talked about, in metastatic colorectal cancer, these patients have a very dire outcome. So this can move quite quickly. We want to just make sure that we get the dose optimized before we move forward.

And would you expect potentially a single-arm study? I know a lot of early cell therapy programs in hem/onc have been approved on single-arm studies. Colorectal cancer is a novel area for cell therapy and it's a solid tumor. What are your thoughts on the regulatory pathway here? I know you're probably in active discussions to some extent.

So the regulatory pathway in the past has been randomized controlled trials because as we talked about early on, there haven't been products that have brought higher response rates in these patients. And so one of the conversations will be and why we want to put our best foot forward at this meeting will be, would a single-arm trial suffice. As we've talked about, we've expanded our trial to become a seamless Phase I/II design, much like we talked about with ronde-cel. So that's an opportunity for us. It's also an opportunity to do a randomized controlled trial, which might be for overall survival. And one of the things we've seen with this product is, again, a very robust overall survival, particularly for the patients in China where there's been a longer opportunity to follow them.

When you think about a single-arm study, is there a lower threshold of patients that you need for exposure? Have you thought about that aspect if you're able to get this abbreviated single-arm study approach? Is there a minimum size of that trial?

Typically, in oncology trials for single-arm studies, they want to see about 100 patients treated if that's sort of what you're asking, yes, how many patients. So you can generally -- you maybe get approval with a little bit less if the results are robust, but I'd like to think generally about 100 patients.

Great. And then maybe just to round out on colorectal cancer. We talked about CD19 autologous CAR T being a good comp as it relates to the commercial potential for ronde-cel. What do you view as the external comparison for the commercial potential of LYL273? How large is this market?

So yes, this is a large market. There are 150,000 new patients diagnosed in the U.S. alone each year with colorectal cancer. There are 50,000 colorectal cancer deaths. So the number is very likely to be closer to that 50,000, so let's call it, 40,000 patients a year just in the U.S. This is a huge market. And again, as we talked about surging in young people, this is a program where sites and patients are seeking us out because there is so little to offer patients. So this is a large market and cell therapy is really very well positioned for these patients.

Great. That wraps up a lot of questions I had. Maybe just to round it out, can you touch on the cash position of the company and the key catalysts that are encompassed within that cash position?

Sure. As of our last Q, we had $228 million, which gets us into Q3 of 2027, which is important because it gets us through multiple data milestones, including the data update in the second half of this year, which we said is a very important data update on our PiNACLE pivotal trial, where we'll be presenting data from a majority of the patients observed and then also through the pivotal -- final pivotal data set that we'll be using for BLA submission, which we expect mid next year.

Great. Lynn, well, we covered a lot of ground. I don't know if there's any other closing remarks you wanted to pass along. But if not, I appreciate everyone for taking the time to attend.

All right. Thank you. Appreciate the time.

Hello, everyone. My name is Mitchell Kapoor. I'm a senior biotech analyst at H.C. Wainwright. Thanks for joining our Cell Therapy Day at H.C. Wainwright. And our next fireside chat is with Lynn Seely from Lyell. Lynn, thank you so much for joining us.

Thank you for having me, delighted to be here.

So maybe just to start off, as always, for those who may not be up to speed on the story, just give a brief overview of Lyell and the current initiatives. And then maybe we could just segue into the most recent update, the safety update for the LYL273 and just kind of go from there.

Sure. So I'm delighted to have a chance to tell you about Lyell, and we have 2 clinical stage next-generation cell therapy products in oncology. The first is ronde-cel, which is a dual targeted CD19, CD20 CAR T-cell therapy for patients with large B-cell lymphoma. We're in pivotal trials for that. We have 2 pivotal trials ongoing, one, a single-arm study, which we expect to submit for BLA, the data from that next year, so barreling forward. And then we also have a first-of-its-kind head-to-head clinical trial ongoing for ronde-cel in the second line. So a really exciting program leading the way for the CD19, CD20 CAR T-cell next-generation class.

In addition, as Mitchell was just referring to, we have LYL273, which is a very novel CAR T-cell therapy for metastatic colorectal cancer patients. This is something that we licensed in at the end of 2025 based upon data from China, a single center study in China that was published in JAMA Oncology, 15 patients with metastatic colorectal cancer in the third or later line, so late-line patients with a 40% overall response rate and a median overall survival across 2 dose levels of almost 2 years. So really quite remarkable results.

This program was brought to the United States. And actually, when we licensed this program, data from 12 patients with across 2 dose levels, overall response rate of 50%. And again, really, really nice results. There was one case of high-grade diarrhea colitis in that program. So in response to your question, we are -- recently gave a safety update from that program, where we spoke about the safety from the ongoing clinical trial. When the high-grade diarrhea occurred, we put in a pretty stringent both GI prophylaxis and safety management plan so that we could mitigate that risk, and we wanted to give investors some comfort on how that was going.

So we presented data from 10 patients who had GI prophylaxis to compare with 9 patients who did not have any GI prophylaxis. And what we were able to show, I'm very pleased to say is we had a really nice decline from 55% grade 2 or higher cases of diarrhea down to just 10%. So something that was really quite manageable. And sort of as an overall benefit, in fact, there was no Grade 3 CRS seen, no Grade 3 ICANS as well as no Grade 3 or higher diarrhea or colitis seen with the GI prophylaxis. So we're very pleased with that.

Excellent. So great overview. I just wanted to dive in a little bit for LYL273. We're going to have efficacy data in the second half of the year. And I just wanted to understand what investors should be focused on? Is it reproducing the 50% ORR across the first 2 dose levels? Is it 67% at dose level 2 or more of a durability watch point for the 7.8 months PFS that we saw at the dose level 2 as well? Anything else that you would think that maybe we should be focused on?

Yes. So we did provide the safety update. But as Mitchell was alluding to, we have guided that we're going to be having a more fulsome update in the second half at a medical meeting where we'll be seeing both safety as well as clinical outcomes. We have, as I just described, some really nice data showing clinical activity both from China that was then confirmed in U.S. patients. We're continuing to recruit this program and define the optimal recommended Phase II dose.

And so the question is what's the bar for outcomes? And I would say very unfortunately, for patients, the bar is very low for late-line metastatic colorectal cancer, which is what we're studying. And I think in this case, if you looked at approved products for this patient population, response rates are 6% or less. Median progression-free survival is 6 months or less and median overall survival is less than 12 months. So the bar is very low. We think, as Mitchell alluded to, that we've already shown 50% overall response rates across 2 dosing levels, but the bar for approval is anything 20% or above. So it's really quite low. So we're very well positioned.

Okay. Great. And as you think about the regulatory path forward, can you talk about how that path has evolved moving from the Phase I to the amended Phase I/II design? And then what are your planned key topics that you want to discuss with the FDA for an end of Phase I meeting? Is it kind of the recommended dose, the single-arm nature of the trial? What kind of things would you like to iron out with the FDA after you have data?

Yes. So great point. So we did, at the time of the safety update, announce that we had amended this Phase I protocol to become a Phase I/II protocol. And what that means is we have an opportunity to do a single-arm expansion into a Phase II/pivotal trial if the FDA were to allow us to do a single-arm response rate trial. Now overall response rates haven't been used in metastatic colorectal cancer patients, quite frankly, because therapies haven't been able to bring the sorts of response rates that the FDA might be looking for.

But in our case, that remains something that is a topic of conversation that we can have with them. So one possible path would be a single-arm response rate trial. We have built that into this expanded Phase I/II program as well as looking at some additional cohorts. Whenever you have the next step in a development program after Phase I, it's an end of Phase I meeting. So we have guided that we expect to have that by the end of the year. And sort of as you alluded to, the #1 topic for conversation is always what is the recommended Phase II dose.

So that is the work of Phase I to really define that, what is the patient population, the inclusion/exclusion criteria. And then, of course, for us, what is the overall design because this is sort of novel territory in the setting that we are bringing a potential product candidate to them that may have an opportunity in response rate. So we'll have to see what that discussion is. Of course, there is always the option of a randomized controlled trial with overall survival as an endpoint.

The FDA does offer interestingly through Project FrontRunner an opportunity to do an accelerated approval pathway in such a trial using response rates as the accelerated approval endpoint within that initial trial. So that's another interesting design that we can consider. So it will be a really interesting conversation to see how that turns out with the FDA.

Yes, that's great. So I'm wondering, in your view, what you think would be necessary to kind of demonstrate from an efficacy perspective in terms of overall -- I mean, yes, ORR to justify a single-arm trial? And then I think previously, we had talked about some data from this asset that has had 25-month overall survival, I believe you had mentioned. And so can you talk about how confident you would be in something like that, a randomized trial with an overall survival endpoint?

Yes. I mean I think both are possible. It really depends upon the conversation with the agency. Now typically, for response rate trials in late-line oncology, I mean, we can't speak specifically about colorectal cancer, response rates, 20% to 30% are generally required to allow that as an endpoint and the agency has to be confident that it would correlate with better overall survival. So I think we've talked a little bit that the bar for approval here, any response rate, 20% or better would be great for a response rate trial, I might set that a little bit higher at 30%. But in general, something that is in the range of what has previously been seen with this product.

So it will be a good conversation to have. But I think the other thing, as you alluded to is that the dose level 2 that was studied in China, granted it with a small number of patients, but they were very late-line sick patients. The overall survival is 25 months. So again, if we can have the median overall survival currently for those patients in the U.S., third or later line is 12 months or less. So we do have an opportunity with an overall survival endpoint as well.

Yes. That's one of the interesting points for us, too, is the fact that you have kind of a large room for that overall survival to even move lower a bit because you're doubling overall survival from standard of care.

Yes. That's correct.

Yes. So -- and why do you think that this solid tumor CAR-T is working the way it is? Solid tumors are so tough to treat and nothing has been moderately efficacious, and this looks quite remarkable. What do you think is doing the work for this asset?

Yes. So at Lyell, we're very committed to developing next-generation cell therapy for solid tumors. And we know it's been a challenge, right? And why is it a challenge? It's a challenge in solid tumors to get the CAR T-cells to expand well to infiltrate into the tumors. And then quite frankly, the solid tumor microenvironment is very hostile and the T-cells rapidly exhaust and die. So you have to get them to continue to live and thrive in this hostile tumor microenvironment.

Well, this product, LYL273, was very specifically designed to overcome those obstacles. And it is a very novel design. First and foremost, it has a great target, which is known as Guanylyl Cyclase C or GCC. It's a target that is overexpressed on 95% or more of colorectal cancers and their metastases. So it's a great target. It is expressed very little in normal tissues, just low levels in the GI tract. So it's a great target.

But then in this product, we couple it with CD19 CARs and not just any CD19 CARs, these CD19 CARs secrete cytokines. Think of them as supportive hormones that then help these CAR T-cells expand. So when we give this product to patients, the first thing that happens is it hits B-cells circulating in the bloodstream. The B-cells have CD19. So when these CD19 CARs hit their engage with their target, they release cytokines. This helps all the cells expand. We get nice infiltration into the tumor.

And then again, these CD19 CARs continue to secrete cytokines in the tumor microenvironment, which we believe helps really flip and warm up that hostile tumor microenvironment. And we believe it is this mechanism of the great CAR target, GCC, coupled with the CD19 CARs that express cytokines, which is the secret sauce here, which is giving us the type of benefit in solid tumors that we'd hope to see.

Okay. And can you just discuss where you are with your trial in terms of dose escalation and how you think about dose selection and the performance of the first 2 dose levels versus a potentially higher dose level? What are you -- what would you be looking to see out of a higher dose level versus kind of what we've already seen? Is it just kind of finding that upper bound of what's possible? Or can you just discuss what the rationale is for that?

The job of Phase I is to find really the right dose to move forward. You want the best benefit for patients that you can get with a tolerable safety profile. And so yes, we're continuing to recruit patients in the Phase I trial, including dose escalation to get to that optimal dose for patients that we can then take to the FDA at that end of Phase I meeting, which we've guided we expect to have by the end of the year.

So we, again, are just looking for 3 things, right, the best response rate, the best duration of response with a very manageable safety profile and takes some work to get that just right, but that's the job of Phase I so that then this program can move very quickly. Our hope would be through pivotal trials.

Okay. And can you discuss the prophylaxis regimen that you're implementing in the trial? How practical is that in the real-world setting? These agents, how familiar with them are physicians? And do you see this as kind of like a permanent part of 273 administration? Or do you think there will be some changes in the future?

Yes. Great question. So the -- when we have this case of high-grade diarrhea, significant GI prophylaxis regimen was put in place before any symptoms develop. So patients are getting infliximab, vedolizumab and budesonide. And so these are immune modulators, you might think of them of that really protect the gut. So infliximab is an anti-TNF. Vedolizumab is used to block integrins to protect the gut, for example, in ulcerative colitis. And budesonide is an oral steroid basically that's limited to gut exposure.

And so very -- as we've shown, very effective in sort of mediating some of the diarrhea that we saw earlier with our CAR treatment. These are commonly used treatments. They're well tolerated by patients. There's nothing exotic or unusual about them and something which I think are easier for patients to use. What we're working through a little bit now is what do we give upfront for prophylaxis, what do we use for treatment as symptoms develop. And I think like all therapies, you've got to sort of protocolize and optimize the safety management plan for them, and that's what we're trying to do because I think that will make this a very easy to administer product to really have the safety management plan protocolized, much the way we've seen happen, for example, with cytokine release syndrome in the lymphoma space with others.

So I think that's great. And one thing about this product, which is also very nice is there's only a single day of lymphodepletion because as I alluded to, we want some B-cells remaining to be circulating. So this is actually quite an easy product to administer when you think of 1 day of lymphodepletion and then a single treatment. And so when we -- we're talking about diarrhea, but when you think about what these patients have to go through, this is an ideal treatment for them because it's a onetime treatment. So if you have some diarrhea that lasts, let's say, for 5 or 7 days, that's not the end of the world. When you think about chemotherapy that is ongoing over time, that sort of diarrhea side effect is a big problem. But this is just a onetime treatment. So it makes the toxicities much easier to manage.

Wonderful. Okay. And then I think it's important to kind of talk about the modality here versus others that are being explored. As an autologous CAR-T, there is a process that's involved in terms of administration and it's maybe a bit of an undertaking for a patient in late-line CRC. Given the context of what we've seen so far and what you -- the wiggle room you may have for data to change, what kind of magnitude of benefit would you imagine would be sufficient for a physician and a patient with late-line colorectal cancer to decide to proceed with an autologous CAR T, thinking about, for instance, like the 7.8 months median PFS, is that something that's impressive to physicians and patients? Or would they, at the end of the day, from a commercial perspective, want to see overall survival saying, hey, if I can live 2 more years, that's a compelling value proposition to me to undergo a treatment like this?

Yes. Well, a couple of things that are really important to know about colorectal cancer. And I have to say if ever there was a perfect indication for autologous CAR T-cell therapy, this is it. It right now is surging in younger patients and people don't understand exactly why, whether it's processed foods or environmental toxins. But the answer is -- the message is that the incidence of colorectal cancer in 35-, 40-year olds, 45-year-olds who are in the prime of their life is surging. And so these patients desperately want a onetime treatment so they can get back to their normal life, get back to their kids, get back to their work, get back to their active life.

And ongoing chemotherapy is a problem, right? Because with ongoing chemotherapy is ongoing toxicities. And so when you look at the products that are approved today, they're getting less benefit, but with ongoing cycles and ongoing toxicities. And so we actually think the opposite that this is a situation where patients are actually going to really want this CAR T-cell therapy because it's a one-and-done treatment. And as I said, as we get this management plan really protocolized and working out, well, this is a pretty easy treatment because it is a onetime treatment with just 1 day of lymphodepletion. So I think the -- this is exactly what CAR T-cell therapy was designed to do, right, be this one-and-done treatment, so you don't have to go through chemotherapy and ongoing toxicities.

Yes, that's very interesting. And then when we think about the patient selection for this and the trial design, can you talk about how you're thinking about liver metastases? Is that a restriction that you've put in there to more kind of homogenize the data where you can kind of see what the true effect is without some complicating variables? Or how do you think about patients who have liver metastases?

Yes. So one of the things that made us most excited about this product was the data, both from China and in the U.S., where patients have liver metastases that have in one case that's published in JAMA Oncology completely resolved with this treatment. And liver metastases, as you may know, are notoriously very, very difficult to treat. And so what we have done in this particular trial is picked what I call a middle-of-the-road moderate liver metastases. So we're not allowing patients with end-stage liver metastases to come in because that's very difficult to treat. But we are allowing up to 7 liver metastases, just none greater than 3 centimeters. So maybe pick -- allowing them, but keeping them in a moderate range so that we can really understand the benefit of the therapy.

Great. Okay. That's very helpful. I want to move on to a very prevalent topic in my investor conversations, in vivo CAR T. What is -- what are your thoughts on the in vivo CAR T landscape? So for -- shifting a little bit to DLBCL. Ronde-cel autologous CD19/20 CAR T and then now we have in vivo CD19/20 CAR T, albeit much earlier. Maybe you could start by framing how far ahead you are in the competitive landscape of CD19/20 CAR T-cells in DLBCL. And then just your thoughts on in vivo CAR T and how that competes or is kind of separate from the autologous approach?

Yes. So yes, in vivo is quite a hot topic. But let me start, as you advise, with where we are with our autologous CAR T-cell program because this is here and now. We just presented safety data in 100 patients where we have no high grade -- no Grade 3 or higher CRS, single digits of ICANS. So very well-tolerated safety profile with our next-generation CD19 CAR T-cell therapy. We have presented 97% manufacturing success with a 16-day turnaround time. So excellent availability of the product for the patient.

And then at ASH last year, we presented 93% overall response rate, 76% complete response rate with very importantly, 18-month median progression-free survival in the third or later line. Just for comparison, CD19 CARs have about 6 to 7 months. So this is the best data that I'm aware of that's out there for large B-cell lymphoma patients here and now with great durability.

So yes, in vivo is very, very exciting technology. We're very interested in in vivo CAR like many others. But autologous CAR is here and now with a very high bar to beat. It's been around for a decade. We know a lot about the safety. We also know a lot about the durability and this sort of durability is very important. And so we're all interested in the Legend data that is now put out CD19, CD20 in vivo CAR in 6 patients, only 3 had large B-cell lymphoma followed for 2 months.

So interesting, but this is not a competitive data set yet. So let's see what happens. But in the meantime, ronde-cel is here and now. It's barreling forward. We are going to have a a significant data update from the ongoing pivotal trial. It's a single-arm study at the second half of this year, so coming soon. And then we expect BLA submission next year. So that's a really important milestone. And we are leading the way with the next-generation CD19/20 CARs. We think we're about a year ahead, and that gives us a great opportunity to really well position ourselves as the product of choice in the centers.

Great. Okay. And then as we look at the other autologous approaches, we had J&J who recently kind of got out of the race, it seems. And then Kite, who has changed constructs. CD19/20 constructs is now a little bit further behind. How do you see the rest of the landscape beyond just Legend as the in vivo competitor? Obviously, you're in the lead with the median PFS of 18 months. Again, we aren't also aware of anything better than that. So how do you see the rest of the landscape and the ability to catch up or what the differentiation is whenever we look forward in a year or 2?

Yes. And I would say right now, we just don't know enough about the Kite product because as you said, the data are very recent. And so I think we have much more -- we presented data on more than 100 patients. So I think we have a very good idea about what our profile is. As I said, we think we're several months ahead, if not a full year, which is great for us. And I think this is really autologous CAR T-cell therapy is still -- if you're a patient, you want the best outcomes you can get. And right now, for patients, our product is being developed in patients for all ages.

We allow bridging therapy. So again, it's the sort of product that I think it can be given in the outpatient setting. So patients don't have to go in the hospital anymore for that. And they have, right now, as of the last data presentation, 75% chance of going into remission and not a short remission, but a really meaningful remission. And so that's, I think, what patients are looking for. So we are working very hard to get this approved. We hope to be first. We know that physicians who prescribe CAR T-cell therapy will switch, and we believe they'll readily switch from the CD19 CARs to ours.

We know that about more than 50% of patients who are getting CARs today based upon Medicare claims analysis have previously had 2 prior lines of chemotherapy. So we'll be on label for our third or later line population. So that's a significant portion of the market with this fast to approval strategy. And then once we're there, it's going to be very hard to swap us out because our data are quite strong. So we think this is a great fast to approval strategy for us and it's going to bode very well in the commercial marketplace.

