[Music] Welcome to this week's episode of The Read Out Loud, a weekly biotech podcast from STAT. I'm Allison DeAngelis. I'm Anna Forrestine. And I'm Elaine Chun. It's Thursday, April 16th, and we have two very newsy guest interviews to share with you this week. First, we talk with Alligene Chief Medical Officer Zach Roberts about new study results that bolster the company's effort to develop an off-the-shelf CAR-T therapy for B.Cell lymphoma, a type of blood cancer. And then we'll dive into the biggest news of this week. Revolution medicines and the stunning survival benefit reported for its experimental drug in a phase three pancreatic cancer study. Dr. Paul Overseen, a pancreatic cancer expert from NYU Lingoon will join us to discuss the data and what it means for pancreatic cancer patients. We'll bring you those interviews right after a word from our sponsor. I'm Jesse McCordor's Editor of Stafford & Studio and I'm joined today by Priti Hedda, Senior Vice President and Global Head of Research at Kite, a Goliad Company. Priti, can you tell me a little bit about the multitude of platforms that you're working in? In most companies, the scientific teams engage in one platform or the other, very really fortunate at Goliad and Kite where we have access to expertise in small molecules, we have expertise in large molecule development and we have expertise in cell therapy as well. And so the question here is what is the right scientific question for the right modality and bringing them together is what ultimately will result to transformative benefit for patients. Later in this episode, we'll hear more from Priti and her colleague, Jackson Egan, in a sponsored segment with Goliad Sciences and Kite. Allogene therapeutics is one of the few biotechs still developing and off the shelf CAR T treatment for B cell lymphoma. It's been a struggle. Clinical setbacks and changes to the treatment landscape have caused delays in strategic pivots. Many of the biotechs competing with Allogene to develop off the shelf CAR T's for cancer have abandoned their efforts and are now focused on autoimmune disease. But Allogene has persevered and on Monday, the company announced preliminary results from a clinical trial in patients with B cell lymphoma that may vindicate its efforts. Joining us now to discuss this week's study results is Zach Roberts, Allogene's chief medical officer. Zach, welcome to the podcast. Thanks Adam, happy to be here. We're going to get into the exact study results in just a moment. But first, can you give us some background? They'll be helpful for listeners about Allogene's CAR T treatment and how it differs from currently approved CAR T treatments. Sure. So Allogene has, as you mentioned in your intro, been developing Allogene, CAR off the shelf CAR T cells since its inception several years ago. And we have a few products that we've had in the clinic and generally they've been safe and efficacious in phase one studies. And that includes the product that we're going to be talking about today called I'm going to say the whole thing here, Semicaptegine and Segoed Lucille. But we'll call it Semicill. I think that's a good idea. Yeah, I think so. Even I struggled on that one a little bit. So Semicill has been in the clinic now for several years, probably five or six years now. And we actually published the phase one experience last year in the Journal of Clinical Oncology. The product itself is a off the shelf CD-19 Allogeneic CAR T cell. And we manufacture this product from healthy donors. We do some minimal gene editing to make them safe for infusion in an allo recipient. So a HLA unmatched recipient. So we take out the T cell receptor, which is the part of the T cell that mediates graph versus host disease. And then of course, we also put the CAR molecule in. And as I said, it's a CD-19 CAR. It's got a 401BB coast-imdomain. So similar to Lysocel on that regard. And we started the program looking at relapse refractory large B cell lymphoma. And we had quite an extensive experience in phase one, treating patients with bulky progressive disease. And we showed a nice response rate, nice CR rate, and good durability. So comparable in phase one to what we see with the autologous products. And then in 2024, we decided to shift gears a little bit and move away from the relapse refractory setting and enter the first line consolidation setting, which is what, which is the data that we shared earlier this week. Okay, Zach, so to get more into this indication that the aim is, you know, if the company is successful with this therapy, the aim is to delay or prevent cancer relapse or death. Can you explain a bit more about this indication, the setting, and why off the shelf-car tea treatment might benefit patients in the situation? Sure. So to get to that, I think we need to start maybe a half a step upstream. And that is to think about the natural history and the treatment journey of a patient with large B cell lymphoma. So typically in the current era, what happens is, you know, you are given the diagnosis of diffuse large B cell lymphoma, which is the most common subgroup of LBCL generally. And the standard treatment is the same, the world around, for the most part, it's a, it's a regimen called R-Chop. And that's a five drug regimen, each letter stands for its own separate drug. And that's given for six cycles, they're given every three weeks, and at the end of that roughly five month treatment period, you undergo a disease assessment to understand whether your disease responded to that treatment or not. And the typical way that we do that is something called a PET CT scan, which both measures the size of any residual tumors, but also their metabolic activity, so they sort of glow on the scan. And about 90% of patients who follow this path will achieve a remission of some quality. Most of those are complete remissions, meaning on the