Lyell Immunopharma, Inc. ($LYEL)

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 [Audio Gap] 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 [Audio Gap] 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.