Great. So I think the last thing I want to touch upon is the fact that right now, with all the things we talked about, Lyell is trading at a very attractive valuation. And so as investors look for inflection points and what could cause the stock to kind of rebound, could you just highlight the year ahead, the next 12, maybe 18 months of data catalysts for Lyell and what investors should look forward to?

Sure. So this is a great time to invest in Lyell, as I think Mitchell said, I think the stock is undervalued now. We have potentially transformative data update coming with our colorectal cancer program. As we know, this is a large market with tremendous unmet need. We have a data update coming from our pivotal trial at the end of this year, which will be very nicely mature data and will be the last look at the data before the data that we'll use for BLA submission. So I think a great confidence builder for investors.

And then, of course, next year, we'll have the pivotal data from this program and be submitting the BLA. So really gearing up for commercial launch. And we didn't talk -- have a chance to talk too much about it, but Lyell has our own manufacturing plant. We have our own manufacturing facility. We are running our commercial process as we speak, and we can launch this product with very effective and efficient cost of goods. So this is a great marketplace for us. And again, we have the capabilities to support the commercial launch from a manufacturing position.

Wonderful. Thank you so much, Lynn, and thank you to the Lyell team for joining us today. And thanks to all of the investors who dialed into this conversation as well. Wish you a good day ahead.

All right. Thanks, Mitchell.

Great. Good morning. It's my pleasure to introduce with us Dr. Lynn Seely, President and CEO of Lyell Therapeutics.

Lynn, to start here, could you give us an overview of where your two oncology programs stand today and how to think about the catalyst path as we look to second half and beyond?

Absolutely. Well, I will be making forward-looking statements here today. So Lyell is a cell therapy company focused on next-generation cell therapies for cancer, and we have two programs in the clinic. One is a dual-targeting CD19/CD20 CAR T-cell program for large B-cell lymphoma, where we are in pivotal trials. We have a single-arm pivotal trial underway where we're going to be providing a major data update in the second half of this year.

That will be the last look before the pivotal data are expected mid next year, and then we'll be following with an expected BLA submission before the end of the year. So we're really excited about that. And then, of course, we have started and are actively recruiting patients into the first of its kind head-to-head trial of CAR T-cell therapy, Ronde-cel, our program versus investigators' choice of one of the two approved CD19 CARs, Yescarta or Breyanzi.

And then in addition to the Ronde-cel program, we have LYL273, which is a GCC-targeted novel CAR for patients with metastatic colorectal cancer. So we're really excited about our progress on both programs.

For Ronde-cel to start there, your lead program, it's currently in registrational trials, as you mentioned, in both the second-line and third-line plus settings. For the third-line setting of data -- on the data update expected in the second half, post strong reports at ASH last year, which demonstrated about a 93% ORR, 76% CR rate and an 18-month median PFS. Can you frame expectations for the upcoming data in terms of both patient numbers and length of follow-up?

Sure. So as we said, we last presented data from this program at ASH, where we did see this really robust overall response rate of 93%, which is, in fact, the primary endpoint of this single-arm trial, which is just continuing to enroll. We did show a 76% complete response rate and that all-important median progression-free survival of 18 months. And this compares very favorably to what's been reported in the pivotal trials with the approved CD19 CARs where their median progression-free survival is 6 to 7 months.

So we are obviously continuing to enroll this program, and we'll look forward to presenting updated data both with more patients for the next pivotal trial as well as longer duration of follow-up. So we'll be looking forward to updating, of course, on the median progression-free survival as well.

And on durability, what gives you confidence on the drug's profile? And do you expect the 18-month median PFS results will hold or potentially improve with more mature data?

Certainly, there is always the possibility that it could change and we think hopefully improve with longer follow-up. I have confidence in Ronde-cel for a few reasons. And I think number one is its mechanism of action. This was designed meticulously to be a full potency CAR at either CD19 or CD20. So it makes perfect sense that if you're hitting two targets, you're going to have more complete responses.

And then also more durability of responses because it is known that with CD19 CARs, for example, some of the escape comes because these malignant B-cells can escape 1 antigen. It turns out it's much more difficult for them to escape 2 antigens. So I think more complete responses, longer duration of response. And then, of course, this idea of durability, we select the cells that we transduce very carefully. These are selected with CD62L, which gives us more naive CAR T-cells and central memory CAR T-cells, which have been shown to persist longer.

And then we also know from the UCLA experience on through that the duration has really been consistent throughout. So we're looking forward to providing the update in the second half.

And for the pivotal data in third line that's expected in mid-'27, followed by a BLA submission by year-end '27. What is the bar for success here from a commercial and regulatory viewpoint? And are there any execution risks that could [indiscernible].

Yes. I think it's good to point out this difference between regulatory and commercial expectations because, actually, the regulatory bar is reasonably low. As I said, we've shown a 93% overall response rate when the regulatory bar is below the CD19 CARs, which is at 70%. So we have a wide margin here, I would say, very derisked.

Commercially, I think we want to show better than the CD19 CARs because our objective, really, is to switch out the CD19 CARs and have them replaced by our Ronde-cel CD19/CD20. In terms of execution risk, I would say the magnitude of benefit, I think, is pretty clear. Now we just need to complete the trial and get the BLA submission in.

And you previously suggested that the third-line plus market is larger than appreciated that it could be potentially 6,000 to 7,000 patients. Can you walk us through the data supporting that estimate and your confidence in physicians' willingness to switch?

Yes. Well, maybe I'll start with the back part first because I do think this is a known switching market and that we've seen it when physicians have switched in the lymphoma space from Yescarta, which was the market leader. Now Breyanzi is the market leader, presumably based upon its better safety profile. And then we've seen it in the myeloma space where ABECMA was the market leader and now has been replaced by CARVYKTI based upon improved efficacy.

Well, Ronde-cel, we expect to bring both better efficacy and better safety. So lots of reasons to switch. And because we're leading and expect to be the first CD19/CD20 approved, then once we're in place, it's going to be very hard to switch us out because the benefit doesn't leave much headroom, for example. And the safety profile, we've not seen any Grade 3 CRS in this program, and our ICANS rates are in the single digits. So that's great.

[indiscernible] idea about how many third-line patients are there. Some people think maybe that's a small market because it's late line. But the fact of the matter is we know from a retrospective series from Memorial Sloan Kettering that up to 50% of their patients who go for apheresis for CAR T-cell therapy have received 2 regimens of chemotherapy. That means they would be third-line patients. We actually confirm that with using a U.S. Medicare claims fee-for-service database analysis, and we're able to show that 57% of patients undergoing apheresis for CAR T-cell therapy had received 2 prior lines or prior regimens of chemotherapy and therefore, will be on label for a third-line product.

Today, physicians don't really count because the approved CARs are approved both in the second or third line. But if you were in a situation where our CD19/CD20 was only approved in the third line, it would be important to count those regimens. And I think we're going to find that the third-line population is much bigger than people anticipate.

In the second-line setting, you're currently running an unprecedented Phase III head-to-head superiority trial against investigators' choice of Yescarta or Breyanzi. Can you provide some color on the design and powering assumptions for this study?

So we made a decision not really for regulatory reasons, but for commercial reasons to run this head-to-head trial, because it's really the study that physicians and patients want to answer. Our job is to switch out the CD19 CARs to our product, and this gives us apples-to-apples comparisons. And so we're randomizing 200 patients per arm. They're going to be stratified because we know that disease characteristics and demographics matter in lymphoma outcomes. So they're going to be stratified for key risk factors.

And then the primary endpoint of this trial is event-free survival. Patients are randomized either to Ronde-cel, our product, or to investigators' choice of Yescarta or Breyanzi. And so we think this trial is designed to give the information that doctors and their patients are looking for. We have built in an interim analysis. So the trial is powered very conservatively for the final analysis, but we have built in an interim analysis in case the effect size is bigger than hoped for. I think as we know, event-free survival is very much driven by that durability of response, and that's been our strong suit to date.

Differences in enrollment criteria preclude direct comparisons versus prior Yescarta and Breyanzi studies. So what are your expectations for the control arm performance? And what is the desired efficacy profile for Ronde-cel given the inclusion of high-risk LBCL patients?

Yes. So we are including really a range of patients. We have no upper age limit. We're including patients who have primary refractory disease, relapse within 12 months after frontline therapy, but also some late relapsing patients. So we believe we have a nice range of patients.

And again, this trial has not been done in this time frame. So we're going to have to see what happens in the control arm. And it's one of the reasons that we are running this randomized controlled trial because all we have to show is superiority, right? Once we should see a successful benefit in terms of event-free survival, I think physicians will switch.

And just to go back to a point you made, if you're taking an interim look here, maybe speak to the alpha that you're allocating to that interim look.

Yes. It will be -- we are taking an alpha hit. It's small, but if we see superior at that interim, we can get out at that interim. It's much the way Breyanzi got out with an early interim and their approval in the second line as well.

Can we touch on the competitive landscape here? We recently saw data from Legend's CD19/20 in vivo CAR-T, which showed strong initial responses, but with limited follow-up. What are your views on the in vivo approach and Legend's data? And in your view, does the result further validate this dual targeting strategy?

Yes. So Legend is developing a 19/20 in vivo CAR. So yes, it validates the whole movement to the 19/20 CAR being superior to 19/20. Look, the field is excited about the coming of this new technology in vivo CAR. We're excited about it. And I think -- but we view it very much as maybe an opportunity to extend from autologous CAR and that there's still going to be a need for the very best therapy.

And there's a lot that's unknown about in vivo CAR at this point. And I think with Legend, we've seen data with responses in six patients, three of those had large B-cell lymphoma. Two responded, but the follow-up is only 2.2 months. So there's a lot left to learn. And I think we're going to see how this field develops, but I think it's also an opportunity for us to expand market access for patients.

But for now, Ronde-cel is here and now we know what the complete responses are in large numbers of patients. We know what the duration of response is. And you have to remember, we very specifically transduce naive and central memory cells. So we select the cells that we're transducing. It's hard to know which cells are going to be transduced with in vivo CAR. So jury is out in terms of durability and even longer-term safety. So we'll all watch and wait and see how this field evolves.

And on autologous competitors, Gilead announced a head-to-head trial with dual targeting KITE-753 versus Yescarta. Noting that your trial includes Breyanzi in higher-risk patients, does differentiation between the studies presents a competitive or commercial advantage? How do we think about this?

Yes. So the first thing to know is we started recruiting centers for our trial well over a year ago. So I think we're leading, we're actively recruiting patients now. And yes, we wanted to make this study designed to answer the questions that physicians were interested in. And we know that more than half the patients being treated with CAR today are receiving Breyanzi. And so we felt like this was the best trial design to represent what physicians are doing today. And so we do think that's an advantage for us. And we do think we have a significant lead and are actively working on this program.

And maybe touch on CD20 bispecifics and where that could play out in the frontline setting.

Yes. So bispecifics are another tool in the toolbox for patients. They are being evaluated in the front line. So we'll be learning more about what advantage they bring. They're being used and evaluated in combination with other therapies like R-CHOP. So we have to see what advantage they bring, what the durability of the data are and the toxicities, particularly infection.

And then I think one of the key issues in the field is going to be overall survival as well and sequencing. Many experts continue to believe that receiving CAR before bispecifics is important because the bispecifics really result in substantial T-cell exhaustion. So there's a lot yet to be learned and everybody is going to be closely watching this. But I think this -- to date, all the data that we have seen really suggests that autologous CAR with its onetime treatment and potential for cure is something that brings great benefit and durable benefit to patients.

And finally, Allogene reported some first interim futility results here in the -- with its allogeneic in the frontline consolidation setting. How could this approach change the treatment paradigm as we think about the second line and third-line setting?

Yes. I think this is probably a rather narrow slice of the overall population. And so it's patients who are high risk who remain MRD positive and then get consolidation with Allogene's therapy. So I think it's a relatively small patient population. They're still early, right? This was a futility analysis with very little durability.

So they're going to have to really continue to recruit patients and see what the outcomes are on their primary endpoint. But in the meantime, even if they are approved and patients get another option, I think it's a relatively small subset of patients given they have to be MRD positive.

Just big picture, when we look at Ronde-cel, where is the risk here in the translation? It seems like the third line is pretty straightforward. But as you think about second line, given the moving parts with the control arms essentially, how do you think about that probability of success?

So I think, obviously, we think the probability of success is very high. That's why we're doing this because I think we know from the biology why this is going to be better. I mean it just makes complete sense that CD19/CD20 is going to be better than CD19. We've seen that play out in space and our data, both in the third and later line, but also in the second line where we've shown really strong responses in primary refractory patients. This is the hardest of the hard to treat.

And then the durability that we've seen in the third line, which is absolutely expected to read through to the second line is substantially more than is seen with the CD19 CARs. We think based upon the CD62L selection, it's something our translational data continue to show. And so we think that the risk is low. We think that the fact that the trial is randomized and stratified so that we will have true apples-to-apples evaluation also gives us great confidence.

So I think the biggest most important thing for us is to execute with speed. We're in the lead. We intend to keep the lead. And the sooner we can get this trial recruited and read out will be better. And so I'm hopeful, of course, that we'll read out with the initial interim.

Pivoting to LYL273, your autologous dual targeting GCC, CD19 CAR-T for solid tumors. This morning, you announced new safety data from the ongoing Phase I study where post-implementation of the new prophylaxis regimen, only 10% of patients experienced GI toxicity, which was down from 55% prior. Could you discuss the regimen and your results and your confidence in the safety profile here as you move through Phase I dose escalation?

Yes. So maybe I'll take a step back for a moment and just talk about this GCC CAR program for metastatic colorectal cancer because I really believe this is potentially transformative for the company. I mean I think we know that there's a huge unmet need in colorectal cancer. But I think what a lot of people don't appreciate, we've all sort of heard in the news that it's surging in younger patients. Well, those are exactly the patients who want a one-and-done treatment and not this ongoing chemotherapy. And so I think we have a real opportunity.

We licensed this product at the end of last year, and it was based upon data, first of all, 15 patients from a single center in China, where they treated patients at dose level 1 and dose level 2, and showed a 40% overall response rate across those 2 doses in active CAR. It was brought to the United States where we had data on 12 patients, 6 at dose level 1, 6 at dose level 2, the same doses. And in the U.S. study, there was a 50% overall response

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data that was shown or that was published from China.

There was one patient who died. This is a patient who died from colitis from a GI side effect. The colitis was managed, but the patient -- with some immunosuppressive therapy successfully, but the patient got a secondary infection and did die. Importantly, at autopsy, there was no evidence of disease in this man who had widely metastatic disease. So a pretty tragic outcome.

At that time, GI prophylaxis regimen was implemented, which getting to your question now. So the GI prophylaxis regimen is -- includes vedolizumab, infliximab and budesonide. And these are 3 therapies which are directed to the bowel to prevent inflammation, if you will. And so what we announced today to help people understand how this program is progressing on the safety side is that with GI prophylaxis

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lower the grade 2 and above.

So before the GI prophylaxis, we had 9 patients with a 55% rate of grade 2 or higher diarrhea, colitis. And afterwards, it dropped to 10%, as you pointed out. And therefore, no grade 3 diarrhea or colitis. And in fact, we also got some added benefit in that there was no grade 3 ICANS or CRS observed either. So really tells us that there's a nice therapeutic window here.

Lynn, can you also touch on the protocol amendment that you announced?

Yes. So based upon the safety data that we're seeing and the progress of the program, we have now expanded the program so that in the third or later line metastatic colorectal cancer, where we're treating patients now, we can have a seamless expansion into a pivotal response rate trial if the FDA and the data warrant.

And so we are busy working on establishing the recommended Phase II dose to get this to an end of Phase I meeting, which we've guided we expect to have by the end of the year. And in addition, we have added cohorts to the trial so that we can explore earlier lines of therapy and some combination therapy.

Can you frame expectations for the efficacy data in the second half? And what's the bar of success? And how do you think about it in the context of standard of care?

Yes. So as we sort of spoke about the standard of care treatments in the third or later line are really lacking for patients. I mean the overall response rate for the best combination therapy has a 6% overall response rate. Median progression-free survival is 6 months or less and overall survival, less than 12 months, 11 months or less. So there's tremendous need and particularly need for these younger patients for a one-time treatment.

So what is the bar as we're thinking about this? Well, obviously, we think anything 20% above, better can get us approval. And then I think if we want to have a single-arm response rate trial, maybe 30% response rates. So the bar is low.

And you've talked about advancing it beyond this indication you're currently in. So what are your plans for expansion given the broad expression of GCC across solid tumors?

Yes. So I think to start with the most important thing for us to do right now is to find the recommended Phase II dose. That's what we'll take to our end of Phase I meeting, making sure that we have, again, this first to get the right safety management plan and the right dose. And then we have this opportunity to expand. We believe this is very appropriate for the second line. And so we have added a second-line cohort to this Phase I trial. We believe that potentially, there is some opportunity for combination with, for example, radiotherapy.

And then as you pointed out, I mean, GCC is a great target. It is expressed in 95% of patients with colorectal cancer. It's something that gets overexpressed quite early in colorectal cancer development. But it's also expressed in pancreatic cancers, and we think about 60% of pancreatic cancer. So there's further opportunity there as well.

In that context, can you just remind us where you stand in terms of cash position and runway?

Sure. So we have $261 million in cash, and this gets us into Q3 of next year, 2027 through multiple clinical milestones.

Big picture, we've seen Lyell pivot, I think, as we've seen the work you've done in solid tumors. Talk about kind of where you stand today, both from these programs, and it seems like there's extreme confidence in both of them, but also how you're thinking about the future and any additional pipeline assets?

Sure. And so I would like to say, so Lyell has never pivoted. We were founded to develop CAR T-cell therapy for solid tumors, and we're continuing to do that as we just discussed with this colorectal cancer, but we did broaden our aperture to include this hematology/oncology program in large B-cell lymphoma, which we're, as you know, very excited about.

So I think we want to continue to execute, and we have lots of opportunities. And I think this -- for example, the novel design of this GCC CAR that we're developing gives us a window into maybe how to treat solid tumors in a broader perspective because it's got a very novel mechanism. It is coupled with or enhanced by CD19 CARs. And that's a very unusual concept because you're like, why would you put a B-cell target with a colorectal cancer target. And the reason is with this CAR, we only give a single dose of lymphodepletion, so that we have some B cells remaining.

And this then jump-starts cell expansion because the CD19 CARs hit the B-cells, they release cytokines, and we get much better GCC CAR and doublet cell expansion. And so we think this is one of the key reasons we're having such nice responses in colorectal cancer and also as a window into solid tumor at large.

The in vivo marketplace is also not lost in us, and we think it is very much in terms of a line extension. Certainly, the fact that Ronde-cel is here and now with great overall response rates and complete response rates and importantly, durability is great. And this may be in vivo CAR may be some way to increase access. So lots of opportunity for us.

Sorry, I meant pivot from a...

No, a lot of people say pivot but...

Given the leadership changes at CBER, maybe speak to your latest read on the FDA's willingness to grant full versus accelerated approval on single-arm studies when we're looking at Ronde-cel here in the third-line setting? And any color on regulatory interactions to date with the changes of leadership?

Yes. It certainly has been a revolving door at the FDA. But one of the things I'm very proud of is our development strategy for Ronde-cel. And I would say in lymphoma, single-arm trials in later line have a long history of being accepted, both Breyanzi and Yescarta were approved with single-arm studies full approval. And our conversations with the regulators have been around full approval in the third-line setting.

But in the case that they say, no, you can't have full approval, you can have accelerated approval. That's fine for us. We still get on the market and our well-controlled randomized controlled trial, the gold standard head-to-head CAR T-cell therapy trial is already underway. It will be well underway by the time we submit the BLA. So we're in a very good place regardless of whether it's full approval, which would be our expectation or in the case that accelerated approval is what happens.

And in the case of metastatic colorectal cancer, there have not been a lot of precedents for single-arm trials simply because products haven't shown response rates in the later lines, which is where they might be considered. So that is something that we'll have to determine in conversation with the agency, but they are well aware of the large number of young people who are currently suffering from metastatic colorectal cancer.

