All right. Morning, everybody. Thanks for coming to the TD Cowen Healthcare Conference today. I'm Nathan Weinstein from TD Cowen, and thanks for coming for the presentation for Lyell. Without further ado, I'll turn it over to CEO Lynn Seely.
Thank you. 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. 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.
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 multi-billion dollar markets. Lyell has potentially best-in-class or first-in-class CAR T-cell programs targeting large markets with significant unmet need. These two 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 benefit. Our lead program is Rondo-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 two pivotal trials underway, Pinnacle in the third or later line setting, on track for data in mid-2027, with expected BLA submission also in 2027. We have recently announced first patient dosing in Pinnacle-H2H. It's a first of its kind phase 3 head-to-head randomized controlled clinical trial. 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 US phase 1 trial in third or later line patients. I will tell you today that we have treated seven 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 1 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. Finally, at Lyell, we have scalable wholly-owned manufacturing capable of commercial launch. 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 Rondo-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 select 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 two ongoing pivotal trials, Pinnacle and Pinnacle head-to-head. I said we'll be having updated data from the Pinnacle 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 Pinnacle head-to-head trial has started treating patients, and we'll be giving a progress update on that in the second half. For the colorectal program, you'll be seeing data coming in the first half, 2026, as well as in the second half.
A lot of milestones all guiding us to an end of phase 1 meeting in the second half of this year and pivotal trial initiations to follow in the first half of 2027. A lot going on at Lyell. Dig in for a moment and deeper into Rondo-cel and large B-cell lymphoma because this is our lead program, and we're just really excited about our progress. Rondo-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. If a malignant B-cell has low CD19, it can still respond nicely to this product, driving more complete responses.
We have two antigens, it's harder for antigens to escape from two antigens than it is for one, again, helping to drive longer durability. 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 these central memory and naive T-cells are associated with improved persistence, less exhaustion, and lower adverse cytokine production. We think this is a really unique and important feature of our product. We know Rondo-cel is very well-positioned for a growing multi-billion 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 US, 12,000 patients in the second line, which is being targeted by our Pinnacle head-to-head study. Importantly, we believe that there are 6,000-7,000 patients in the third or later line, and this is really important because that's our fast-to-market approval strategy with the Pinnacle 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. A really important market is the third line.
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, I'm gonna walk you through it because it really gives you the data you need to understand where this marketplace is. You see at the top the data from Rondo-cel, which was from a phase 1/2 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 6-7 months. 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 Rondo-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.
Then you see on the right-hand side the myeloma market, where you can see CAR Abecma losing market share to CARVYKTI as it brings better efficacy into the marketplace. This is important because Rondo-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 Pinnacle pivotal trial with a 76% complete response rate. 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. These are very promising data for Rondo-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 are enrolled, demographics, disease characteristics. On the next slide, I'm gonna walk through similarly some of the data that are available to us to consider. The Rondo-cel data you see in the second line was presented from a single-arm second-line cohort in our phase 1/2 trial presented at ASH. 83% overall response rate, 61% complete response rate. Now, how does that stack up? You can see three trials are available to us, two in BREYANZI. You can see the first and 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 Rondo-cel, 94% of our patients had primary refractory disease. 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 front-line therapy. 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 Rondo-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, they reported out in their 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. I just wanna point out that in 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 Rondo-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.
Again, you see these green individual swimmers plots, the patients swimming past 6 months, 9 months, 12 months. This again bodes very well for Rondo-cel in the second line. Here are the swim lanes that you can see. Green is again patients in complete remission. 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 Pinnacle-H2H trial in the second line.
This is our leave no doubt superiority trial design, where we will be comparing Rondo-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. I'm proud to say we've already begun patient dosing in that program. Just a moment about the safety profile. What you can see here is that Rondo-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. 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.
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 three or higher neurotoxicity. I'll just say that we have robust and scalable manufacturing for Rondo-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. 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.
Now I wanna move on to our other very exciting program, a program for metastatic colorectal cancer. 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 and expected in the US, and more than 50,000 deaths occur. The incidence is surging in younger patients who may be very attracted to a one-time 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.
Yet, the standard of care for metastatic colorectal cancer in the 3rd 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. 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 US Phase 1 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 US clinical trial is supported by data, proof of concept data from China in 15 patients with a 40% objective response rate. Overall, we have data in 27 patients. 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.
We have enhanced this GCC-targeted CAR with CD19 CARs, really novel enhancement. These CD19 CARs express cytokines, and we believe this is what really helps this mechanism of action. Again, scalable, automated, closed system manufacturing. 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'd 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 on the showing that, you know, really bad at baseline and then not observable by month 3. Importantly, her PET scan showed a 96% reduction in tumor burden.
This patient lived for almost four years. A really great result and indicative of what this CAR can do. This was the type of data that led the US FDA to accept the IND and to initiate a US phase 1 clinical trial. There are four 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 University of Colorado. Three doses, two have already been studied. Dose escalation to dose level three 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. Again, studying patients in the third or later line, liver metastases are included, with up to seven lesions, and then the largest not being greater than three centimeters.
Here are the patient demographics. You'll note the young age of the patients, which is now increasing in what we see in these patient population. The median lines of therapy were three, with about 25% having already been treated with Lonsurf. Here you see the overall response rates, 33% at dose level 1, 67% at dose level 2. You can see there was 1 complete response, I'll tell you about that patient, and several partial responses. The disease control rate is high at 83%. 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.
Again, you can see this patient 12. This is a somewhat unfortunate story. This is a man who entered the trial with 600-700 lung lesions, disease in the liver, and he was treated and unfortunately died, and on autopsy had no evidence of disease. 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 a non-target 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. 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 a single center in China. This also comes with a manageable safety profile. You can see there's been some CRS, generally easily managed. There was 1 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 median duration of 11 days. Again, this is a 1-time treatment, so that's for colorectal cancer, certainly tolerable. We had this one very unfortunate case of 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. 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, a sepsis and died from that, but no evidence of disease. We've since implemented a more aggressive prophylactic and treatment management plan. As I said, we've treated seven additional patients, using this plan with no evidence of dose-limiting toxicity. How does this novel CAR work? It's got a very novel design. You see the GCC target, guanylyl cyclase C, highly expressed on colorectal cancer, partnered with CD19 CARs that are engineered to express cytokines, very specific cytokines when activated. This GCC, CD19 CAR, partnering allows it to jumpstart CAR T cell expansion.
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. 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. Let me just run through our milestones.
We have cash runway into Q2 2027 through multiple clinical milestones. You can see here that we'll be having updated data from the Pinnacle study in the second half of the year, a progress update on how the Pinnacle-H2H T-cell trial is going. More with Pinnacle, we'll have the pivotal data set in mid-2027, followed with the expected BLA submission that same year. For LYL273, 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 1 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.
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, in the room. Okay. Thank you.
Why is cytokine release syndrome not an issue? Like, why in your drug and in everybody else's it is?
we do CD62L... Are you talking about for Rondo-cel?
Yeah.
We do CD62L selection. This enriches the cell product for naive and central memory cells. They're not differentiated as much. They have lower adverse cytokine production, and so it has a little bit of a gentler profile. 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 ICANS, which some have seen. We haven't seen any grade 3 or higher cytokine release syndrome.
Can you use that strategy on other indications?
Possibly we can, yeah. It's been well studied in the ZUMA-7 trial, so that's why it was shown there not to impact outcomes. We've shown in our cells that our cell expansion data look exactly the same with and without dexamethasone. Okay, great. Thank you.