scan, there is no visible tumor at all. And then a minority of them will achieve what's called a partial remission, which is the CT scan or the portion of the scan, the part that glows, will indicate some residual inflammation or abnormality in the anatomy that suggests potential for residual tumor. Once that sort of remission is achieved, certainly in the case of the complete responders, the patients are effectively surveilled at that point with longitudinal scans. And after two or three years, if the disease hasn't come back, we start to let out a sigh relief. And if that five years, it still hasn't come back, we declare that patient cured of lymphoma. So it's really, you know, you're on the edge of your seat the whole time waiting for for these next scan results. In fact, I used to call it when I used to take care of patients, scans IAD because you just don't know what's going to happen. So with that background, alpha three is kind of turning that paradigm a little bit upside down. And what I mean by that is in addition to that ever so critical scan at the end of frontline treatment, there's this new group of diagnostic tools called minimal residual disease. These are blood tests that are customized for each patient. And effectively, they are are a much more sensitive and also specific tool to ascertain whether there is any tumor left in your body. So for those patients that have a complete remission or a partial remission, approximately a third of them, by the way, will eventually have their tumor come back. Two-thirds are cured, but a third of them will have their tumor come back at some point in the future. If we perform this minimal residual disease test, at the time that they're given their good news from their scan, we can actually break patients into two groups. If you're if you're MRD negative, meaning that we use this this new test and we cannot find any molecular residual disease in your in your body, we are much more confident that you are actually going to end up being cured. And in fact, you can probably begin to breathe that sigh of relief much much sooner than under the current paradigm. If on the other hand, you're found to be MRD positive, meaning we can find DNA evidence of residual lymphoma in your body at ever so slight quantities. That puts you in a very different risk category. And in fact, prior research has indicated that you are likely to have a disease progression event probably within the next six to 12 months. And so alpha three, sorry, with that long-winded background, alpha three is a study that is designed to see if we can eradicate that minimal residual disease. If we can give the semisell to these patients who are MRD positive at the end of first-line.
treatment. And you race, you know, in other words, as oncologists used to say, mop up that residual disease and put patients into a cured state before the relapse occurs. So that's the alpha-3 concept. So as we mentioned earlier, Zach, allergy and reported these preliminary results from the alpha-3 clinical trial on Monday. And in that interim analysis, 58% of the patients treated with C. Macelle, your your car T, came out with MRD or minimal residual disease, negativity. They were negative on that MRD test that you mentioned. And that was compared to 16% MRD negativity of patients who were just observed. 58 versus 16%. Obviously a nice wide margin there favoring C. Macelle. Tell us what what you can glean from these results. What does these results mean? Sure. So it's important to remember that this analysis was planned when we wrote the protocol. And in fact, we called it an interim futility analysis because this is a novel study. No one has done this study in lymphoma before. And certainly not with an off-the-shelf allergenic CD19 car T cell like C. Macelle. And so we the primary endpoint of the study is event-free survival, which is a standard validated clinical endpoint. It was the same endpoint that was used in Zuma 7 and transformed that led to the approvals of Yuskarta and Breonzi. But this interim futility analysis is an early look within this ongoing pivotal study to see whether the hypothesis of alpha-3 was sound. And the hypothesis being, can we mop up that disease? Can we eradicate minimal residual disease? And then the next big question is, does that elimination of residual disease portend an improvement to event-free survival, which is what, of course, the study really cares about? So in this interim futility analysis, we looked at 12 patients in each arm. And Adam, as you rightly pointed out, we saw 7 out of 12 or 58% of the patients who received C. Macelle lose the MRD positive status and move into that MRD negative category, which we believe is a good prognostic category to be in, versus only 16% in the arm that is just being observed and just a quick note on that control arm. The reason it's observation and not an active treatment is because MRD currently today, as I articulated in my little introduction, is not part of the standard of care. If you were to perform this test in an everyday lymphoma patient, you're not going to act on that result. And so the current standard of care is to just continue to watch these patients and see if their disease comes back. So back to your question, Adam, what does this mean? We take this to be a very strong, de-risking, sort of, affirming observation of the core hypothesis of alpha-3. That is, can we eliminate this residual disease? Now, we think we don't know, because we have to complete the study, but we think that this means that these patients are going to do better in the big picture than the patients who don't convert from MRD positive to MRD negative. And in the context of the clinical trial, we, of course, are optimistic that this means that this will bring about an improvement to a then-free survival. And what have you seen so far from the safety perspective of the clinical