And just maybe a last question here in the second-line setting for LBCL, is enrollment tracking in line with expectations and maybe speak to any early physician feedback on the study?

Yes. So we've guided that we'll be giving an update on how the program is going in the second half. I will say we're busy both recruiting patients, but also continuing to activate centers. And I would say that the enthusiasm for this trial has been very strong. And I think we hear consistently that you guys designed the trial that physicians and patients want to see. And so I think they're nothing but excited about it, and we're getting a lot of positive feedback.

Great. Well, with that, thank you very much, Lynn.

Thank you.

All right. Good afternoon, everyone. I'm Stephen Willey, one of the senior biotech analysts here at Stifel. I'm very glad to have with us in the next session, Lynn Seely, who is the President and CEO of Lyell. Lynn, thanks for joining us. Always appreciate it. Any opening statements you want to make or a brief overview of the company you want to provide before we jump into Q&A?

Sure. I'm happy to give an overview for those who may not be as familiar with Lyell maybe for the record, I should say I'll be making some forward-looking statements here. So consult our website. But for those of you who don't know Lyell Immunopharma, we are a cell therapy company, and we're focused on next-generation cell therapies, both for patients with hematologic malignancies as well as for solid tumors. And we have 2 lead programs in the clinic, both for large markets one in large B-cell lymphoma, where we intend to displace the currently approved CD19 CARs, which have a $3 billion and growing marketplace. And then the second, very novel CAR for metastatic colorectal cancer. So I look forward to telling you about those. / And then I should also just make note of the fact that Lyell is a little bit unique in that we have our own manufacturing like facility where we can launch from that facility and get well into launch with our own manufacturing. So that puts control under our own destiny, which we really like.

Okay. That's great. So maybe before we get into any of the data development plans for the assets for ronde-cel specifically, maybe you can just first speak to what differentiates ronde-cel from the first generation of CD19 targeting CARs and other competitive offerings in the CD19/20 space. I know you have some very unique attributes on the engineering front. You have a unique manufacturing process. How do those things, in your opinion, contribute to the clinical profile that you're seeing emerge?

Yes. So our CAR product, the CD19/20 construct was very rationally designed by a brilliant engineered biologist at UCLA, known as -- her name is Dr. Yvonne Chan. And this is a tandem CAR. So it's a single CAR construct that binds either CD19 or CD20 with full potency. So she meticulously did this work to ensure full potency at either. So all in just one CAR construct. So that's important because we are looking to get more complete responses and longer duration of response. And we know that some malignant B cells that cause lymphoma have low CD19, so may not respond well to CD19 therapy alone. But with the CD1920, the dual targeting, we can drive more complete responses.

And then one of the key mechanisms of escape from CD19 CARs is loss of antigen. These cancer cells are very smart and they can drop one antigen. It turns out it's much more difficult for them to drop 2. So that gives you longer duration of response.

And then the third thing that is part of this product, which is quite novel is that we are enriching our cell products for what we call CD62L positive cells. These are cells that are more naive T cells and have a tendency to persist longer and have more activity and can help us with a bit more softer safety profile. So these features all come together to bring the product profile that we're looking for, which is more complete responses, more durable responses and a nice safety profile.

Okay. I know the data that we've seen for ronde-cel thus far, both in the second line and third line plus settings of large cell B-cell lymphoma certainly looks to be optically superior to what we've seen historically from the CD19 CARs in each respective setting. I know that comparison can be complicated by differences in eligibility criteria, baseline patient characteristics, disease characteristics across various studies. Can you just contextualize the safety and efficacy data that you are seeing with ronde-cel relative to the types of patients that you've specifically enrolled and treated within each setting?

Sure. So maybe I'll just start with safety because when we present safety data, we put our second and third-line patients together so you can see the most patients. And there, I think we're very proud of our safety profile. We have not seen any grade 3 or higher cytokine release syndrome in the program. Our neurotoxicity or ICANS rate is single digit, less than 5%. So very competitive with respect to the currently approved CD19 CARs. But you are exactly right, Steve, when you talk about whenever you're looking at lymphoma data sets, you need to know who are you treating because things make a difference in terms of the outcomes. Older patients don't do as well as younger patients. Patients with primary refractory disease don't do as well as patients, for example, with earlier late relapse from their frontline therapy. And so who you're studying really matters.

We've put up data sets in both the second and the third line, which are really quite competitive. In the third or later lines, we presented data at ASH, where we were able to show a 93% overall response rate, a 76% complete response rate and really importantly, a median progression-free survival of 18 months. Now how does that compare with the approved CD19 CARs in their label, you have -- [ Cardia ] and Breyanzi are relatively comparable. They show with in terms of efficacy, they show about a 70% overall response rate and a 50% complete response rate. So about 20 percentage points lower than we showed. But more importantly, the median progression-free survival for the approved CD19 CARs is 6 to 7 months. We have 18 months. So it's not a subtle difference. And this is really important because the primary endpoint of our trial in the third or later line is overall response rate, where we have 93% in the patients that we presented thus far.

We are going to be having a significant data update in the back half of this year where even more patients from that ongoing trial will be presented with even longer duration of response. So that's the third line, which is, we think, a really important market for ronde-cel. And then in the second line, we also have put up a group of patients, a second-line cohort. Interestingly, these patients were almost completely primary refractory patients. So the sort of the sickest of the sick, those patients who don't even respond to frontline chemotherapy. And there, we were able to show an 83% overall response rate and a 61% complete response rate. And so it sounds a little bit lower than the third line, but it's because it's such a sick patient population. And again, when you compare to what data are available, you can find in Breyanzi literature for their single-arm study, a complete response rate in older, sicker patients like we enrolled of 42% in the primary refractory patient population, again, much lower than what we're seeing.

So it's these data, particularly when you look at the age and disease characteristics that really tell us we're on the right track. When you look at the Breyanzi and Yescarta randomized controlled trials, they don't enroll any patients over the age of 75. We have no upper age limit. And we think this is really a great sign for our product profile.

Okay. So you're now in registration within this third-line plus population, and you're doing that via the single-arm PiNACLE trial. Can you maybe just speak to the number of patients you're targeting for enrollment here? And I know you've guided to a top line data disclosure, I think, in mid-'27 and the BLA submission at the end of '27. Will this update that you just referenced occurring in the back half of the year, will that include a meaningful amount of incremental patient data from the last cut? Or will it just include kind of a snapshot of durability from the last cut?

So we're going to be showing both. This is an ongoing trial. So we'll have more patients. We'll have longer duration of follow-up. You are right that our goal is to enroll about 120 patients. We need 100 treated patients to submit to the FDA. And so when we talk about the pivotal data set, what we're talking about is 100 treated patients approximately who have been followed for at least 6 months after their complete response -- after their first response. And so what that tells you is we'll be finishing up enrollment by the end of this year to stay on track for a mid-next year pivotal data disclosure. So this is going to be a meaningful update, and I think we'll give investors a really great look at ronde-cel. This, as you know, the data have been quite consistent. We've had our dose and recommended Phase II dose as of the first data presentation really at Lugano. Last year, we presented at ASH. The data have really been quite consistent and promising.

Okay. How would you characterize -- it's a popular topic for all biotech executives right now. But how would you characterize the current regulatory environment at FDA? We followed Arcellx. This was always a question we were getting from investors. Obviously, Prasad is no longer at the helm of CBER, but he was obviously a very vocal opponent of granting full approvals to CAR-T therapy on the basis of single-arm data and I think pending editorial in December that suggested that randomized OS data would be needed for full approval in earlier lines of therapy. So have you just had any post-Prasad interactions with the agency on some of these topics? And do you think all of that was just bluster that's going to follow him out the door?

Well, there has been a revolving door at the FDA for sure. But I think I can say a few things. I think lymphoma is a place where there's a lot of precedent where things like overall response rate correlate with overall survival quite well. So our FDA interactions to date have suggested that a full approval could be possible with this third or later line single-arm study. But worst case, an accelerated approval is just fine. We get on the market.

What we have to have if we get accelerated approval is an ongoing randomized controlled trial, right? We have that. We have the gold standard of randomized controlled trials because we're currently treating patients in head-to-head randomized controlled trial, ronde-cel versus investigator's choice of Breyanzi or Yescarta. So our development program fits squarely into whatever the FDA is going to require, whether it's accepting the third or later line for full approval, which they have done previously for Breyanzi and Yescarta.

And remember, we have RMAT designation, which says that tells you that the FDA also agrees for us in both the second and third line that we're bringing a meaningful product, a product with meaningful data forward. So we are getting sort of the most attention there that sort of as the designations allow. So I'm very optimistic. And then in the worst case, we get accelerated approval, we're on the market, and then we bring in the head-to-head trial to confirm and convert that. So we're in a very good position, we believe, from a regulatory standpoint.

Yes. So you initiated the head-to-head study you just referenced earlier this year. Again, this is a pretty bold trial design, got a lot of press when it was rolled out appropriately. So how do you think about the patient eligibility criteria in this study? How is it different in any way relative to transform the Breyanzi study, ZUMA-7, the Yescarta study? And how do you think those eligibility criteria may prove to be a competitive advantage for you, right? I know, for example, you mentioned that Breyanzi didn't study anyone over the age of 75. So can you just speak to that part of the...

Yes. Look, we have a clear goal in mind. We want to displace the approved CD19 CARs. We have a development plan, which is built to do that. And this head-to-head trial is designed very specifically to give doctors and patients the information that they're looking for. It's a superiority trial. It's a real-world trial, meaning that if you're eligible for CAR, you can be pretty much in the study. We don't have an upper age limit. We don't require testing for CD19 or 20 before you come in. We allow bridging therapy. We allow primary refractory disease, late relapses, early relapses. So it's a very real-world study.

I would say in comparison, when the randomized controlled trials were done with Breyanzi and Yescarta, they didn't take patients over the age of 75. Yescarta didn't allow bridging therapy. And even today, you may be aware that Kite Gilead is going to run a head-to-head. They also have a different CD1920 in development, and they're about a year behind us because it takes about a year to get these sites activated. We've been working on that program for well over a year. And they are not taking -- they're not allowing bridging therapy, and they're only randomizing patients to Yescarta. We're allowing randomization for the investigator to pick either Yescarta or Breyanzi. So a little bit more real world, and we think that's going to be very much to our advantage.

Yes. And given how the market share appears to have split out between Breyanzi and Yescarta, that may represent a competitive disadvantage for them in terms of enrollment accrual. You talked about the Kite product, right? And I know in your opening statement, you referenced a tandem binder that was engineered in the ronde-cel. Kite uses this bicistronic binder. How do you think just that engineering difference alone gives you a leg up as you think about comparing and contrasting the 2 products in this setting?

I mean I think the data are going to speak for themselves as time goes by. I think so I have to speak in theoreticals. But I think what typically is thought of is that a tandem CAR means there's CAR expressed. So that's advantageous to the cell. If you have 2 CARs expressed, it's more metabolically difficult for the CAR to express. And in this case, one of the -- in the case of Kite, they're expressing Yescarta for the CD19 component and then a CD20, a separate CAR. So that is some metabolic stress. It's a little bit more difficult in manufacturing, isn't it, to make sure you get consistent expression of both over time.

And then there's some school of thought that having these 2 different CARs, one with a CD28 co-stimulatory domain may lead to sort of more T cell exhaustion, which would not be good for durability. So these are theoretics. We're going to have to see how the data play out. But right now, we are very pleased with the performance of our tandem CAR, both in terms of the complete response rates we're seeing and very importantly, the durability and the safety profile.

Okay. J&J recently announced that it was discontinuing its CD19, CD20 dual CAR-T program. Do you think that this reflects any read-through in terms of their interpretation or perspective of the competitive landscape or commercial opportunity? Or do you think this was just probably kind of an isolated asset-specific decision that the company made?

Well, one can never know what goes on inside of Johnson & Johnson. I think, obviously, they said it was a business decision. I have to believe it did have to do with the competitive landscape, but maybe not in the way people think. So we know that J&J licensed their product from China from a company known as AbelZeta. We know that they were having some trouble with dose finding because the dose used in China to present some very nice data was about 150 million cells. They'd already dropped back to about 75 million cells, which implies something was happening. Interestingly, they didn't show up at ASH with any new clinical data, which was sort of surprising the big hematologic cancer meetings at the end of the year. And then they pulled out altogether.

And I think one of the things that we know we did was we went out very early with this head-to-head study. We got all the major sites agreeing to participate in our study. We put up our steering committee. And over time, we knew that J&J was going to these same sites and saying, oh, we want to run a study, and they were told, no, well, we've already committed to Lyell, and we're working with Lyell in the study, which is what -- so we turned them down. And so it could be Johnson & Johnson doesn't like to be second, right? Or third they like to be the leader, particularly in a marketplace like this. And so it's possible that they just got behind and decided that it wasn't worth it for them to be the third head-to-head trial ongoing.

And so I think we took a very aggressive strategy, and I think it paid off. But for whatever reason, it doesn't matter, this is great news for Lyell because it's one less significant competitor in the marketplace, and we think sets us we're clearly in the lead at this point and not by a small margin. So to be honest, it's on us to continue this aggressive execution and stay on track to have this major data update at the second half of this year and then get that BLA submitted next year.

Okay. Any thoughts on what Allogene is trying to do with their ALPHA3 trial, where they're looking at cema-cel as consolidation therapy in patients who are MRD positive, absent clinical progression post frontline therapy. Do you think that success for them in that study somehow impacts the market opportunity in the second-line setting?

Well, I think any success in cell therapy is good. I mean I'm always happy when cell therapy companies do well like Arcellx being acquired because all boats flowed. But I think in terms of threatening ronde-cel, no. I think this is an allogeneic product. They are going into -- they showed some futility data that in 24 patients, 12 in each arm showed that they were able to achieve MRD-negative status. They've got a ways to go, right? We didn't get any durability data. It wasn't the primary endpoint of the story of the study. So they've got a ways to go. And it's -- for us, it's a small patient population, right? I mean it's not going to take away the major percent of the population because when you sort of look at even if there are 20% or 25% of patients are MRD positive after frontline therapy, half of them get testing and get cema-cel. It's a pretty -- it's not a major drawback for us. So I'm happy for them. I wish them the best of luck, but I don't think this is a threat to ronde-cel.

Okay. One more competitor question.

Okay.

So I know -- so Legend just announced that they're going to be presenting some preliminary data for an in vivo 19/20 product at a medical meeting sometime later this year. I'm sure you're going to get this question asked a lot, if not already. But how do you just think about in vivo CAR-T as an existential threat to autologous and even allogeneic cell therapy within the setting of oncology specifically?

So I -- in vivo is very exciting. It's a new technology. Autologous CAR T cell therapy has been around for a decade plus. We understand it a lot, right? We've worked hard to get this next-generation CAR T cell therapy. So we are very excited about in vivo and interested in it as well. But -- if I were going to say this is threaten ronde-cel, I would say, no, I think it's complementary because the probability, I mean, Legend is going to put out their data. What are they going to have to do to threaten ronde-cel? Three things. They're going to have to put up complete response rates or overall response rates that are 90%, complete response rates that are 76%, which is what we've presented. And more importantly, median duration -- median progression-free survival of 18 months. They just dosed their first patient in the summer, right? So they're not going to be able to have that, plus safety. That's a lot of variables that have to be hit first time up at bat with a very new technology.

So can in vivo get there? Maybe over time, but it's not going to be as soon as maybe people currently think it is. This is a study done in China. It's going to have to be repeated even if it is the be-all, end-all. And so I think where I sort of see in vivo being very important, autologous CAR is the gold standard, right? And these -- our CD19/20, I think, is putting up data best-in-class. And so we believe we're going to be able to improve access because the value proposition for patients and for providers is improving. And then in vivo CAR can expand that access. That's a great thing for patients and the field at large. But do I think in vivo first shot out of the first time up bad is going to replace and threaten autologous CAR, Maybe, but I'd be surprised.

Okay. Maybe in the last few minutes, we can switch gears to 273. So this is the GCC targeting CAR that you in-licensed last year. very unique mechanism of action. Can you explain the rationale for adding a separate CD19 CAR along with the CAR that's targeting GCC that's expressed on tumor cells. What does that buy you from a biological perspective?

Yes. So CAR T cell therapy in solid tumors is hard. A lot of CAR T cell therapies have failed. They may have had a good target, but that was not sufficient. It's necessary but not sufficient. guanylyl cyclase-C or GCC is a great target for metastatic colorectal cancer because it's upregulated in more than 95% of them. But we know a target alone is not sufficient. And the inventor of this CAR realized that there were 2 main barriers that had to be overcome. One is we need more cell expansion. And two is we need some way to make the hostile tumor microenvironment warmer, more friendly to these CAR T cells so they don't just rapidly exhaust and die. And so the concept is there's GCC CAR expressed. This is a dual targeting product and separate, this is a CD19 CAR expressed. And here, what you have is the CD19 CAR is engineered to release cytokines or supportive hormones, you can think of it as. And so CD19, you're going, wow, that's a B cell target. Yes, intentionally, there is 1 day of lymphodepletion. So when this product is infused, B cells remain. The cells hit the B cells, they activate, they release cytokines, this jump-start cell expansion. And in particular, we get nice expansion of these, what we call doublet cells, which have both CD19 and GCC, which can get into the tumor with secretion of cytokines and warm up that tumor microenvironment. And then the largest number of cells are GCC alone, they get in and kill the tumor. And so we've been seeing response rates across 2 dose levels in the 50% range. So it's an active CAR. This novel mechanism, we think, is really something that's not been studied before. It's very unique. It's very next generation. And we think that's why we're seeing the activity that we are.

Okay. I know you've guided to having a couple of incremental clinical updates from this program later this year. What should we be expecting to see in conjunction with each of those disclosures?

So we're in the first half coming soon, we're going to have an update on the program. And a lot of that is going to focus on safety because one of the side effects of this product is some diarrhea. And there was one patient who did get a pretty significant colitis that required some significant immunosuppressive therapy. And the patient actually died from an infection. The colitis was controlled that got a subsequent infection. When he died, he had an autopsy, there was no evidence of disease. Again, this is an active CAR, but we need to show that we can manage the diarrhea. So after this case, a significant prophylactic regimen was put in place with a safety management plan. And so we're going to be updating on the next round of patients that were treated with that safety management plan and to give investors an idea if we can control and manage appropriately the diarrhea. And then in the back half, we'll have a more fulsome update at a medical conference where we'll be giving outcomes data as well.

Okay. You suggested that peak capacity at your facility for ronde-cel, I believe, is around 1,200 doses a year. How do you accommodate 273 into your manufacturing plans? Are you transferring that in? And then what are your options to scale capacity for each of these products?

That's a great question. So we do have our own manufacturing facility. It's state-of-the-art. It's all paperless. We are running right now for ronde-cel, our commercial manufacturing process, and we can manufacture more than 1,200 doses per year, which can get us well into launch. We are transferring in this GCC CAR program. It's very automated. So it's sort of made on the Miltenyrotiggy, and it's quite easy and standard to run. So for the time being, we can do both. And again, we can launch ronde-cel without difficulty.

Over time, we'll need more capacity, more space. But again, that's a great problem for us to have, and it's not a near-term capital requirement. We can get far into launch before we need to go there. And I think we can do both within our facility.

Okay. And then just lastly, speaking of capital requirement, what is the current balance sheet? And what does that allow you to execute on here as you go forward?

So the great news for us is we have, as we've just spoken about some data-rich catalysts coming up here in the next period of time. We have -- as of our Q1 filing, we had $261 million in cash, and that gets us through Q3 of next year and through these catalysts, including the pivotal data.

Right. Well, we're out of time, Lynn. I really appreciate it. That was great. And thanks, everyone, for listening.

All right. Thank you.

Hello, everyone. My name is Mitchell Kapoor. I'm a senior biotech analyst at H.C. Wainwright and the covering analyst for Lyell. Today, I have the pleasure of welcoming Lynn Seely, the CEO of the company.

Today, we're going to have a fireside chat, talk a lot about the CD19/20 space, what they have going on in colorectal cancer and anything else that Lynn thinks would be important to discuss.

So maybe with that, you could just start by giving those who are not up to speed with the story, a brief overview of the company and the current initiatives and maybe just an overview of the data that we've seen so far.