trial? That, I think, is as exciting as the efficacy. So let's talk about the safety profile first before I get into the implications. So the safety profile that we saw in this early group of patients was quite promising. In the control arm, remember, the control arm is observation. So, you know, they're not getting any kind of treatment at all. So, effectively, what you're measuring there is what happens to this group of patients in the immediate aftermath of six cycles of our chop. We saw a couple of low-grade infections in those patients. We saw one patient who had reported some low-grade dizziness in the treatment arm, which is, of course, the one that we're most focused on in such a study. What we're really worried about with CAR T cells is things like CRS and the neuro-toxicity syndrome called ICANNs. And we saw zero cases of CRS of any grade, zero cases of ICANNs of any grade. And what that means is these patients were able to be managed entirely in the ambulatory setting without any tosalism ad being given to mitigate CRS without any pre-treatment with steroids or treatment after, in fact, infusion with steroids. These patients were infused in largely in the infusion clinics and then sent home and never had to come back into the hospital. We did have two patients come in for treatment unrelated things in the sort of weeks after semisell. We had a one patient who had an atrial fibrillation and another patient who had some musculoskeletal chest pain that required some brief admissions, but those were not thought to be related to semisell. So, effectively, it had a very clean safety profile. And why is that important? That's important because that allows us to bring this product outside of the academic centers, which are currently the only places where you can get autologous CAR T and into the community, which is where the bulk of the patients are treated. So, this is why we're so excited about that safety profile. Zach, the study is ongoing. It's still enrolling patients. When do you expect to report more results? And what are you hoping to see when more results read out? So, this is an event-driven endpoint, event-free survival, and just for the audience's information. In our case, event-free survival is a composite endpoint that is made up of progression of disease, death from any cause or new anti-lymphoma treatment. The study is powered to detect a 50% reduction in risk of EFS in the treatment arm relative to the control arm. And so, for us to read out the primary endpoint, we have to accumulate a certain number of EFS events. And so, the first trigger to perform an analysis on the primary endpoint will come middle of next year, and that is with an interim analysis on EFS. And then the primary analysis will come about a year after that in mid-2028. So, Zach, we mentioned the autologous or the patient-specific CAR T therapies earlier. They are fairly entrenched as second-line treatments in B-cell lymphoma, and have been shown to prolong survival. One question or doubt that I hear about allergy and strategy with CMA-cell is whether treating patients in this frontline consolidation setting, which is, I guess, the way I think about it is essentially in between the first and the second line. Will that really offer more benefit for patients, rather than just treating patients with an autologous CAR T after they relapse in that second line setting? Like, I'm sure you've heard this question or this criticism or this doubt. Like, how do you respond to that? Sure. So, I'm going to answer the question in two ways. The first way is looking at the product profile that we've just shown this week, and the efficacy and the safety. If the MRD clearance that we observe 58%, translates in the way we think it will, based on historical precedence and comps, to event-free survival, meaning preventing the relapse from occurring. Then, our efficacy is likely to be quite comparable to what you would get with a ESCARDA or a Brianzi in the case of a relapse disease. This is still a little early, and we have to wait for the full study to read out. But just for the sake of this discussion, if we're equivalent or near to equivalent on the efficacy side with semicell treating at MRD state as opposed to waiting for relapse, then I think that part of the teeth of that question go away. But if you look at the safety profile on top of that, then clearly, I think the benefit risk ratio here clearly favors semicell. Again, we have to wait for the full study results, but the way this is shaping up suggests that this is an outpatient regimen. We call it the seventh cycle of treatment. These patients go home. That's a very different proposition than treating somebody with relapse disease with ESCARDA or Brianzi, where you've got a 40-50-60% chance of needing to be hospitalized for treatment of side effects. So that's one way to think about this, the answer to that question. The second answer to your question is about the venue in which the autologous cartes are administered. Right now, in 2026, and this is not controversial. This is an analogy and talking point. This is widely published and even acknowledged by some of our peer companies who make autologous cartes. Only about 15% of patients who would be benefit, who would benefit from cartes. So these are relapse lymphoma patients. 15% of them actually make it to autologous carte. That means 85% of patients are not even being offered
offered this potentially curative modality in the second line. So that question I think is always coming from doctors who give yes, Carter, who give Brianzi in second line and it's no problem for them to administer this to their patients because they work in academic center where this is readily accessible. But for the bulk of patients, 85%, that's just not part of the conversation. And so if you've got an off the shelf product that can be shipped to just about any clinic in the country, administered in the infusion clinic with little to no expectation that these patients are gonna need a hospital readmission, that's an absolute game changer. - You know Zach, the early semisl results on MRD negative we're better than expected. And as we've talked about, you have this nice clean margin between patients who are being observed and patients who are being treated. Investor reaction was mixed. The stock went up initially and then it fell and Alligen raised $175 million at $2 a share, which is lower than where the stock traded before the data was announced. I know you're not the finance guy, but can you try to glean what's going on here? Was this bad execution? Are there still kind of lingering questions about Alligen and Carti therapies? Is this kind of confusion about this clinical trial which I think as this conversation shows, there's a lot of caveats there. - So it's a great question and you're absolutely correct. I'm the science guy, I'm not the money guy. First, I'll lead with Wall Street dances to the beat of its own drummer and investors are out to generate returns. That's their job. Bankers think that they can outsmart them or outfox them. And I think we might have got caught up in that machine a little bit this week. And let me also say that I'm not so sure that investors, when I speak to investors about this data and I've spoken to dozens of investors in the last week, the reaction to the data is actually not mixed at all. It's actually quite positive. And so the dynamics that we observed in the market this week, I do not think are coupled to the data. There's something else going on that is well above my pay grade to understand. And while you're correct, there, you know, Allogene has been around for a long time. We've had to pivot our development and we're reading the tea leaves on how the clinical field is evolving. But when we embarked on this path two years ago, we saw as clear as anything where the field was heading these of the MRD and we knew that this was going to be part of everyday care. And when you look at the outcomes between MRD positive, MRD negative patients, now it's been published, you know, time and again, it is quite obvious that there is an opportunity to run a clinical trial in that context. And so we took that opportunity. We were out in front. And I think what we have done is we have defined a new path for alleging a CAR T cell. So all that history about CAR T cells, you know, ALO doesn't work as well as auto, which I disagree with, but that's an error that's taken root. We have found a place where ALO can shine. And in fact, what the data showed from this week is that we are shining. We have a product profile that is impossible to match with its off the shelf availability. It's, you know, early, but very encouraging and a benefit risk ratio. You can't do what we're doing in alpha three with an autologous CAR T. You just can't. So our one time off the shelf sort of outpatient community friendly product, this is going to change how we take care of these patients. And the rest is history. - Zach, thank you so much for joining us. - It's been a pleasure. Thank you so much for the invitation. (upbeat music) - We saw a lot of clinical data announcements on Monday and none were bigger than the striking survival benefit reported by Revolution Medicines for its targeted pancreatic cancer medicine. - Patients with advanced pancreatic adenocarsinoma who were treated with a company's daily pill called Diracson Rassad lived a medium of 13.2 months compared to 6.7 months for patients who received standard chemotherapy. - Revolution Medicines said it plans to use the data to apply for FDA approval, although it did not say when. When it does submit the data to the FDA, approval might come fast. The company is already a recipient of the Commissioner's National Priority Voucher for Diracson Rassad. - Joining us to discuss the data and its potential impact for pancreatic cancer patients is Dr. Paul Oberstein of NYU Langones Pearl Mudder Cancer Center. Dr. Oberstein is an investigator in the Dirac's phase three study. Paul, welcome to the podcast. - Thank you for having me. Good morning. Paul, let's start by talking about pancreatic cancer generally. Why is this so challenging to treat it and what are the current survival rates? - Yeah, so pancreatic cancer generally refers to pancreatic adenocarsinoma as this drug is targeted against. And that's the common form of pancreatic cancer. It affects over 50,000 people in the United States every year. And for most people, it's diagnosed at a late stage where cure is impossible. The cure rate for metastatic pancreatic cancer is in the low single digits, around two to three percent of patients live for five years. We think some of the reason for that is that the tumors often very advanced by the time it's diagnosed because it's silent in the body. But another primary reason for that is that almost all pancreatic cancer has this very strong driver mutation called K-RAS, which is present in over 90 to 95% of these tumors. - So chemotherapy regimens have been the established standard of care for pancreas cancer. Despite advances in immunotherapy and targeted therapies in other types of cancer, why haven't we seen the same kind of traction in pancreatic cancer over the last few years? - It's a great question. And unfortunately, one of the mysteries of pancreatic cancer where we definitely see that chemotherapy helps people. So very often, someone will come up with pancreatic cancer with a lot of symptoms like pain or weight loss. And very often, chemotherapy will make them feel better. The challenge has been that it usually only works for a few months. And so the average time that someone can benefit from chemotherapy is somewhere between four to six months on the initial chemo and then maybe a few more months, three to four months with