Great. Well, thank you for having me here today. I will be making forward-looking statements for the record, so consult our website and securities filings.

For those who aren't as familiar with Lyell, we are a cell therapy company developing next-generation cell therapies, both for hematologic malignancies as well as for solid tumors. And we have 2 lead programs in the clinic, both targeting large markets. The first is our -- is ronde-cel, our CD19/CD20 dual-targeted CAR, which we're developing really to become the standard of care in the $3 billion CAR T cell CD19 marketplace that's established today in large B-cell lymphoma. And then secondarily, we have a program for metastatic colorectal cancer, which is a very novel CAR, which, we think, is a really, obviously, large market surging in young people. And CAR T cell therapy for young patients is really just a great fit.

So these programs are both in the clinic. The lead ronde-cel is, as I said, a dual-targeting CD19/CD20 CAR T cell therapy. We are currently in 2 pivotal trials. The first is in the third or later line, and this was a program that we presented data on last year at ASH, where we were able to show a 93% overall response rate, a 76% complete response rate and really importantly, a median progression-free survival of 18 months. And these are data that really set the CD19/CD20 apart from the CD19.

Based on this, we have a pivotal trial ongoing, which we call the PiNACLE study, which we expect to have a significant data update in the second half of this year. And then we intend to present the pivotal data next year with BLA submission next year. So this program is barreling forward in the third or later line.

We also have a first-of-its-kind CAR T cell therapy head-to-head trial, which we initiated several months ago, actively enrolling patients, which we think is really -- it's in the second line and is going to just further set this program apart. So we're really excited about the progress we're making in the ronde-cel program.

And then we also have this colorectal program, which is in clinical trials in the U.S. This program was licensed from a company who initially developed it in China, but then brought it to the U.S. and has replicated, to a great extent, the data seen in China in the U.S. And so we're continuing this program forward in a way. It's a very novel CAR. We think something that is potentially transformative for the company.

And then maybe lastly, I'd be remiss if I didn't tell you that Lyell has its own manufacturing center. So this is a state-of-the-art facility where we can launch commercially from this facility and manufacture up to 1,200 doses annually. So it really gets us nicely into launch. So we do have control of our own destiny, which is important.

Excellent. So just starting with ronde-cel, CD19/20 CAR T space. We've got a lot of investor interest in that out of ASH and all the way since. A lot of competitors have emerged. So maybe to set the stage before we jump into a little bit more finer questions is how do you view ronde-cel in the competitive landscape? Of course, one of the things that sticks out to us is the median PFS of 18 months and the geography of where that has been established. But maybe you can just kind of help us understand the competitive differentiation in the emerging class of CD19/20 when, arguably, you're leading the space.

Yes. Well, thank you. It's a big question. So this field is moving rapidly, as people know, and I'm very proud to say Lyell is in the lead. And when we acquired this product at the end of 2024, people weren't even really that confident that the 19/20s were going to be important in the field. And fast forward to the spring of 2025, at the premier lymphoma meetings that are held in Lugano, Switzerland, 3 companies put up data for their CD19/CD20 CARs. There was Lyell, there was Johnson & Johnson, and there was Kite Gilead. And all 3 were showing nice data that appear to be clearly better than the CD19 CARs, which was important.

But what I'd like to say is Lyell has continued to advance forward very rapidly. As I said, we initiated 2 pivotal trials. We selected our recommended pivotal trial dose and have moved rapidly forward presenting at ASH in 2025 this really strong data that I just told you about.

In the meantime, Johnson & Johnson, you may have heard, has just recently stepped out of the CD19/20 race, and we can just talk a little bit about that. So they didn't present any data at ASH 2025, which was surprising -- any clinical data, I should say -- which was surprising to us.

And then Kite Gilead, who's also in this race with a different type of CAR construct, actually discontinued the program that they were initially moving forward with and opted for a different manufacturing process. That set them back. So they're coming, they're still in the race, but with several months, if not a full year or more, behind us.

So I think what I'm very proud of is Lyell has emerged with a strategy that really is putting us in the lead with a very strong program, both with respect to the clinical outcomes that we're observing, the safety profile as well as a very reliable manufacturing process.

Thank you. Yes. Very interesting. And recently, as you mentioned, J&J discontinued its ex vivo CD19/20 CAR T along with its CD19 mono CAR T as well. Just curious what you think that signals for the field, if anything, and maybe help us understand how you view their data. I think it was generated in China. They had a 5-year median PFS. Anything that we can learn from a competitive lens that frames where ronde-cel operates today and if that has any signal for the class in general?

Sure. I think there's a lot of important messages there. The first thing I would say is this is great news for Lyell. And I think it just takes out a competitor, which is always important, obviously, not only for the recruitment time lines and clinical trials, but more importantly, for the commercial marketplace.

And so the big question is, why did they drop out? Did they have some big strategic insight into the way the market was developing? Or I would put forth, quite frankly, I'm very proud of Lyell's strategy, right? We moved, we moved aggressively. We picked our dose. They were having a hard time finding their dose. If you look back at the data they initially presented, they had -- they looked at 150 million cell dose. They looked at a 75 million cell dose, and it wasn't quite clear what direction they were going. They didn't present any new clinical data at ASH, which was surprising.

In the meantime, we barreled forward. And so if you think about a company like J&J, if they're not going to be first-in-class with a large market, they're generally not one to play. And it's possible that Lyell beat them, and they didn't want to be third after Lyell and Kite Gilead. And it's also important to note that the constructs between the 2 programs were highly similar. Prizlon-cel or the J&J product originated in China from a company called AbelZeta that began developing this after the originator of the Lyell product, Yvonne Chen, patented and published her data and her structure. And then they came out with this data from China, which was very compelling. AbelZeta came out with this data from China that was very compelling.

One of the lessons that's very important to appreciate is that in lymphoma and, of course, other cancers as well, who you enroll in your patients, what the demographics and the disease characteristics are do impact outcomes substantially. And so in that trial initially done in China, if you look at it carefully, the median age of patients was 55. Well, large B-cell lymphoma is a disease of the elderly. If you look at the median age in our trials, the median age is 65, a decade later, with 20% of patients over the age of 75. So that was surprising.

The other thing that was surprising, if you look at something like performance status, the overall health of the patient, it's captured in something called the ECOG performance status. About 65% of their patients were normal. You might see only 30% of patients having 70% being elevated or decreased performance status in the [indiscernible].

So those are sorts of things that would impact the outcome. So I think at this point in time, what I'm really proud of is that, I think Lyell is moving forward. We've been moving forward consistently with the same dose treating patients. Our data have been consistent over time. And we're really looking forward to providing a significant data update on this program, data from the pivotal trial in the third or later line in the second half of this year.

Great. Yes. And I'm just going to maybe jump around and talk us a little bit because it's related. But with Kite, you mentioned so with J&J, one interpretation could be that maybe potentially you were beating them on durability and other metrics and that they decided, hey, we're not going to compete. Do you -- is that what you think happened with Kite as well when they move from 363 to 753? What is your interpretation of them stepping back from 363?

Well, obviously, we don't know what goes on inside of companies, but taking a careful look at the data they presented at the Switzerland Lugano lymphoma meetings, they had a 46% rate of Grade 1 or 2 ICANS. That means about half of their patients were developing ICANS, which is not a great product profile. And if you think about the problems they're having with YESCARTA to date with their neurotoxicity, they probably didn't want to get into that same situation. So they moved to a different manufacturing process, I have to suspect, obviously, I don't know, to get that ICANS rate lower.

What we do know about their construct is it's very different from ours. We have a single CAR express that binds both CD19 and CD20. So it's in a single CAR, and it's full potency at either CD19 or CD20. They express 2 CARs on T cells. And so one is YESCARTA and the other is CD20. And so these are going to be a test of which is better, a bicistronic CAR or a very well-designed full-potent tandem CAR. And so we'll see. But I have -- that's what they're moving forward now.

Great. Okay. And then so on J&J's construct that has been discontinued prizlon-cel. That was a potential benchmark for durability. I think it was up in the air for folks since the data hadn't been replicated yet. But now that, that's not even really a question, what do you view -- who do you view as the main competitor? And what do you think the right bar is in third line, I guess, to start off since that is where most, I think, will start as kind of the later line setting for J&J?

Yes. So I think the bar is our key competitors which are Breyanzi and YESCARTA. Our objective and from day 1 has been to bring next-generation CAR for large B-cell lymphoma. And the first generations were transformative, but now we're ready for the next step, right? And so we really are looking to replace them. And so what is the bar, they set, in the third or later line. They have about 70% overall response rate, 50% complete response rate and 6 to 7 months median progression-free survival.

We're coming with a 93% of our response rate, 76% complete response rate with a median progression-free survival of 18 months. So substantially not -- I mean it's clear data. It's not -- you don't have to wonder about is that really better. That's pretty clear.

With a safety profile where we have seen no Grade 3 or higher cytokine release syndrome in our program and that our ICANS rate that we reported at ASH is less than 5%. So a very nice product profile appropriate for outpatient administration.

Great. Okay. And then for Kite's newer construct, 753, obviously, they took a step back and it's going to take them a while to show durability. But the durability on the first construct was okay. And they didn't have mPFS yet, and you all do. So you're still in the lead, and now you're in the lead by a larger margin.

But if they continue to show, let's say, similar early CRs and durability of those CRs, do you view them as a competitor? Or do you think that lead is very important? How do you see them as a competitor? Obviously, YESCARTA, Breyanzi, definitely you're -- I think it's -- a lot of folks feel like the CD19/20s are trumping those at this point. But how do you view these emerging?

Well, I mean, first of all, I think it's very validating that somebody who's in the space also agrees that the CD19/20s are going to replace YESCARTA and Breyanzi. I think, of course, they will be a competitor. But one of the things that, I think, we have done and done very well is we've got this third-line program that we're taking for approval. And remember, the primary endpoint of that study is overall response rate. And I just told you our overall response rate is 93%. So that bodes very well for us to getting approval.

And getting out first and replacing the CD19 CARs is very important to us. We -- because think about it, we know these physicians. CAR T cell prescribers are very much data-driven. They will switch products based on better safety or better efficacy, and we intend to bring both. So if we can get them to switch to us, then whoever comes second is going to have to supplant us, but there's not very much headroom left, right? The efficacy is already very good. The safety is already very good. So to be better is going to be hard. So being first is actually, I believe, in this particular situation, quite important.

And then the other thing we've done is we have a very elegant design for a head-to-head study, which they are not matching. And I think I heard from many, many of the investigators and leaders in the space that they really like our head-to-head study design because we allow a real-world investigator's choice that physicians are able to select either YESCARTA or Breyanzi as the comparator, whereas in the Kite study, they're only comparing against YESCARTA.

Okay. Wonderful. And I think the final competitor that I have yet to bring up, it's much earlier, but people are really interested in this. In vivo CD19/20 CAR T Legend has a construct, and we may hear more. We're going to hear more soon at a major medical meeting midyear.

How do you view in vivo versus your ex vivo approach? And obviously, all the things we talked about, the little headroom to beat where you're at. Some folks say, with in vivo, there may be an off-the-shelf approach and you can maybe be a little bit more equivalent or the bar is a little lower for them. Wondering how you view in vivo broadly versus ronde-cel?

Sure. So the field is very excited about in vivo CAR, as are we, right? This is an exciting new technology. But as you pointed out, it's very early. And so what is in vivo CAR going to have to bring to the table to be a threat to ronde-cel, right?

And so 3 things. It's got to have the same CR rates; it's got to have durability; and its safety. So you have to assume that the very first CD19/20 in vivo CAR is going to come out with all 3 of those variables on par at first shot to be a threat to ronde-cel. And while that might happen, I think the probability is it's going to take a while, right?

And in the meantime, the Legend program, which is coming out, we're all looking forward to seeing the data, is being developed in China. So they're going to have to repeat that, right? And durability, as we know, takes some time. I've just told you our median progression-free survival is 18 months. So we feel very confident in our position with ronde-cel. We believe that autologous CAR is the standard of care and will continue for CAR T cell therapy.

Where in vivo is exciting, as you say, it can broaden access, right, that it can be available for patients who can't get the standard of care, but in terms of a threat to ronde-cel, it's going to take some time, and I think we're in a great position.

And I would also say that we believe we're going to be able to improve access with ronde-cel. And I say that because the value proposition is changing. If you think about it, the safety profile is much better. So you can be treated as an outpatient. It's much easier for community hospitals or centers to manage. Number two is the benefit is better. So before you -- in the third line, for example, you had a flip of a coin, 50% chance of going into remission. Now we're saying 75%, right, much higher. And so with that value proposition for patients and for providers, I think that's also going to help with the access for autologous CAR.

Great. Okay. And so moving from third line to second line, you have the head-to-head trial, which is super important. As you mentioned, it's DLBCLs. It's very hard to compare cross trial because of the patient characteristics. What result would be sufficient? What result would be positive? Help us walk through the scenarios. And I think the obvious answer is just beating the competitor, right? But if you beat just by like 1% CR, it's not -- is it a big deal, right? Because safety is better. Like walk through maybe some scenarios how we should interpret second line.

Well, this is the gold, gold standard randomized controlled superiority trial. So the p-value is going to determine success, right? It's a benefit that, I think, we're going to be randomizing patients. They're going to be apples-to-apples with stratified for risk. And so that if we show better event-free survival, which is the primary endpoint that's statistically significant, that's going to be absolutely fantastic and sufficient and something that we think is very probable based upon the data that we have observed to date.

And then there is safety, right? Because remember, physicians, these prescribers make decisions not only on the efficacy benefit, which is the most important, but also on the safety profile. So we have 2 opportunities really to demonstrate the full potential of our product.

Great. Okay. And from -- when we're thinking about the second-line opportunity versus the third-line opportunity, I think it would be helpful for the audience to understand how do you view the third line and the second line in terms of contribution to the commercial opportunity for Lyell. I think some folks previously had thought, like, well, they need to get to second line, right? So help us understand, what if it's a third-line therapy and that's all you're pursuing? And what's the additional benefit of getting into second line? How do we think about that?

We think this is something that a lot of people are missing. And we know from series that have been published at Memorial Sloan Kettering from our own experience, from claims data, that more than 50% of patients have already experienced 2 lines of chemotherapy before they undergo apheresis. And so we know that the intent of CAR is cure. And so if you're not getting cured by that second line, meaning going into complete response or a very good partial response, that is, in essence, an on-label third-line patient.

So we think that there are 6,000 to 7,000 patients eligible for CAR in the third line. Being first with this third line with the BLA submission expected next year, we think this is a substantial opportunity for us. And then remember, our footprint for our head-to-head trial, we've got sites all over the country enrolling patients on to ronde-cel and get experience with the product now as we're recruiting this head-to-head trial. So we think this combination, this strategy bodes very well for the launch of this product.

Could you also help just clarify that third line? Like who are those third-line patients? Sometimes physicians don't even realize right now that maybe they have a third-line patient and it's a second-line patient. We had discussed a little bit about that, but that was super interesting to me. I think we could share with the audience so they can understand that this is maybe even bigger opportunity.

Yes. So doctors don't count lines right now. CARs are approved in both the second and the third lines. And so NCCN guidelines say, give CAR in the second line. So there is intention to treat in the second line. But what happens is if you're in the community and you progress on frontline therapy, about 50% of the time or more, you get started on another line of chemotherapy as you get referred in and get that medical appointment for apheresis. And so that's the second line. If you don't have a CR to that, if you don't have a very good partial response to that, you're a third-line patient. And so that's what we're seeing. And so that's why we know that the potential market for this is much bigger than many people expect.

Excellent. Okay. And last on ronde-cel before we move on. Can you help us understand where the CD62L enrichment is doing the work and just a little bit of the differentiation of the construct?

Yes. This is very much our secret sauce, and I think this is something we do during manufacturing. It's a very short cell selection process where we are enriching our product for naive, more fit central memory and naive T cells, which really have multiple purposes, but I like to think of it primarily is giving that duration of response. They persist. They don't get exhausted and die off as quickly as those more differentiated cells do. And then, of course, it also helps with what we call the softer safety profile.

Okay. Great. And then moving to CRC. LYL-273 is showing activity that's really unprecedented for cell therapy in solid tumors. What gives you the most confidence that the signal that we've seen so far is real and reproducible as a solid tumor CAR T? And just help us understand how beneficial the data look in later-line colorectal cancer where the options are so low.

Yes. The options are really sad, quite frankly. They're sort of frontline therapy and then a whole bunch of stuff that doesn't work, quite frankly, or doesn't work well. And I think what we're seeing is an active CAR T cell therapy for metastatic colorectal cancer. Why can I say that? Because we're seeing patients having responses and even patients with -- we have a patient, for example, that we've presented data publicly with that is now 2 years out from her CAR T cell therapy, ctDNA-negative, right? So no evidence of disease at this point. So we're seeing very nice response rates. We know it's an active CAR. And so the onus is on us now [ is ] to move the development forward as quickly as we can.

And so why am I confident? Because this CAR design answers a couple of the key barriers in solid tumor, right? One is the fact that we get the cell expansion that we need because we have partnered our CAR with CD19 CAR, which is a really unusual novel design, which helps get that cell expansion that we need to get the GCC CARs into that hostile tumor microenvironment.

And then the other thing we've done is engineer the CD19 CAR to release cytokines or these, sort of, supportive hormones, basically, is a simple way to think about these cytokines, that they actually open up the hostile tumor microenvironment by supporting these CARs inside the tumor and allowing them to expand and kill. So it is this novel mechanism, coupled with the activity that we're seeing in patients in the U.S. that is giving us that confidence.

Excellent. We've covered a lot of ground today. I think, to close, I would love to have you recap the catalysts ahead. I think this is truly an eventful year for the company. So maybe help us set the stage for those who now have Lyell on their watch list for 2026 and 2027.

Thank you. No, we're super excited about the upcoming time frame. We really think we're in a great position to have tremendous value creation. We have a substantial update on the pivotal trial in third-line PiNACLE coming in the second half of this year, which is, I think, going to be an important update. We have the pivotal data coming next year as well as BLA submission from that program. And then in the colorectal program, there's going to be 2 updates. The first, in the first half coming soon, is going to be a safety update, largely to show that not only do we have an active CAR that we can treat these patients with a good safety profile. And then in the back half of the year, a presentation at a medical conference we hope where we can have more broader clinical outcomes as well.

Excellent. Thank you so much, Lynn. Thank you to the Lyell team, and thank you to all the investors that joined us today.

Thanks, Mitchell.

Good morning, everyone, and thank you for joining us at the second day of the Needham Healthcare Conference. My name is Gil Blum, and I'm a senior biotech analyst here at Needham & Company, and I cover the cell and gene therapy space. It is my pleasure to have with me today, Lynn Seely, the CEO of Lyell Biopharma or is it Immunopharma now?

Immunopharma.

Immunopharma, to discuss their very exciting programs, specifically in the CAR-T space. Very happy to have you here, Lynn. It's good to continue to see some efforts in this space despite certain investor sentiment. So maybe just starting with a broad overview of the company and its lead assets.

Sure. Well, thank you, Gil, for inviting me. And yes, I think investor sentiment is clearly changing in the CAR T cell therapy space. For those of you who don't know Lyell, Lyell Immunopharma is a late clinical stage cell therapy company, really focused on bringing next-generation cell therapies to patients, both with hematologic malignancies as well as solid tumors.

And we have 2 programs in clinical development for large markets. The first is ronde-cel. This is a dual targeting CD19, CD20 CAR T cell therapy, which we have really designed to replace the CD19 CAR T cell therapies. We know this is an established $3 billion marketplace, but it needs better therapies. And ronde-cel has been very rationally designed to bring higher and more durable lasting complete responses. So we are currently in 2 pivotal trials for ronde-cel. One is a single-arm fast to approval study in the third-line setting. And the other is a first of its kind head-to-head randomized Phase III CAR T cell therapy trial of ronde-cel versus investigator's choice of 1 of the 2 leading CAR T cell, CD19 CAR T cell therapies.

So these programs are well underway, and we're very excited about that. And then in addition, we have a very novel next-generation CAR T cell therapy for metastatic colorectal cancer. And this is a program that is in Phase I dose escalation in the United States, but it's based on a program invented in China that has already shown very nice clinical activity, both in China and in the U.S. So I'm excited to tell you about both of those. And then lastly, one thing that you should know about Lyell is that we have our own manufacturing center that is capable of commercial launch. And so we are, as we speak, manufacturing with our commercial manufacturing process for ronde-cel. So in many ways, we're very fortunate to control our own destiny when it comes to manufacturing.

Excellent. So let's start with ronde-cel. A first look as it relates to -- how do you feel it's differentiated from the standard of care CAR-Ts?

Yes. So it was designed very rationally from the beginning to be differentiated and to bring a new value proposition for patients over and above the CD19 CARs. And so the first feature of ronde-cel that really differentiates it is the fact that it has 2 targets instead of just one. So it has CD19 and it has CD19 at full potency, but it also has CD20. So it's designed as this tandem CAR to have full potency at either CD19 or CD20. And this is important for 2 reasons.

First, it kind of makes sense that if you're targeting 2 antigens, you can drive more complete responses. And that's because some malignant B cells have low or no CD19 and might not respond to the current CD19 CARs, but they do have CD20 and so would respond to a dual targeting 19/20 CAR. In addition, one of the key mechanisms of escape from CAR T cell therapy is, in fact, antigen loss. So these malignant cancer cells can drop an antigen like CD19, but it's much more difficult for them to drop 2 antigens and sort of escape the benefit of a dual targeted CAR. But that's not all.

So in addition, our CAR is differentiated because we have a very special manufacturing process where we enrich for naive and central memory T cells. These are -- we call them more fit T cells so that they basically can persist longer, have a little softer adverse profile and actually expand quite nicely. So the combination of this dual targeting and the fact that we have more naive T cells in our cell product, we think, is a very important combination to bring the outcomes that we're seeing with ronde-cel.

One really important aspect of your development program is this really aggressive head-to-head study where you're pitting CAR-Ts against each other. I think this is the first such study in this space. What makes you confident that you can outperform on efficacy of the existing standard of care CAR-T, specifically Breyanzi, that has some like pretty decent long-term follow-up.

So it is a bold strategy, and it's a bold strategy, which suggests we are very confident. And traditionally, in development, you're not -- you're taught not to run head-to-head studies. But in this case, it's the right study to do. And it's for several reasons. And first and foremost, we're developing products for patients. And if we expect physicians to change their prescribing behavior from CD19 to 19/20s, and we believe this is the next-generation CAR T cell therapy, we need to provide the data to support that.

And we do believe this is the next generation. We do believe the data are better. And so as always, we are very science-driven. So we understand the biology here and the mechanism as we just talked about. So it makes intuitive sense biologically that a 19/20 could drive more complete responses with longer duration of response. And then we've generated data. And this product, we presented data in an oral presentation at ASH last year in the third and later line setting, where we've shown 93% overall response rate, 76% complete response rate and very importantly, a median progression-free survival of 18 months, data which are significantly improved compared to the third-line data from the CD19 CAR.

So that's the first set of data. We've also presented data in the second line in a very difficult-to-treat patient population. Patients who have failed even frontline chemotherapy. So they never even responded to chemotherapy. These are primary refractory patients. And there, again, we're seeing very nice complete response rates and duration of response, better significantly than what has been presented or published for the CD19 CARs.

So when we put this data together, we feel very confident in our design of this head-to-head study. And I think we're looking to bring value to patients not only in outcomes, better complete response, longer duration of response, better event-free survival and also the safety profile. And so I think we know that the currently approved CD19 CARs have some neurotoxicity. They have some Grade 3 or higher CRS, and we're looking to bring a better safety profile as well to allow for more outpatient administration.

So would you say that copying is a form of flattery? What are your views on the announced head-to-head study that's pitting Kite's own dual targeting CAR-T 753 versus their own YESCARTA? And do you feel this complicates the therapeutic landscape in the second line?

I feel like at Lyell, we are leading with ronde-cel, and we, more than a year ago, started this trial. We are currently well underway in dosing patients as we speak. So this is something that we have been working on for quite some time leading the field. And so of course, if you have this beautiful study design, others may have to copy, and it sounds like Kite Gilead is beginning to work on their trial.

But again, they're substantially behind and being first matters in this space. And I think being able to bring out our data and to get there first with our single-arm pivotal trial, we hope to be the first CD19, CD20 CAR T cell therapy approved gives us a substantial advantage because with the safety data that we're showing to date and the outcomes, we think we have a really nice opportunity to supplant the currently approved CD19 CARs. But then it's going to take a lot to supplant the data that we're bringing because there's not much room left in terms of efficacy or safety benefit.

Maybe a more pointed question there. I mean taking of the details matter. You guys' control arm is both assets, while Kite is going to just go against their own YESCARTA, which we already have an idea, has some issues. So I'm just wondering what the therapeutic landscape may look like with kind of like a separate labels and how would physicians and payers navigate that?

Well, I think we designed our study to be as real-world and inclusive as possible. So we know that physicians today are choosing some use Breyanzi, some use YESCARTA, some use both depending upon the patient. And so in our trial, patients come in and then they're either randomized to ronde-cel, our CD19/20 or investigators' choice of either YESCARTA or Breyanzi so that the physician can do what the physician wants to do, and it makes it very real world for them.

And I think so it really will give them the data that they need to make these decisions by looking at both, right? So we believe that we're going to be able to show superiority despite including both products in the control arm. So we think that's a real advantage to our product. And I think complexity, I don't know. I think physicians, we've designed our trial to bring data to the patients and physicians that they're looking for. And we think that, that will be quite clarifying, quite frankly.

And the beauty of the randomized controlled head-to-head trial is that patients are stratified. So we're not going to have to look at cross-trial comparisons. We're not going to have to worry about what was done many years ago. We're going to be able to look at this trial and say, is ronde-cel superior to the approved CD19 CARs or not? And that's what doctors and patients want to know. So it's bold, but it's also the right thing to do.

And when you think about it commercially, it's going to be very easy for take this data out. And you can -- these are data-driven physicians, and they're going to be able to see very clear data or not based upon the superiority of this product. And if we're not superior, we shouldn't be on the market. But we believe that the science and the data clearly indicate that we have a great opportunity here.

I do want to spend a second on the safety profile. This is an important selling point for products and so-called second-gen products in general. So there's no high-grade CRS, but there's still a low level of high-grade ICANS. Is that a barrier for adoption in the community setting? How do physicians treat low incidence of high-grade ICANS?

Yes. So we've seen, as you pointed out, no Grade 3 or higher CRS, cytokine release syndrome in our program. We have seen less than 5% grade 3 or higher ICANS. This is generally short-lived and readily treatable with current standard of treatment. And so I think this is being administered in the outpatient setting today and in our pivotal trials. So we think it's very amenable to outpatient administration.

And I think one thing this is uncommon, right? And I think one of the things that we know is physicians are more and more getting used to things like how to treat and diagnose ICANS as well as CRS. So we don't think this is going to be any barrier to outpatient administration. In fact, it's so low, we think it's going to be a great advantage of our product.

And yes, all patients given CAR T cell therapy need to be monitored certainly in the first couple of weeks after treatment. But again, this is a very, very low incidence. So we think the safety profile is quite favorable versus what we're seeing with CD19 CARs.

You currently allow bridging in your studies. This is not something that was common in many CAR T studies. I think in the past, it was only steroids, at least for a few of these. Any specific comments there? I mean, it feels more real world, I think that's probably the takeaway here.

So that's right. And in the past, different companies have done different things. We feel like allowing bridging therapy is important because we want any patient who's eligible for CAR to be able to come into our study. And some patients are progressing rapidly, right? And they can't wait for CAR manufacturing without, for example, bridging therapy. So by excluding bridging therapy, you're excluding a group of patients that could potentially benefit for the product. So we are allowing bridging therapy in our trial, and we think that's an advantage of the trial design.

I know we did this a little backwards, but going back to your third-line study, what would you say the commercial strategy is here? I mean it's a single-arm accelerated approval study.

I think this third-line study is incredibly important and probably more important than most people realize. And let me tell you why. First of all, the data, which I described to you, but let me do so in a little bit more detail, are quite compelling. I mean we have a 93% overall response rate with a 76% complete response rate. That remission rate or complete response rate compares to 50% complete response rate for the currently approved CD19 CARs.

But more importantly, the median progression-free survival, which is the time at which 50% of patients have progressed or died, in the CD19 CARs is 6 to 7 months. It's 18 months as of our ASH presentation last year. That's a big difference. So we know that the prescribers of CAR T cell therapy, they're very data-driven. And so they may be loyal to CAR and believe in CAR because of its curative intent, but they will change CARs based upon safety or efficacy.

And with ronde-cel, we intend to bring both, okay? So we want to get into this marketplace as fast as possible and begin this process of switching from the CD19 CARs. And it turns out that in the third or later line, which is what our first approval is planned to be in is a much larger market than people think, we believe.

And the reason I say that is because we know from a series from Memorial Sloan Kettering that patients who undergo apheresis. So 50% of patients who undergo apheresis for CAR have already seen 2 regimens of chemotherapy. Now physicians may count lines a little bit differently, but really, it's 2 lines of chemotherapy. This could be a third-line patient if you are counting on label for our approved 19/20.

So we think this is a 6,000 to 7,000 patient market opportunity, which is very important and will allow us to get this strong foothold. And so commercially being first, which we're currently in the lead in this space is really important for us, and we think gives us this commercial advantage because once we get there, what are you going to bring to switch us out? I mean the primary endpoint of this trial is overall response rate. We're sort of sitting at north of 90%. That's going to be hard to make a meaningful benefit over.

So one of the challenges, and this is easily figured out is that there are quite a few patients who are theoretically eligible for CAR-Ts. But if you only look at the label, it's much, much, much narrower than that. How do you bridge this gap as it relates to patients who should be eligible but are currently not receiving therapy?

Yes. That's -- I mean it's a great question. And the field has changed a lot, right? It used to be we talked about transplant eligible and transplant ineligible. Those days are kind of gone, right? And one of the things that Lyell we're doing with ronde-cel is we don't have any upper age limit. So you can -- we've successfully treated 85, 87 year olds. And this is important in large B-cell lymphoma because these patients have a median age of 65.

That means there are a lot of patients older than 65 who need this treatment. We want to make it as available as we can. So for example, in our head-to-head trial, we're taking patients of any age who have primary refractory disease, early relapsed disease, late relapsed disease, if you have bridging therapy or not bridging therapy. So we're really trying to give this a broad label. So if you're eligible for CAR, you can sort of be on label is sort of our ultimate goal.

And just to remind everyone kind of the time lines as it relates to data disclosures from the pivotal study and when its final readout is expected.

Yes. So the third later line study, we call it PINACLE, we're going to be having a significant data update in the second half of this year, which will really be the last look at the data before the pivotal trial data comes. So we think is a real opportunity to get a good look at what it will be.

And then the data, the pivotal data itself, the data we'll use for BLA submission will be available expectation is mid next year, so coming very soon and then with the BLA submission to follow next year. So this is upon us. We're super excited. And we think this is a really meaningful commercial opportunity, which is going to give us every opportunity to be first-in-class, which we think is going to be a big deal in this marketplace.

So I want to touch on other competitive dynamics, recent readout just yesterday from Allogene in the frontline setting consolidation, really interesting idea where you can use an allogeneic CAR-T for a mop-up. My question is, does this like -- let's say it's approved, this consolidation. Does this change the type of patients that might come down and receive your product?

Yes. So you're referring to the data put out by Allogene yesterday with their product, cema-cel, which they're evaluating this consolidation therapy after frontline therapy in MRD-positive patients, right? And so first and foremost, I'm always pleased to see a cell therapy company have positive data. So that's great for the field.

And hopefully, at some point, will be great for patients. I think what we have to look at, this was a futility analysis. So the goal was to say whether or not the company should continue to enroll patients. It wasn't an efficacy analysis. It wasn't the primary endpoint of the study. So it's early days, right? So I think there is some encouraging MRD positivity data, some safety data, but we're going to have to see how that translates in durability into the primary endpoint, which is a change in event-free -- benefit to event-free survival.

At Lyell, we are full-on believers in autologous CAR T cell therapy. This has the potential for curative intent. We already have data showing that we have better complete responses and have median progression-free survival that have been seen with the CD19 CARs. And so we are barreling forward. I mean I think this idea, there's a long road to go to get, first of all, to the efficacy analysis for new allogeneic treatments, then we have to get MRD testing done. We have to change the practice, get consolidation therapy and sort of embedded into the community practice.

And quite frankly, it's still a relatively small segment of the overall large B-cell lymphoma population, right? It's patients who are MRD positive with response after their first-line therapy. Maybe it's -- we don't know they didn't say, but maybe it's 20%, 25% of patients, maybe optimistically half of those are going to get MRD testing. It's going to end up being maybe 12.5% of the patient population. We're not worried about it.

I think the benefit of autologous is still very real. And if Allogene is available to increase accessibility of cell therapy for patients, that's a good thing. We don't think that in any way changes the outcome for ronde-cel.

Great. Maybe a more real topic because this is further down the line. We've talked to a lot of physicians over time, specifically on T cell engagers, which have been kind of positioned in late-stage patients. Everyone kind of expects these to move forward. They've had some challenges, but I think it's a bit of a matter of time. How do you think that changes the type of patient that you get at later line?

Yes. So it's -- Gil always asked the hard question. So bispecifics are here. They are being evaluated in the front line. And I think I'm always very focused on patients, right? What's in the best interest of patients. And I think what patients typically want and that we hear consistently is a onetime treatment that gets them back to their normal lives with disease-free treatment-free periods.

And that's exactly what CAR T cell therapy is designed to do. That's not what bispecific therapy does. Now there's a role for bispecifics, absolutely. But I think many people who know the most about CAR T cell therapy and bispecifics believe, quite frankly, that CAR T cell therapy -- that bispecifics may harm actually the benefit of CAR T cell therapy, and it may be in the patient's best interest to get CAR T cell therapy before bispecifics.

And so yes, they may add some benefit in the front line, but the current chemotherapies work quite well. And it may be better actually to use bispecifics after CAR T cell therapy. So this is going to be evolving over time. The bispecifics are here, I agree. But I think in no way, I've been able to show the sorts of data that, for example, ronde-cel is showing. So the onus is on us is to get our trial data out there and completed so that patients can see the choice that they have.

So just focusing for a second on manufacturing before we shift to solid tumors. Just how scalable is ronde-cel manufacturing? And what level of capital investment are you guys putting in? And also, how should we think about margins because most cell therapies in the beginning are negative margins?

So great question. So Lyell is quite unusual here in the sense that we have already invested years ago in building a commercial manufacturing center. And so that sort of some cause. We have now control of our own destiny. This manufacturing center is staffed with people highly experienced in cell therapy manufacturing.

And we are running today our commercial manufacturing process for ronde-cel. We're capable of commercial launch, well into commercial launch. We can make more than 1,200 doses per year at that facility. So we are in a very good position to control our own destiny. We're currently making all of our clinical trial material there, and then we'll continue on into commercial launch. Our process is very reliable and robust. We have more than a 95% success rate.

It's a simple process. The vein to site time is 16 days, which is quite competitive with Kite, Gilead and better, quite frankly, than BMS. And the process is simple. So fortunately, for us, the cost of goods is very reasonable, and it will only get better over time, but we're estimating something like 20% of overall for cost of goods. So we're in a very good position for manufacturing. And again, I have -- it's tremendously grateful for the manufacturing team that we have at Lyell.

Great. I do want to spend some time here on the LYL273 program. It's a very interesting program. Maybe just start with the unique mechanism of action for this particular CAR-T.

Yes. So we've talked a lot about ronde-cel, which is sort of our late stage on the way to pivotal and I think is really our lead program. But now we have this very potentially transformative program coming up behind, which is in the clinic, and we call it LYL273. It's a guanylyl cyclase-C targeted CAR with a novel mechanism, which Gil is alluding to.

GCC is expressed on more than 95% of colorectal cancers in the metastases. So very highly expressed. So we don't need a biomarker for this. And also, a lot of people don't know, it's expressed on the majority of pancreatic cancer. So it's a really great target. But cell therapy for solid tumors had kind of a rough road and just a great target alone is sort of not sufficient. And this was invented in China and the thinking was a target is not enough. You have to couple that CAR with something else to overcome some of the barriers we've seen.

And the biggest barrier in solid tumor is to get enough cell expansion to allow the CAR T cells to infiltrate into the cancer. And these cancers are oftentimes very cold. So you also have to flip the hostile tumor microenvironment. You have to warm it up, so to speak. So here's the concept. This GCC targeted CAR, which is a great colorectal target is coupled with CD19.

Well, that's unusual, right? Because that's a B-cell target. But what happens is these CD19 CARs are also engineered to release cytokines. So as you infuse these cells into patients, the CD19 CARs get activated when they hit the B cell, start to release cytokines. There are these very special doublet cells, which have both CD19 and GCC CARs, which then expand and release cytokines.

These can now -- these increased cell numbers can infiltrate into the tumor, continue to release cytokines and help warm up this hostile tumor microenvironment. And then, of course, the GCC CARs expand and persist over a very long period of time. And so together, this is giving us a window, I think, into how to treat solid tumors large. It gives us this opportunity to get the right cell expansion.

And with this very specific cytokine secretion, help get a better immune response in the solid tumor itself. So it's a novel mechanism. Fortunately, the manufacturing is quite straightforward. And the bottom line is this is in Phase I study in the U.S., and we're seeing very nice clinical activity.

So maybe a bit of a general question here. One of the off-tumor on-target effects is B-cell aplasia. Do you expect any pushback from the agency as it relates to elimination of a cell population and a sick individual, but that's not the target cell.

Yes. And that's a fair comment. But as you know, these patients have a life expectancy of 12 months or less. These patients are dying. The B cell, it is a true statement that the B cell does get targeted, but it's very short-lived. And so maybe a month or so in duration, they start to repopulate relatively quickly.

So there's almost like the CD19 spike in cell expansion in the CAR T cells and then it tends to dwindle away and the B cells repopulate. So we haven't seen any pushback or issues with B-cell aplasia because it's relatively short-lived.

And also a related question, GCC targeting has been attempted. It's not easy. There's some expression in the gut, which leads to diarrhea, can be severe. I know you guys have seen some of that in your own studies. Can you walk us through some of the mitigation strategies there?

Yes. So that is absolutely a fair comment. So GCC tends to be overexpressed in cancer cells that is expressed at low levels in normal gut. So this is a potential on tumor -- on-target off-tumor toxicity that we have to be very careful about. And we have seen some GI toxicity.

So what's been implemented into the program is a quite robust prophylactic regimen as well as a very standard treatment management plan to work with that. And when we brought on this program at the end of last year, we presented data in about 12 patients. We -- that prophylactic regimen had just been sort of implemented. And we sort of said that since then, we've enrolled another 7 patients, including escalation to dose level 3 without any dose-limiting toxicity.

So that at least gives you an idea that the program is continuing and that the diarrhea is being managed. So -- but this is a side effect to watch. It's one of the reasons we said we're going to be doing a safety update in the first half to really let people know how that safety management plan is working.

Great. And just to remind our viewers what the efficacy data looks like in the first couple of cohorts and how does that compare to existing standard of care or even emerging therapies?

Yes. So maybe I'll start with emerging therapies, which unfortunately are not what we might hope for, for the patients. And I would say, in particular, because this is a disease that is surging in younger people, and we're seeing patients more and more frequently in their 40s, 30s. I mean it's very -- it's a devastating disease.

And so one might imagine CAR T cell therapy, a one-and-done treatment for these -- particularly these younger patients are incredibly important so they can get back to their families, their work. The current therapies that are approved in the third or later line for metastatic colorectal cancer, which is what we're currently studying, have single-digit response rates like 6% or less. The median progression-free survival is 6 months or less and the median overall survival is less than 12 months. So we need better therapies.

The bar for a response rate for this CAR T cell therapy is anything 20% above could be approvable without -- much above a 6-month PFS, I mean, very honestly. So anything more than that is, of course, even better. I would say what have we seen so far? So the -- I think I mentioned that this product was invented in China. They ran a single center study in China, which was published in JAMA Oncology, where they studied it in Chinese patients and showed a 40% overall response rate and a 25-month or a 2-year median overall survival.

They saw such promising results that the company brought the product to the U.S. They got an IND approved as they set up manufacturing, and they got some premier medical centers to participate with them, Dana-Farber Cancer Institute, the University of California, San Francisco, City of Hope and the University of Colorado. And have -- at the time we last presented data, we had 12 patients, 6 at dose level 1 and 6 at dose level 2.

And across the 2 dose levels saw about a 50% overall response rate with some really 1 patient in particular with a partial response -- 100% partial response that is now getting close to 2 years out from her initial treatment. So an active CAR, the -- I think we are continuing to optimize dose and regimen. And then, of course, it's coming on us to manage the safety profile. And I think if we can do those things, this can move quite quickly simply because, as I said, there's so little for these patients.

So let's talk about what guidance you can provide as it relates to the data disclosures upcoming in this program.

Yes. So we have 2 data disclosures this year. The first, we said will be sort of a company announcement. I mean we just got this at the end of the last year. So there really wasn't time for major medical meetings in the first half, but we did want to update on how that safety management plan is working. So it will largely be a safety update. But then in the back half of the year, we intend hopefully to have a presentation at a major medical meeting where we can show more outcomes.

Sounds very exciting. Maybe ESMO? Maybe.

Always fishing for information, Gil. But I think, again, this program can move quite rapidly. And our goal is to get the data we need to move it to the regulators to talk about what a pivotal trial might look like.

And maybe kind of the last comment as it relates to emerging therapeutics. We saw some interesting data on ADCs and others. There is a sense that there's maybe a cutoff at about 30% response rates. But given this is a CAR-T, what we should really be looking for is probably long-term efficacy. Would you agree on that point?

So I think the good news about response rates is typically because they drop disease burden, they tend to also prolong outcomes for patients. And I think it would be great to see nice response rates because that's something that, of course, is very helpful for patients. And also, it makes it easier on clinical trial design. So I think the fact that we're seeing response rates is something that is very helpful to us.

And then I think right now, the best drug approved has in the third or later line has a median progression-free survival of 6 months. So yes, we need something longer than that. And the longer, the better for patients, no question about it. So I think that's what the agency -- if we can see some meaningful response rates that have some durability, which, as I said, we've already got patients that are showing that, then I think that can be very helpful to us. But the data needs to mature for sure.

Last couple of points, cash runway, cash position.

Yes. So as of our last Q, we had $247 million or this I should say, as of our 10-K. We took a second tranche of $100 million private placement we had of $50 million. So that gives us a cash runway well into Q2 next year.

And kind of as the last one, anything you would like to highlight as it relates to what you think investors are missing in the story or just open-ended?

Yes. I would say, I think the most important thing investors are missing is that ronde-cel is in the lead for the next-generation CD19/20 class with a third or later line approval that is coming very soon. And I think what they're missing is this is a much bigger market potential than people appreciate because of this fact that even despite how lines are counted, 50% of patients have received 2 regimens of chemotherapy before they undergo apheresis for CAR.

And so that's a really important point. We think there's a significant number of patients out there, and it allows us to be first and get this stronghold as the next-generation CD19/20, then it's going to be much harder to replace us because of the data set that we're bringing. So we think this third-line lead that we have is really important and that we are looking forward to executing on that.

Thank you very much for attending today.

Well, thanks for having me. I really appreciate it.

All right. So we'll go ahead and get started. Thank you all for attending, and good morning, still about 5 minutes away from afternoon. But welcome to the inaugural Citizens Life Science Conference, inaugural because it's here in Miami. And it's my pleasure to introduce the next presenting company, Lyell Immunotherapeutics and so Immunopharma. Presenting for the company is Lynn Seely.

So this is a very unique story. We actually initiated on the company on Monday. We have an outperform on the name. The data has been spectacular in our view. And so Lynn is going to talk to us a little bit about that. We'll dig into some of the details there. But I always like to start off our conversations. I never know who's listening on the webcast, who's in the audience who might or may not know the story. Can you just give us an overview in 2 to 4 minutes about the Lyell Immunopharma story?

Sure. I'd be delighted to, and thanks for having me in this beautiful spot. So Lyell Immunopharma is a cell therapy company. We're focused on developing first-in-class next-generation cell therapies, both for patients with hematologic malignancies where CAR T-cell therapy is well established and also for patients with solid tumors.

Lyell has 2 clinical programs, each focused on large multibillion-dollar marketplaces. The first we have is a dual-targeting CD19/CD20 product we call ronde-cel. It's in development for patients with large B-cell lymphoma. And it was designed very specifically to bring more complete responses and longer duration of complete responses based upon its dual-targeting mechanism, which is sort of obvious and then also because it has a very special manufacturing process where we specifically enrich our product for patients with more fit naive T cells that have more ability to persist and kill cancer cells for longer.

So that's ronde-cel. It is in 2 pivotal trials as we speak. So we have a single-arm trial in the third or later line patients with large B-cell lymphoma that is well underway, and we'll be having a significant data update in the second half of this year. And then we have a first-of-its-kind head-to-head CAR T cell trial ongoing, which is ronde-cel versus investigator's choice of either the approved products, YESCARTA or Breyanzi. And this gives you some idea of just how confident we are in the performance of this product.

And then there's more. We have our second clinical program, which is called LYL273, and this is a very novel CAR for patients with metastatic colorectal cancer. And I think you all know that metastatic colorectal cancer is surging, particularly in young patients who would really appreciate a onetime treatment that could bring them some meaningful benefit. I think one of the problems with colorectal cancer is that there are really not good therapies for patients who progress after more than 1 or 2 lines of therapy. And so we're in development in a Phase I trial for patients with metastatic colorectal cancer in the third or later line.

This is a really novel CAR design. It was invented in China. There's proof of concept data, clinical data in 15 patients from China, where they saw 40% overall response rate and a median overall survival of 25 months, which really is better than anything that's been seen in approved products to date. This Chinese company brought the product to the U.S., and some premier medical centers have been participating in this Phase I study. Lyell acquired the product at the end of last year and is continuing to develop it. And we're seeing meaningful clinical activity with a manageable safety profile. So we believe this is a really transformative product for the company that we'll be having 2 data updates this year and really an opportunity to move rapidly, we hope to pivotal trial.

Excellent. So let's dive right into it. The third line plus setting in LBCL. This is the PiNACLE study. It's ongoing. You mentioned in your overview that there's a significant data update in the second half of this year. And at least according to our milestones, there's the potential for the final data by the middle of next year. And so can we talk a little bit about this trial design? I believe you mentioned it was single arm. What kind of data -- major data can we get in the second half of this year? And then I guess, also, this trial has been enrolling quite well. Can you tell us a little bit about the enrollment dynamics?

Sure. So just to set the stage, this is what we call our fast to approval strategy. It is a single-arm study. And this is a really elegant design where the Phase I/II clinical trial can seamlessly expand into the pivotal trial. So we've been enrolling patients in this trial for a while now. We presented data at ASH at the end of last year, where we showed a 93% overall response rate and a 76% complete response rate with importantly, a median progression-free survival of 18 months.

And just to talk about how that compares with the market leaders right now in the CD19 space, for large B-cell lymphoma, the market leaders that we intend to displace, they have about a 70% overall response rate, a 50% complete response rate and only a 6- to 7-month median progression-free survival. So this represents really an opportunity to have a significant advantage. And our data all come with a very well-tolerated and manageable safety profile that patients have a cytokine release syndrome rate of 0 for Grade 3 or higher. We've not seen any cases of Grade 3 or higher cytokine release syndrome and less than 5% incidence of Grade 3 or higher ICANS, which is a neurotoxicity syndrome.

So the efficacy and the safety in the third or later line has been looking really good. So as you say, we're going to have a meaningful data update, which is more mature data with more patients in the second half of this year because we're on our way to having the pivotal data set mid next year with a BLA submission to follow.

And so why are we so excited about this? Because the primary endpoint of this trial is overall response rate. And I just told you, we have a 93% overall response rate. So even if there's some attrition over time with more patients, it's still well above the bar, which I just told you the CD19 CAR is set at about 70%.

So we're in a very good position there. We are even adding some new larger centers that are coming online in the first quarter of this year. And so that will even help us bring the trial to completion on track. So we're really pleased with this.

And I think the one thing about the third or later line that a lot of people don't really appreciate is that it's potentially a much larger market than people think. We estimate it's about 6,000 to 7,000 patients because a lot of times, physicians intend to give CAR in the second line because that's what's recommended, and that's their intention. But these patients are oftentimes diagnosed in the community or they fail their frontline therapy in the community, and then they need to be referred into a CAR T-cell center. It takes time to get their appointment and their apheresis here. And so many of these patients get a second regimen of chemotherapy before they receive CAR, and data in the literature suggests about 50% of patients. So we think that this market in the third or later line is really meaningful, and we intend to be the first approved in the third or later line among the CD19/20s.

And so as you had mentioned longer follow-up in the second half of this year. Remind us how many patients worth of longer follow-up data will we see? And what should we be expecting? Because the median PFS is already there, right? Is what -- are we seeing just longer spider plots? Like what is it that you really want to highlight?

Sure. So I think it's going to be -- we presented about 30 patients with a median duration of follow-up of about 12 months in December last year. So we're going to -- we're continuing to enroll. So we're going to be having more patients with a longer duration of follow-up. And so we'll see if that median duration of progression-free survival of 18 months holds. If it gets longer, if it's a little bit shorter. But I think mostly, it's to give people confidence in the safety profile and the overall response rates that are going to make up the BLA submission at the end of next year in the pivotal data set. So we are very confident this product has behaved very consistently since inception. It has a very reliable manufacturing process. So we're feeling very good about where we are with this program.

So let's switch gears to the earlier opportunity, the PiNACLE head-to-head study now in second line. You just started dosing patients. So congratulations on that. It's a pretty ambitious trial, if you will, right? 400 patients, correct me if I'm wrong, head-to-head against CAR T, I don't think that's ever been done before. Why do that? And tell us a little bit about what you expect from this study kind of based on prior data that you've had? And when do you think this study could potentially complete?

So a lot of questions in there. I'll do my best. So I think the most important thing to know is PiNACLE is our fast-to-approval or fast-to-market strategy. PiNACLE head-to-head is our leave no doubt strategy. We're obviously very confident in the performance of our product. And so we want to give patients and the physicians who treat them the very best data they need. And it's very hard to do cross-trial comparisons in the CAR T-cell space with large B-cell lymphoma. Who you enroll, the patient disease characteristics and demographics really matter when you're interpreting outcomes. And so running a head-to-head trial gives us an opportunity to randomize and stratify those patients.

So it's going to be very even. You're not going to have to look back and struggle with cross-trial comparisons. You're going to be able to see in the data set. And we've already talked about in the third line how much better we're seeing above what's been presented to date in the -- from the CD19 CARs. And this typically will read through to the second line.

Already, in our second-line data, we did have a single-arm cohort in our Phase I/II. We're showing really robust in the highest risk patient population. These are patients that are called their primary refractory. They didn't even respond to frontline chemotherapy. And so they're the most difficult to treat.

If you talk to lymphoma experts, and we had one lymphoma expert from MD Anderson, who told us that when he sees these patients, he oftentimes initiates end-of-life conversations with them. These are very difficult-to-treat patients. And yet we were able to show a 61% complete response rate in these patients.

And that -- it's hard to find the comparator number for the CD19 CARs in the second line because, quite frankly, they don't report them out, and maybe there's a reason for that. But we did find that in the pilot study, which enrolled similar patients to ours, older patients, they did report out their primary refractory data and it had a complete response rate of 42%. So that's with Breyanzi, the market leader right now.

So we're feeling very confident about our second-line data. We're going head-to-head. And I think physicians and patients are going to know this is a superiority trial. You're right. It's 400 patients. It's sort of powered conservatively for sure. But we also have an interim analysis there. So we have an opportunity to get out early if the data are even better than expected. So we're very confident. We're not guiding yet about when the data will be out because, as you know, we need some time. This has never been done before. We're the first. And so we want to get a little bit better feel for how enrollment is going and how events are coming, and then we'll give some update on our progress in the second half of this year.

So as if LBCL and the data you've generated already wasn't surprising enough, right? So you've actually improved upon the current standard of care. I think the one thing -- and I've been following the cell therapy space for a while. CAR-Ts have been trying to get into solid tumors for a long, long time and with unfortunately, not so good results. This CRC data that you've reported is probably some of the best that I've seen. And so not just from approved, call it, third line plus CRC agents that are out there, which I think have objective response rates of less than 10%, but also from a PFS perspective.

You did this deal at the end of last year. I would love to kind of just hear how you're thinking about the CRC space. You've mentioned some of the data. We're getting 2 updates this year. The first half update and the second half update, what's the difference between the 2? And ultimately, what do you do with this -- once the data is done, how do you advance this forward?

Yes. So this metastatic colorectal cancer program is really important for Lyell because I think it has the potential to be transformative. We have great data derisked data in the large B-cell lymphoma space with ronde-cel. That's moving towards pivotal trial.

But the holy grail of CAR T-cell therapy, as you say, is solid tumors. And this is something that Lyell has been focused on since inception. We've learned a lot, and we know a couple of things that -- the first thing we know is that you must have a great target. And the target for this colorectal program that we acquired in the last year is a really great target. It's known as GCC for Guanylyl Cyclase C. It is expressed highly on the vast majority of colorectal cancers, over 95%. We don't need a biomarker for this program. And it's not spotty across the tumors. It's very homogeneously expressed.

So this is what a great target looks like. But we know we need more than just a great target. We need something to help the cells expand well in the solid tumor space because if they don't expand, they can't infiltrate into tumors. So we need good expansion, which has been a problem in the past. The other thing, of course, that's a problem is the very cold hostile immunosuppressive tumor microenvironment. It makes it very difficult once the cells infiltrate to actually continue to kill cells. Well, this product really has overcome those barriers with a very novel design, and it's active in patients.

We have 15 patients from China that have been published in JAMA Oncology that show a very active agent, including in patients with liver metastases. So these aren't the best of the best for the patients. These are patients that have liver metastases, which, in some cases, have resolved with this CAR. We have patients that -- had 15 patients from China that had a median overall survival of 25 months. When you look at approved therapies in the U.S. for later-line metastatic colorectal cancer, the median overall survivals are 6 months or less.

So this appears to be an active agent. This company, as I said, brought it to the U.S. Premier medical centers are participating in this trial, University of California, San Francisco; Dana-Farber; City of Hope; University of Colorado and are seeing and confirming those data, a clinically active CAR with a manageable safety profile.

So what are the data updates coming? When I talk about the safety profile with any target, you're always looking for are there any side effects that come from this. And diarrhea has been a side effect from this CAR. It's highly expressed on colorectal cancers. It's expressed at low levels and the normal bowel. So there has been 1 patient that had problems with some significant diarrhea and some consequences from that. He got treated with immunosuppressive therapy and ended up unfortunately getting a sepsis, a fungal sepsis and died. The diarrhea was controlled, but the infection that followed was a problem. That patient died with no evidence of disease despite having widely metastatic disease.

It's an active agent. So what we're going to be reporting on is more safety data in the first half with a real focus on additional patients treated and what that safety profile is looking like. We have said that we've already dosed an additional 7 patients and escalated to dose level 3. We've currently been treating at dose level 2 and haven't seen any further dose-limiting toxicities.

So -- but more detailed safety data will be coming. And in the back half of the year, we'll be providing more outcomes data. And I think this is really important, right, because this program, we expect to go quite quickly. We are targeting an end of Phase I meeting by the end of the year and expect to be in pivotal trials by the first half next year.

The unmet need in this space is tremendous. And when you see the surging incidents in young people, I mean, these are people who are perfect for CAR T-cell therapy, right, because they want one-and-done treatment, get back to their normal lives without ongoing chemotherapy. They're working. They have children. They have -- this is a huge problem. So we're very excited about this program, and I think we're continuing to execute and look forward to getting out more data.

The uniqueness about this CAR, I think you had mentioned it's a different design. This is one of your armored CARs. Is that correct? And can you just remind us what that is?

Yes. So this was a product. I have to give credit to the innovators who is a company called Innovative Cellular Therapeutics that we licensed this from. But what the inventor did picked a great target, GCC, but then actually partnered it with CD19 CAR. And you say, well, CD19 CAR, that's unusual. That's a heme target. But in fact, what the CD19 CARs do, they're not just CD19 CARs, they're engineered to release cytokines upon activation. And so when you infuse these CAR T-cells into patients, they hit B cells, cytokines are released because the CD19 gets activated and the cytokines help with the overall cell expansion. And so we get really nice cell expansion of the GCC targeted CARs and some doublet cells that have both GCC and CD19.

These then infiltrate into the tumor, continue to release cytokines, which help flip the tumor microenvironment, warm it up, attract more immune cells into the tumor. And suddenly, you're starting to see this activity and cell killing in solid tumors. And so we believe this is not only important for colorectal cancer in this product, but it's actually a window on how to get cell therapy to work in solid tumor more largely.

And the other thing we really like about this CAR is GCC is expressed on the majority of more than 50% of pancreatic cancers as well. So this has potential in late-line colorectal cancer. If the data continue to look good, it can move earlier and then, of course, to pancreatic cancer. So we're very bullish on the novel mechanism on the target, but most importantly, on the fact that it's a clinically active CAR.

Before we go to manufacturing, which I know is a big deal in our -- in the cell therapy space, in terms of the registrational study, is this something that would likely be a single-arm study and less than 100 patients? Or is it something more? Do you need to wait to tell?

You're going to ask me to speculate on the FDA with all the changes going on. Look, there is -- the bar here is very low for patients. And so whether it's going to be a response rate, single-arm study or a randomized controlled trial, that will come later after we have our interaction. But I think this will go quickly because there's so much unmet need here.

So in the last 4 minutes we have left, let's tackle manufacturing because that is a big deal in the space. What's the vein-to-vein time here with both your products, ronde-cel and 273. And then maybe just a little bit about your in-house capabilities.

Yes. So manufacturing is always a supreme importance in CAR T-cell therapy. And Lyell invested very early on in its own manufacturing center. It's state-of-the-art. It's digital. It is capable of commercial launch. So we've got the infrastructure that we need. We'll add some headcount, but we have our facility that will help us launch commercially.

Currently, for ronde-cel, we have a semi-automated manufacturing process. It's relatively low touch. It's very simple and straightforward and reliable and robust. We have a vein to -- we call it vein-to-site time because once it gets to the site, sometimes they get delayed for various reasons. But a vein-to-site time, a median of 16 days. That's highly competitive with the best, which is Gilead may be around 14 days, BMS is longer. So we're very competitive from that standpoint, and we have a greater than 95% success rate.

So I feel like we're very strong. The GCC CAR, LYL273 has actually even a more automated manufacturing process. We're in the process of transferring that to our LyFE facility now, but it is a very straightforward manufacturing process, quite standard and takes relatively about the time.

Okay. You have your own manufacturing plant. You have 2 pivotal studies that are ongoing, potential for a third by next year. Clearly, you need finances to fund all this. Give us an update on your latest kind of financial position. How long do you think it lasts?

Yes. Well, we just announced on Monday that we have taken the second tranche of $100 million pipe that we did in July. We did the first $50 million tranche at the time of doing that at a 30% premium to the price at the time, which was $10. We just took the second tranche after hitting a clinical milestone in our ronde-cel PiNACLE trial, and that was at a 150% premium or a price of $25.61. So that helps. We do have cash well into Q2 and getting us well along our path.

Yes. So I think we probably quickly did the math, I think between the payment that you had to ICTs, is that right, in the fourth quarter and this $50 million that came in, you're probably around $320 million. Did I...

So we haven't put out our K. So -- but yes, if you do the math, we had about $320 million when we came at the end of the last quarter, and we did have this outflow to ICT.

Got it. So in the last minute or so that we have, I guess, one, your thoughts on the competitive landscape because clearly, Kite, Gilead, right, BMS, they're not just going to give this. They're going to keep fighting. They're established. Outside of that clinical data, are you -- well, are you noticing dynamics in the space that suggest that, hey, even if you're a third entry or a second entry, you can still change the market around based on the profile you have?

Yes. So we are the first in class. This is a CD19/20. We're clearly in the lead. We're outperforming our competition that we've got 2 pivotal trials ongoing. And I think this is known to be a switching marketplace. If you look at YESCARTA, which is the Kite, Gilead product, they were first to market, and then Breyanzi is now the market leader because they bring most likely a better safety profile. And so switching is occurring.

These CAR T-cell prescribers are switchers. They're very data driven. So if you bring better safety or efficacy, in our case, we intend to bring both, they will switch. You've seen that ABECMA got taken out by CARVYKTI. And we like to say we are the Arcellx of lymphoma because in multiple myeloma, Arcellx is now planning to get the field to switch from CARVYKTI to Arcellx. So this is a switching marketplace, and Lyell intends to bring better first-in-class safety and efficacy data.

So the last 5, 10 seconds, we talked about different milestones kind of sprinkled throughout our conversation. But just to end it with a concise note, what are the next several milestones?

Time to pay attention to Lyell is now. We're going to have a data update in the first half of our colorectal program, a data update in the second half in our colorectal program in the second half and then a big data in the second half on PiNACLE. So this is a big year for Lyell, and I think it's -- now is the time to pay attention. It's a new story, and it's a rapidly evolving story.

Excellent. Lynn, thank you very much. Appreciate it.

Thank you.

Okay. Good morning, everyone. My name is Daina Graybosch. I'm a senior equity research analyst here at Leerink Partners. I cover mostly immuno-oncology companies. And in that, I'm really thrilled to be hosting the CEO of Lyell, Lynn Seely, as one of the -- we were just talking, cell therapy company, still dedicated and focused on oncology indications.

And I think we'll start. You had some news this morning. So maybe everybody has been busy. They haven't seen it. You could just give us a quick overview of the news, and then we'll get into the programs.

Sure. So I think everybody knows Lyell Immunopharma is focused on next-generation CAR T-cell therapies for large B-cell lymphoma, and we also have a new novel CAR T cell program for metastatic colorectal cancer. Today, we had 2 big news items. First and foremost, we hired our new Chief Financial and Business Officer, Smital Shah, who's joining us with significant experience in the financial and business development areas. And then we also announced the -- taking -- the hitting of a clinical milestone and allowing us to take a second $50 million tranche from a PIPE that we did in July of 2025 at a price of $25.61. So a big day for Lynn all around.

That's great. So let's talk about -- since we only have 30 minutes, the first program, Ronde-cel. Is that how you say it? Ronde-cel?

Ronde-cel, yes.

Which is your bispecific CD19/CD20 auto CAR T. One, can you just tell us more about Ronde-cel and why you believe it has a best-in-class profile?

Yes. We believe Ronde-cel is going to be first-in-class and also has a best-in-class profile. It is a dual targeted CD19/CD20 CAR T cell. It was really meticulously designed to have full potency at either CD19 or CD20. It's a tandem CAR. And it was designed very specifically to bring more complete responses because some malignant B cells, for example, don't have CD19 or express low levels of CD19. And so patients don't go into complete response with CD19 CARs. It also -- because there are 2 antigens, it's much more difficult for a cancer to escape from 2 antigens than it is to 1. So we expect that dual targeting also to help with longer persistence and duration of response.

And then finally, the other very special thing we do is in our manufacturing, where we do something called CD62L selection or enrichment. And this is to make our cell product very high in naive and central memory T cells, which have been really shown retrospectively in other trials to help with better outcomes for patients.

So we at Lyell are very much excited that we are -- have 2 pivotal clinical trials ongoing for Ronde-cel. So we believe we're going to be first to the market and then with a best-in-class profile, both with high complete responses, durable responses and then really a safety profile, which is very amenable to outpatient administration.

Let's talk more about the differentiation, the CD62L because that's quite distinct from your competitors. What gives you confidence in that approach versus a lot of the other competitors have gone down the shorter manufacturing or Kite, which is the other company that says they're going to do a head-to-head study like you in second line? So maybe they're the most similar competitor so far in terms of their clinical strategy, they employ the split co-stimulation. So the CD62L versus shorter and split co-stimulation?

Yes. So there's a lot packed in there. I would say Lyell has already initiated our pivotal head-to-head trial. We treated the first patients in February. So we're off and running with many sites up and active and more to come. So we're really excited about that. Our CAR construct and our cell manufacturing is quite unique. And as I said before, we very specifically wanted to have a tandem CAR. This was meticulously engineered.

And so if you're going to have a tandem CAR, which means there are 2 binders on a single CAR, it has full potency at either CD19 or CD20. This is actually very good for the cells. It's a much lower, should we call it, metabolic stress for the cells to express 1 CAR. It's much easier from a transduction perspective and a manufacturing perspective to get nice, consistent expression of a single CAR as opposed to trying to express 2 CARs.

And so this was very intentionally designed by Dr. Yvonne Chen at UCLA to be a tandem CAR and not 2 separate CARs, to get better transduction, higher expression of both the CAR on the cells compared to what might happen if you try to express 2. So we think the design of the tandem CAR is really exceptional and gives us a great advantage there.

And then this is coupled and has been from the beginning with the CD62L selection. We had an oral translational presentation at ASH, where we demonstrated that this CAR has 3x higher cell expansion in patients, both Cmax and AUC, so persistence than axi-cel or liso-cel, for example. And we believe this has a lot to do with the CD62L expression.

We were also able to show for the first time, persistence. We can take CAR T cells from the peripheral blood of patients 2 months after they've been infused, co-culture them ex vivo with cancer cells and show cancer cell killing. Nobody else has ever been able to show that, to our knowledge, because you can't get enough cell expansion and enough persistence.

Cancer cells you took from the patient initially or just like cancer cell lines?

Just cancer cell lines, yes. But the CARs from the patients 2 months after infusion. So they're not only present, they are functional. So this is, we believe, the real advantage of the Ronde-cel design.

So clinically, it's really hard to compare the outcomes of these studies. It's really hard. So we have yours, we have the Kite one. We have one from J&J AbelZeta, and then we have the sort of homebrew Miltenyi version. What do you -- and all the designs are a little bit different, which we find Bill, my associate and the team, and I have tried really hard, and it's almost impossible. So what outcomes do you look at to give you confidence that this translational profile is translating to a great clinical profile compared to the others?

Yes. So I would say, first and foremost, outcomes in patients with large B-cell lymphoma treated with CAR are very much impacted by the patient demographics and disease characteristics. So you have to know who you're treating before you can start to look at outcomes. So really a deep understanding of the types of patients and their disease is important.

Most of the data out there are single-arm studies. So if you really understand who's enrolled, then you can get a good idea about what you're looking at. We are really competing against CD19 CARs, right, that Lyell's in the lead with Ronde-cel, our intention is to displace CD19 CARs. And if you look at the single-arm data that they got approved with in the third or later line, we have a very competitive profile. Our overall response rates are 93%, data we presented at ASH, versus the 70% by the CD19 CARs. Our complete response rate, 76% versus 70%. And really importantly, the median progression-free survival we presented at ASH last year was 18 months in the third or later line compared to 6 to 7 months with the CD19 CARs. So this gives us great confidence as we move into these 2 pivotal trials, the single-arm study and the third or later line.

And in the second line, we also are very confident because historically, with BREYANZI and axi-cel, the third-line data translated very effectively into the second-line data. When you look at our second-line data, it really is the data that experts in the field get the most excited about because we enrolled the hardest-to-treat patients in the second line. These are patients that don't even respond to first-line therapy, known as primary refractory disease patients. And if you kind of look in the literature, you don't see much from BREYANZI or YESCARTA on those patients because they're so difficult to treat. They were reported in the PILOT study for BREYANZI, the primary refractory subset with a 42% complete response rate. In our primary refractory patients, we showed a 61% complete response rate, again, much better.

So we know these patients don't do well and yet in our trial, they are doing well. So we have great confidence not only because of what's known about the biology, but also because of the emerging data profiles.

So you said it's important to know like the patient you're treating. I find it hard to compare to the initial third-line studies of the CD19 CAR T because that's a long time ago. Like, what kind of patients are being put on those studies versus the patients that are being put on your third-line study? Do you think there's a trend towards better or worse prognosis and then there's an impact of all the physicians know how to use CAR Ts now? So could your indirectly better CR rate simply be a difference of who those patients are and better treatment at the centers?

Yes, of course, the problem with single-arm studies. So one of the reasons we are leaving no doubt, we are running the pure test of the head-to-head study in the second line. So we will know that answer, full stop. But be that as it may, every sign we have is that our drug -- our product is performing very well in the third or later line. I mean these aren't small benefits, right? These are large benefits that we're seeing over the third-line patients.

And remember, if you go back to those BREYANZI and YESCARTA trials, they didn't enroll anybody over the age of 75. We have no upper age limit. We're allowing patients to come in. We've treated 87-year-olds, with good outcomes. And so this tells you that we're not -- we're treating, if anything, because physicians are so much more comfortable with CAR today, sicker patients than were treated back then because we know how to treat the side effects.

The other thing is in the YESCARTA trials, they didn't allow bridging therapy, right? So that if you were progressing so rapidly, you couldn't wait for CAR, you couldn't come on their trials. Well, we allow bridging therapy because that's what's done in the real world. So when you look at the patients enrolled in our trial, you'll find that they are quite comparable, and we believe, in some ways, even sicker because they're older.

Yes. So even though physicians are more used to it, that's expanded this population. So you have these 2 dynamics overall and that gives you confidence. Can you talk about bridging therapy? It's been very interesting because Kite always only allowed steroid and I think targeted radiation, whereas you did see some bridging therapies allowed in the BMS and Novartis studies. And I think you were allowing it.

We are.

And how important do you think bridging therapy is? And is that going to be differentiating potentially for these bispecifics if you allow bridging and Kite again does not?

For the CAR T cells? Certainly.

Yes.

Well, real world, they use bridging therapy. So we would want to replicate those standard-of-care practice as much as possible. So we're allowing bridging therapy. The other thing we know is that bridging therapy is often used with patients that are progressing rapidly, right? So that may disadvantage them and not make their data set as translatable to real-world. So we feel like we're in a good position.

And the other thing I might say while we're on this topic is that we're very happy with our fast-to-market approach in the third or later line because we think there are more patients who have had 2 regimens of chemotherapy prior to CAR. Yes, patients want -- or physicians want their patients treated second line, but very often, they have to be referred in to a CAR treating center -- they have to get their fares in order, get that apheresis chair. And so very often, they get a second regimen of chemotherapy. And we believe there are 6,000 to 7,000 patients that are available in the third or later line. So we think this is a substantial market and being first is going to be a real advantage for us.

Are you allowing prior CAR T in that study?

So we are not evaluating CAR experienced patients because the much bigger market, the better place for Lyell to invest our development dollars, is in the CAR-naive population. We intend to displace the standard-of-care CD19 CARs, not go after them.

Yes. I think one difference in the clinical is on the safety side. I think Ronde-cels, you did -- you started in the whole cohort of pretty high ICANS, 12%. You implemented prophylaxis, and you brought that down, I think, to 4%, grade 3, but that's still looking a little bit higher than some of the competitors. But can you just help us understand that? Is that a fair comparison? And with that rate of ICANS, is that going to just always limit you a little bit to be able to go to more community centers?

Yes. So first and foremost, Ronde-cel has never had any grade 3 or higher cytokine release syndrome. So when you think about the 2 key side effects for CAR T-cell therapy, there's cytokine release syndrome. We've had no grade 3 or higher CRS. And then there's this neurotoxicity of ICANS. And by far and away, the highest rates of ICANS observed are with the approved YESCARTA. And when you talk about the data that we've shown, we now, with dexamethasone prophylaxis, have seen less than 5%. We have treated patients and are treating patients in the outpatient setting.

We think our safety profile with no cases of grade 3 CRS, less than 5% ICANS is exactly what patients and their physicians are looking for and gives great confidence to treat in the outpatient setting. So if anything, this is going to expand the ability to get our CAR T-cell therapy into the community centers.

When you think about it, the whole value proposition for patients is changing, right? It used to be, you had a flip of a coin, 50% chance in the third or later line, of going into complete response. Now you have a 76% chance assuming our data hold. You used to have to go in the hospital and have to worry about CRS and ICANS. Now you're treated as an outpatient. You only have to stay around the site for about 2 weeks. So it's a much better opportunity for patients.

So we've mentioned it a couple of times, but you have a really bold strategy. You're doing the first head-to-head versus approved auto CAR T study in second-line large B-cell lymphoma, actually aligns with Dr. Prasad's JAMA vision that was published in December, to do these head-to-head studies. So I mean, what -- I think you've talked about what gives you confidence already, that you can beat CD19 head-to-head. But can you just talk about it, not only are you product to product, you're process to process? And what gives you confidence as a small company with a more naive manufacturing that you can actually -- you're going up against the Kite commercial and BMS commercial processes?

Well, we're obviously very confident. Otherwise, we wouldn't be doing this. And I think, first, we're very confident in the biology behind our product. We're very confident in the clinical data, both the efficacy and the safety profile, as we've already spoken about. And we're very confident in the manufacturing. So Lyell has its own life manufacturing center. It's a state-of-the-art facility that was designed specifically to enable commercial launch. It's fully digital. It's state-of-the-art. And we have a -- it's a very semi-automated low-touch process. It's highly reliable and predictable. And quite frankly, it's easier than the BREYANZI process for sure. And we have a greater than 95% success rate, a median vein to site time of 16 days. So it is really a state-of-the-art process. We're highly confident in it.

Some people think the CD62L enrichment might add time, it might add complexity, but it really doesn't. And it's very simple. We have never had a failure due to the CD62L enrichment. And again, the whole process works quite smoothly.

How does that work in terms of reimbursement? Because I think you're having payers in the U.S. pay for the standard of care in the control arm and then you'll pay for patients on the active arm. But how do you make sure that you're not introducing bias one way?

Well, if you think about it, it's really just the opposite, isn't it? This is very much exactly what happens on a patient's journey. They come into the center, they get approved, right, because you want to have proof of from your payers, whether it's Medicare or commercial insurance. And so we're doing that, and patients get randomized once a commercial or Medicare insurance has been approved, and then they get randomized either to Ronde-cel or to YESCARTA or BREYANZI, physician's choice.

So it's a very real-world experience and directly relatable to what's happening to them today in their process. So we think it's actually a good part of the trial design. It obviously helps us with our -- manage our cost. And we're able to do this trial in the U.S. where we have really a large percentage of the highest enrolling centers, whether it be MD Anderson or Moffitt or all of Sarah Cannon Research Institute. So a really nice footprint. So I think it works out well, but we're also able to do this in Australia and Canada.

Got it. You're going to have a very real-world study. You allow bridging, standard of care choice, and you do the reimbursement.

And there's no upper age limit. You can be primary refractory, you can be early relapsers, you can be late relapsers. We designed this trial very specifically to -- if you're eligible for CAR, you can be evaluating the study. It's as real-world and as a direct comparison as we can make it. So you won't be able to say afterwards, the patients are going to be stratified, so the risk should be spread evenly as we can across the 2 arms. So it's a beautiful test, and we're doing it because we're very confident in the profile of our product.

Do you have -- so how much axi-cel versus liso-cel do you expect on the control arm? Does it matter for your powering? Are you setting any caps?

It doesn't really matter for powering because the efficacy, which is the primary endpoint of this trial, is event-free survival. It's very similar. Obviously, the safety is different. So we believe that we have a better emerging safety profile than either of the 2 products. And we'll see -- we don't care actually, but we think probably we'll see as is happening in the marketplace, a little bit more BREYANZI use than YESCARTA use, but we think it will be relatively balanced.

Got it. So maybe -- you've got financing today. So I was wondering how much of both of these pivotal trials, the third line and the second line head-to-head does your current cash runway support?

So we've guided that the pivotal data from the third-line study, we call it PiNACLE, will be available mid next year. So this trial is coming soon, and then we'll have BLA submission next year as well. We've not guided on the head-to-head largely because this trial has never been done before. We just started it. We said we'll be giving a progress update and more guidance around that in the second half of the year. But I can tell you that the site activation is going extremely well at this point. And yes, we did just bring in an additional $50 million. So that's good news.

Yes. Maybe one more on manufacturing. I think sometimes the challenge has been specification thresholds. So you say 95% spec, but that's your clinical spec. How much of that do you think will translate to what FDA ultimately will have for your spec?

Yes. We're, as I said, very confident in our manufacturing process. We've already presented our commercial manufacturing process to the FDA along with the analytical plan and discuss initial specification. So we feel like we're in a good place. We, as we said, got our eyes on the prize, which is approval in the third or later line, which the BLA submission will be coming by the end of next year. So we're in a good place.

One last one, sort of competitively. I think as you're bringing your product on board, we're seeing the T-cell engagers move early and earlier. I think we should see soon whether a CD20 T-cell engager on top of chemo works in front line. How do you think does that change the paradigm for patients and the need for CAR T and the competitiveness of biologically a CD19/CD20 CAR T?

Well, we're going to have to see what we -- I think that the ability to have a one-and-done treatment, that has the opportunity for cure and patients see very well on, is extremely attractive. I think as the T-cell engagers move into the front line, we'll see what the overall safety profile is and what their ultimate uptake is. I mean there are some issues with exhaustion of T cells and with late infections. And so we're going to have to see what the data show. I think what's good for patients is good for everybody, but I strongly believe that there is going to continue to be demand for autologous CAR T-cell therapy. It's a one-and-done treatment.

Got it. In the 7 minutes, I want to go to your next program. An investor last night encouraged me to ask about it because we have data this year, and some people are really excited about it. So you in-licensed a GCC CAR T. It's for solid tumors. So maybe you could just tell us more about the construct and why you guys are excited about it?

Yes. This is a very novel program. We're super excited about it. We believe it has the potential to be transformative for the company this year. We're going to be putting out data from this program in both the first half and the second half. This is a GCC guanylyl-cyclase-targeted CAR T-cell therapy. So it targets an antigen on colorectal cancer that is expressed in the vast majority, 95% of colorectal cancers. You do not need a biomarker. It's on the cancer and its metastases. By the way, it's also expressed on about 60% of pancreatic cancers. It's a great solid tumor CAR.

But we know solid tumor CARs haven't worked well in the past. But this one is very different. What it has is it is also coupled or partnered with CD19 and not just any CD19, but CD19 that releases cytokines in a very controlled way when it's activated. This CAR has shown remarkable benefit to metastatic colorectal cancer patients treated in China, which is where it was invented. So at a single center, it's been published in JAMA Oncology. 15 patients had a 40% overall response rate and a median overall survival of 25 months in the third or later line metastatic colorectal cancer setting. In comparison, in the U.S., the approved products for the third or later line have single digits, 6%, 4%, 2% overall response rates. They have median progression-free survival less than 6 months and median overall survival of 11 months. There's a huge need. Anything that has an overall response rate 20% or better is going to bring great benefit.

This Chinese company moved this program on their own to the U.S. They got some premier medical centers to participate, Dana-Farber Cancer Institute, University of California, San Francisco, and we're able to show in a dose escalation, dose expansion trial in 12 patients in the highest dose studied at that time, 6 patients, a 67% overall response rate. So really quite remarkable results.

So we're very excited about this program. We think it's a great target. It's a really novel design that is showing benefit because we're able to get cell expansion and infiltration into the tumor.

And I just want to emphasize the design because you went over it quickly. So it has a CAR for CD19, but that's to deplete normal -- it depletes normal B cells, I presume, but that gives you a secondary signal to stimulate the T cells when they're in the periphery.

The goal is exactly that, to jump start the expansion of the solid tumor, the GCC CARs. And so what happens is the CD19 cell -- expressing cells meet the B cells soon after infusion. They get activated, they release cytokines. This helps the other cells expand as well, the GCC cells. And there are actually some doublet cells that have both GCC and CD19. You get nice cell expansion, and then these cells can get to the tumor and infiltrate the tumor. They continue to release cytokines in the tumor, and we believe this really helps flip the tumor microenvironment to -- from cold to warm.

Why didn't I realize that. I thought they all doubly expressed it, but it's a mixture.

It's a mixture of cell types. That's right.

Do you have to get that mixture like precisely defined in every patient? Is that going to be a challenge?

It is done with stoichiometry at transduction. We have really controlled the amount of cytokine released by that. And it was sort of optimized in China, and they have this way to do experiments in patients with their investigator-initiated trials. So they were able to come up with the right mixture, shall you say, and it's remarkably reliable across patients.

So we feel like this is something that originated in China. We were able to have confirmation that it worked well in the U.S. before we brought it in. And now we're really excited to be moving it forward. And we have said that we've treated since we brought it in at the end of last year, 7 additional patients, including escalation to dose level 3 with no dose-limiting toxicities.

So the program is moving forward, and we'll look forward to bringing out data in the first half of this year, so coming soon, and additional data in the second half.

A couple. How are you conditioning it? Are you using CyFlu, or are you using traditional chemotherapy? And do you need to optimize that?

It's a great question. And actually, this has a single day of lymphodepletion. And because you want some B cells remaining -- and again, this is the protocol that was originally designed. So it's only 1 day of lymphodepletion, which is great for patients.

That's great. Manufacturing, have you brought it over? I know we've had challenges in CAR T, like with tech ops getting manufacturing and having the product change in different people's hands.

Yes. So this process is made on the Prodigy. It's very automated. And again, it's being made by the company that we licensed it from currently, in Maryland. We're in the process of transferring it to our LyFE facility. But again, it's a very easy to manufacture product, and it's well on its way to being transferred successfully.

We have 1.5 minutes left. I think we have people in the audience. I'll open it up to anybody has a question.

The cash runway, if you could just speak to it, will it encompass the third line?

Yes. So we have cash runway into Q2 of 2027. So our hope will be, yes, that it will.

So I have another one. With the GCC CAR, do you own -- did you license broader? Like, do you expect that you'd use this platform in the future to develop novel products against novel solid tumor targets?

Well, we do believe this is a window into getting CARs to work in solid tumors in a larger way. We licensed specifically the GCC CAR from Innovative Cellular Therapeutics. But it is a very interesting and novel way of thinking about how to get CAR T cells to work in solid tumors.

Okay. Then maybe one more on Ronde-cel in 16 seconds. Not to add more on to the plate, but do you have plans to start exploring it in other oncology or autoimmune indications?

So we think Ronde-cel has a lot of uses. I mean, could it go earlier even into the frontline high-risk patients? Can it go into autoimmune disease? Can it go into other types of lymphoma? Yes, yes and yes. Right now, we are focused. Our plate is very much full executing on the third or later line and getting this product approved. We want to be first. We want to be best-in-class, and we're going to leave no doubt with a head-to-head clinical study. So the future has opportunity. But right now, we have very focused-on execution.

That's great. Thank you.

Thank you.

Thank you, everybody, for your attention.

Thank you, and thank you to TD Cowen for inviting me to present here today. I'm delighted to tell you about Lyell Immunopharma, a cell therapy company focused on bringing next-generation cell therapy to patients with cancer. We're looking to deliver the full promise of cell therapy to defeat cancer.

I will be making forward-looking statements during this presentation. So please consult our securities filings and website for additional information. So at Lyell, our purpose is to give patients the gift of time. We do this by advancing next-generation CAR T-cell therapies to improve outcomes for patients with first-in-class cell therapies, innovative for hematologic malignancies and solid tumors. Our goal is really to allow patients with a one-time treatment with long-lasting durability to return to their normal lives free of ongoing treatment.

So today, I want you to know that Lyell is well positioned for significant value creation in the next 12 to 18 months through multiple catalysts in multibillion-dollar markets. So Lyell has potentially best-in-class or first-in-class CAR T-cell programs targeting large markets with significant unmet need. These 2 markets are in relapsed/refractory large B-cell lymphoma, which is known to be a $3 billion market for CAR T-cell therapies and then also metastatic colorectal cancer, which is a large and growing market with approved therapies bringing limited. Our lead program is Ronde-cel, which is a dual targeting CD19/CD20 CAR T-cell product candidate with potential to become the standard of care in relapsed/refractory large B-cell lymphoma based on high durable complete response rates and a safety profile appropriate for outpatient use.

We currently have 2 pivotal trials underway, PiNACLE in the third or later line setting on track for data in mid-2027 with expected BLA submission also in 2027. In addition, we have recently announced the patient -- first patient dosing in PiNACLE head-to-head. It's a first-of-its-kind Phase III head-to-head randomized controlled clinical trial. Additionally, we have another program, LYL273, which is an enhanced GCC-targeted CAR T-cell candidate in patients with metastatic colorectal cancer, where we have seen high response rates in refractory patients and a manageable safety profile in an ongoing U.S. Phase I trial in third or later line patients.

I will tell you today that we have treated 7 additional patients since we licensed this product in November 2025 and have observed no dose-limiting toxicities, including with dose escalation to Dose Level 3. We'll be providing updated Phase I data from this program in both the first half as well as in the second half with a potential for pivotal trial initiation in the first half of 2027. And then finally, at Lyell, we have scalable wholly owned manufacturing capable of commercial launch.

So we have the right team, the right programs, the right capabilities to bring value to both investors and importantly, to patients. Here's our pipeline of next-generation CAR T cell therapies. You can see Ronde-cel at the top. This is our CD19/CD20 program being advanced in both third or later line as well as in the second-line aggressive large B-cell lymphoma. We have a unique feature where we enhance our CAR, dual targeting CAR with CD62L enrichment to flex for naive or central memory CAR T-cells, which have, we believe, better benefit to patients. And we're the only company that does this.

We have 2 ongoing pivotal trials, PiNACLE and PiNACLE head-to-head. And I said we'll be having updated data from the PiNACLE trial in the second half of this year. We will be having pivotal data mid-2027, followed by an expected BLA submission also in the second half of 2027. The PiNACLE head-to-head trial has started treating patients, and we'll be giving a progress update on that in the second half. And then for the colorectal program, you'll be seeing data coming in the first half of 2026 as well as in the second half. So a lot of milestones, all guiding us to an end of Phase I meeting in the second half of this year and pivotal trial initiations to follow in the first half of 2027. So a lot going on at Lyell.

Let's dig in for a moment and deeper into Ronde-cel and large B-cell lymphoma because this is our lead program, and we're just really excited about our progress. Ronde-cel, as we've spoken, is a dual targeting CD19/CD20 CAR T-cell product. And that means that it has full potency at either CD19 or CD20. You can see the illustration here that it's a tandem CAR, and it's designed very specifically to overcome antigen heterogeneity. So if a malignant B-cell has low CD19, it can still respond nicely to this product, driving more complete responses.

And then we have 2 antigens, so it's harder for antigens to escape from 2 antigens than it is for 1, again, helping to drive longer durability. And then finally, as I alluded to, we're the only company that enriches for CD62L positive cells. These are cells that give us a high percentage of naive or central memory T-cells in the final drug product. This is important because they're associated retrospectively in randomized controlled trials with better CAR T-cell response. We know that the central memory and naive T-cells are associated with an improved persistence, less exhaustion and lower adverse cytokine production. So we think this is a really unique and important feature of our product.

And then we know Ronde-cel is very well positioned for a growing multibillion-dollar market. The CD19 CAR T-cell market is shown here. It's already a $3 billion market and expected to grow and could potentially grow even more with the added value from a CD19/CD20 CAR. There are 30,000 patients with large B-cell lymphoma in the U.S., 12,000 patients in the second line, which is being targeted by our PiNACLE head-to-head study. But importantly, we believe that there are 6,000 to 7,000 patients in the third or later line. And this is really important because that's our fast-to-market approval strategy with the PiNACLE third or later line single-arm study.

We believe this number is higher than most people think because we know that up to 50% of patients receive a second regimen of chemotherapy as they're making their way to the CAR T-cell center to get the referral to get an appointment for apheresis. So a really important market is the third line.

So let's look at the data in our third or later line. Some people say, wow, the CD19 CARs have revolutionized treatment for large B-cell lymphoma. Why do we need a next generation? Well, let me show you why. This is a busy slide, but I'm going to walk you through it because it really gives you the data you need to understand where this marketplace is. So you see at the top, the data from Ronde-cel, which was from a Phase I/II trial presented at ASH at the end of last year in the third or later line, you can see an overall response rate of 93% and a complete response rate of 76%. Very importantly, the median progression-free survival was 18 months.

For Yescarta and Breyanzi, you see down below, those are the data from their approved package inserts and pivotal trials. You can see the overall response rate was 72% and 73%, respectively, with 50% complete response rates and median progression-free survival of only 6 to 7 months. So there's a lot of room here for a better and improved next-generation CD19/CD20 CAR. One of the reasons we're so confident that these data have the opportunity to really help Ronde-cel become the standard of care in this marketplace is because it's a known switching marketplace. The CAR T-cell treating physicians will switch therapies based on better safety or efficacy.

In the middle panel, you can see the CD19 lymphoma CAR T-cell therapy market, where you see Yescarta, the market leader losing share to Breyanzi as it comes up presumably better because of a better safety profile. And then you see on the right-hand side, the myeloma market, where you can see ABECMA losing market share to CARVYKTI as it brings better efficacy into the marketplace. And this is important because Ronde-cel is designed to have better efficacy and better safety.

Here are the data that were presented in the third or later line at ASH. You can see that 93% overall response rate. By the way, that's the primary endpoint of the PiNACLE pivotal trial with a 76% complete response rate. And you can see these patients swimming the median progression-free survival was 18 months. The complete responders are in green in this swim lane plot on the right, which are the individual patient trajectories. And you can see patients continuing in complete response 15, 18, 21 months. So these are very promising data for Ronde-cel.

Well, let's talk about the second line because as we said, this is a large market. When we think about the second line, it's very important to know that to interpret outcomes in CAR T-cell therapy, you really need to understand the patients who enroll demographic disease characteristics. So on the next slide, I'm going to walk through similarly some of the data that are available to us to consider.

The Ronde-cel data you see in the second line was presented from a single-arm, second-line cohort in our Phase I/II trial presented at ASH, 83% overall response rate, 61% complete response rate. Now how does that stack up? You can see 3 trials are available to us, 2 in Breyanzi. You can see the first in the top trial listed there from their package insert is the pilot study. This is a trial that enrolled patients older than the age of 75, and they actually reported out their primary refractory patient population.

You can see for Ronde-cel, 94% of our patients had primary refractory disease. So understanding this is really important because primary refractory patients is a high-risk feature for this disease. These are patients who don't even respond to their frontline therapy. And you can see that with the Breyanzi pilot study, their complete response rate in primary refractory patients was 42% compared to the 61% we see in the Ronde-cel population. In the Breyanzi randomized controlled trial in the second line, they don't report out their primary refractory patients.

Yescarta also ran a randomized controlled trial, and they reported out in the primary refractory patients only median progression-free survival, which was 7 months, much lower than the 15 months from the overall patient population, again, indicating that primary refractory disease is a high-risk feature. And I just want to point out that neither the Breyanzi nor the Yescarta trial, did they enroll patients over the age of 75, which is another high-risk feature.

If you look at the data from Ronde-cel in the second-line cohort presented at ASH, you can see that 20% of the patients we enrolled were over the age of 75 with 92% -- more than 90% being primary refractory. The overall response rate, 83% and the complete response rate of 61%, with 70% of patients with complete response remaining in complete response at more than 6 months. And so again, you see these green individual swimmers plots, the patients swimming past 6 months, 9 months, 12 months. So this again bodes very well for Ronde-cel in the second line.

Here are the swim lanes that you can see. Green is again patients in complete remission. So this sets up our overall development strategy, which was just very carefully designed with 2 pivotal trials. The first is what we call our fast-to-market strategy. This is a single-arm pivotal trial designed either for full or accelerated approval. We are having overall response rate as a primary endpoint. As I said, we expect pivotal data from this trial mid next year. This is then supported by the PiNACLE head-to-head trial in the second line.

This is our leave no doubt superiority trial design, where we will be comparing Ronde-cel in a first-of-its-kind head-to-head CAR T-cell clinical trial versus investigator's choice of either axi-cel or liso-cel. And I'm proud to say we've already begun patient dosing in that program. So just a moment about the safety profile. What you can see here is that Ronde-cel in data of the second and third line combined, 25 patients treated with dexamethasone prophylaxis, no cases of grade 3 or higher cytokine release syndrome. And in fact, we've seen no cases of grade 3 or higher cytokine release syndrome with or without DEX prophylaxis in this program.

We have 4% grade 3 or higher ICANS with dexamethasone prophylaxis comparing favorably to 12% in all patients with or without DEX prophylaxis. And again, you can see easily that the safety profile compares in a very good way to the current CD19 CAR T-cell therapies, particularly Yescarta with its 31% grade 3 or higher neurotoxicity. And I'll just say that we have robust and scalable manufacturing for Ronde-cel. This is a quite simple, relatively automated process, and we manufacture it in our LyFE Manufacturing Center, which is a wholly owned manufacturing center in Bothell, Washington that can make up to 1,200 CAR T-cell doses per year, getting us well underway into commercial launch.

And this process has a median vein to site time of 16 days, which is very competitive with what's out there. Again, very automated and simple even with the CD62L enrichment, specifically designed to give us a better product profile. So now I want to move on to our other very exciting program, a program for metastatic colorectal cancer. And I think we all know this is a large market with tremendous unmet need. It's the second leading cause of cancer death worldwide and a large and growing market. You can see that 150,000 new cases are expected in the U.S. and more than 50,000 deaths occur. The incidence is surging in younger patients, patients who may be very attracted to a onetime treatment so they can get back to their normal lives. 25% of patients have metastatic disease at diagnosis and up to 60% develop it over time.

And yet the standard of care for metastatic colorectal cancer in the third or later line really does not achieve meaningful response rates and has limited benefit on either progression-free survival or overall survival. You can see here the approved therapies and their labels. 6% is the best overall response rate, 6 months of median progression-free survival and 11 months of overall survival. There is a tremendous need for new and better therapies for these patients. You can imagine a response rate of more than 20% would provide a meaningful benefit.

So we believe LYL273 is a potentially transformative clinical stage program for Lyell. We've seen high response rates with this GCC targeted CAR, 67% overall response rate and median progression-free survival of 8 months at dose level 2 in a U.S. Phase I trial. We're continuing to enroll patients in this trial in the third or later line with or without liver metastases. And I can tell you, since we licensed this product in November of 2025, we've dosed 7 additional patients with no dose-limiting toxicities, including dose escalation to dose level 3.

The data from the U.S. clinical trial is supported by data -- proof-of-concept data from China in 15 patients with a 40% objective response rate. So overall, we had data in 27 patients. And again, the patients in the China study who've been followed had a median overall survival of 25 months, substantially better than the 11 months I just showed you. This is a novel CAR. It's a target GCC, which is expressed in more than 95% of colorectal cancers and its metastases as well as in 60% of pancreatic cancers. And we have enhanced this GCC targeted CAR with CD19 CARs, really novel enhancement. And these CD19 CARs express cytokines. And we believe this is what really helps this mechanism of action. Again, scalable, automated closed system manufacturing.

So let's look a little bit at the data. You can see here, this is data from the proof-of-concepts established in China. This is a 48-year-old woman diagnosed with metastatic colorectal cancer. She failed multiple lines of prior chemo, radiation, surgical resection. She got the 2 million per kilogram cell dose of GCC CAR. And you can see her liver metastases in the panel showing that really bad at baseline and then not observable by month 3. And importantly, her PET scan showed a 96% reduction in tumor burden. This patient lived for almost 4 years. So a really great result and indicative of what this CAR can do.

This was the type of data that led the U.S. FDA to accept the IND and to initiate a U.S. Phase I clinical trial. There are 4 very experienced CAR T-cell therapies who are participating to date. You can see them listed here, Dana-Farber, University of California, City of Hope and the University of Colorado. 3 doses, 2 have already been studied, dose escalation to dose level 3 has just occurred. So I won't be showing you data from that. This is a single day of lymphodepletion, so less than normally that you see. And again, studying patients in the third or later line, liver metastases are included with up to 7 lesions and then the largest not being greater than 3 centimeters.

Here are the patient demographics. You'll note the young age of the patients. which is now increasing in what we see in this patient population. The median lines of therapy were 3 with about 25% having already been treated with LONSURF. And here, you see the overall response rate, 33% at dose level 1, 67% at dose level 2. You can see there was one complete response. I'll tell you about that patient and several partial responses. And the disease control rate is high at 83%. So this slide shows you the data in some detail. You can see the high overall response rates in the waterfall plot on the left, dose level 1 and dose level 2, you sort of get this impression of a dose response. Green is complete response, dark blue is partial response.

And so again, you can see this patient #12. This is a somewhat unfortunate story. This is a man who entered the trial with 600 to 700 lung lesions, disease in the liver. And he was treated and unfortunately died and on autopsy, had no evidence of disease. You see patient #11 and the patient represented in the waterfall plot, you can also see in the same reference numbers on the swim lane plot. Patient #11 is basically 100% partial response. She had a small remaining evidence of nontarget lesion in her lung that got radiated. But otherwise, she has no evidence of disease, and you can see her swimming now well out many months.

So really important data, and I think gives you this idea that this is an active CAR. Again, 12 patients here supported by 15 patients published from single center in China. And this also comes with a manageable safety profile. You can see there's been some CRS generally easily managed. There was one case of Grade 3 ICANS that lasted 3 days and again, was managed. Diarrhea is a toxicity to watch here. You can see we have had some cases of diarrhea, most readily managed with a median duration of 11 days. And again, this is a onetime treatment. So that's for colorectal cancer, certainly tolerable.

We had this one very unfortunate case that's the man that I told you about in pathologic complete response. He died. He got some colitis after his treatment, it was a little bit noticed late, then he got grade 4 colitis and was treated with a lot of immunosuppressive therapy. His diarrhea resolved, but he ended up getting because of the immunosuppressive therapy of sepsis and died from that, but no evidence of disease. We since implemented a more aggressive prophylactic and treatment management plan. As I said, we've treated 7 additional patients using this plan with no evidence of dose-limiting toxicity.

And so how does this novel CAR work? It's got a very novel design. You see the GCC target Guanylyl Cyclase C, highly expressed in colorectal cancer, partnered with CD19 CARs that are engineered to express cytokines, very specific cytokines when activated. And so this GCC CD19 CAR partnering allows it to jump start CAR T-cell expansion. And we know that limited CAR T-cell expansion is one of the key reasons we haven't seen the sort of benefit in solid tumor with CARs that we might like. So this really helps us get cell expansion. You can see that we end up with a mixture of cells. We have some cells that are GCC CAR alone, some cells which are CD19 cytokine expressing cells and some which have both. These cells can infiltrate the tumor. They continue to secrete cytokines and really help flip this tumor microenvironment to one where cancer cell killing is much better able to happen.

Again, it's a very simple manufacturing system, largely closed using the Miltenyi CliniMACS Prodigy, so easily transferable and scalable, and we're in the process of moving this to our LyFE Manufacturing Center. And so let me just run through our milestones. We have cash runway into Q2 2027 through multiple clinical milestones. And you can see here that we'll be having updated data from the PiNACLE study in the second half of the year, a progress update on how the clinical head-to-head T-cell trial is going. And then more with PiNACLE, we'll have the pivotal data set in mid-2027, followed with the expected BLA submission that same year.

And then for 273, the colorectal program, we'll be reporting updated data from that program in the first half of this year and then again in the second half. We expect to have an end of Phase I meeting in the second half and initiate the first pivotal program for this -- first pivotal trial for this program in the first half of next year. So a lot going on at Lyell, and I hope I have convinced you that we are well positioned for success. Thank you.

Happy to take any questions, if there are any in the room.

Why is cytokine release syndrome not an issue? Like, what is in your drug and in everybody else's it is?

So we do CD62 -- are you talking about Ronde-cel?

We do CD62L selection, and this is enriches the cell product for naive and central memory cells. I have -- they're a little less they're not differentiated as much. They have lower adverse cytokine production. And so it has a little bit of a gentler profile. Also, we're using a little bit of dexamethasone prophylaxis, so 10 milligrams on day 0, 1 and 2. And that, again, helps to lower at least in our data, the incidence of cytokine of ICANS, which some have seen. We haven't seen any Grade 3 or higher cytokine release.

Can you use that strategy on other indications as well?

Possibly, we can. Yes. It's been well studied in the ZUMA-7 trial. So that's why it was shown there not to impact outcomes. And we've shown in ourselves that our cell expansion data look exactly the same with and without dexamethasone.

Okay. Great. Thank you.