the second chemo and not long enough. So chemo works, it just tumors become resistant very quickly. The targeted drugs have been by and large on successful pancreatic cancer, including immunotherapy. And there are some rare exceptions for patients with really specific mutations. But for most people, we haven't been able to find something. And part of it we think is because of this Keras driving driver of the tumor. So because so many tumors have Keras, other targets seem to be less effective. - So we definitely want to talk about that Keras mutation in a second. So with that background, Paul, what was your reaction when you saw this survival outcome that was announced this week? - Yeah, I have to say we were elated. It was an incredible positive outcome. As you mentioned, I'm investigating on the trial. I've been using this medication in phase one and other trials. This is not a shock to us that it helps some people. But I think the validation in a large phase three trial and the scope of benefit, both the magnitude, the numbers recorded 13.2 months, median survival. But the fact that it was an unselected population. So it was given to anyone, basically, with pancreatic cancer. And the fact that this held up in a late stage trial was incredibly exciting. And I think is the opening of a new era of how we treat pancreatic cancer. - Paul, can you explain to us how Dorax works? And what about the mechanism of the stroke? Do you think makes it so effective? - Yeah, that's a great question. I'll try with that. It is a little challenging. I'd remind you that we knew we meaning the scientific community new decades ago already that Keras is a common mutation in many cancers. I mentioned it's over 90 to 95% of pancreatic cancers have this mutation. But many, many colon cancers, lung cancers, and other cancers also have mutations in the Keras oncogene. So the target's been known for decades. And the fact that it drives pancreatic cancer has been known for a long time as well. And there have been tremendous national and international efforts to target it. But they've not been successful on this scale until now. And so part of the answer to the question is that it's really complicated and I'm not 100% sure we know exactly why. This one was so successful. But the strategy that the company used to design this small molecule inhibitor, so this oral medicine, is that instead of directly blocking the mutation, the Keras protein that's mutated, it forms what's called a glue, a molecular glue, where the oral molecule, the Deroxen-Rasib, goes into the cell, it binds to another protein called a chaperone protein. And together that compound blocks the mutated protein and prevents it from working. So as you can tell, it's pretty complicated. There's a lot of steps going on there. But it's essentially instead of going directly and blocking it, it's gumming up the machinery and preventing it from working in the cell. I'm curious, Paul. You mentioned that for so many years, we have known as a
scientific community that K-RAS is playing a factor in pancreatic cancer. And it's been really difficult to drug K-RAS to be able to target it specifically. How is it felt as a practitioner to have this information, know what is happening with your patients? And for up until recently, see so many medications that just can't target it. - Yeah, again, I can't share. I came up and told my kids the news that they didn't care as much as me. But to me, this is really, really exciting. Partly because of what you said. I mean, I am a clinical trialist and so I've involved in many of these trials. But of course, people have been trying, including us for decades now. And it turns out that a lot of the animal work has led to this, meaning a lot of validations come from animal models of K-RAS mutated pancreas cancer. But there are, of course, our drugs that work in animals that then we then put them in people and they don't work. And so it's really exciting when you get something that is predicted to work. It works in the animal model. You put it in the people and it does exactly what you wanted it to do. So that's incredibly thrilling. I think there's still a tremendous amount to learn. This is the beginning of hopefully the floodgates of both other companies looking at ways to drug this previously undruggable protein, but also combinations and new paradigms and how we think about patients. And like the world's our oyster. I mean, we do clinical trials and we're just so excited about the prospects for what we can do in pancreas cancer. - So former Senator Ben Sass, who was diagnosed with metastatic pancreatic cancer last December, said in a recent New York Times interview that he's been taking this drug. I think it might have been on a different clinical trial. But he talked about how his tumor volume had gone down significantly since taking the drug. And actually, we in a state interviewed him and he said that he thought that the drug was extending both his quality and quantity of life. I don't know if you heard that interview, Paul, but how does it job? Like I said, you have participated in clinical trials with Derracks, like how would you heard from Ben Sass? How is that similar? Different from some of the patients that you've treated? - Yeah, I think, of course, every person's unique and I am not treating him, not involved at all. I did see some of that interview and obviously read some of his other discussions about his treatment. But it's actually, he has a rash, which I think you probably talked about and we've seen not everyone gets that kind of rash. Some people do, many people don't. But in terms of the response to therapy, it's pretty typical that someone will get benefit, they'll get benefit early. And unfortunately not true for everyone and some people start this medicine and it doesn't work. But for a very large percentage, you see the majority, it provides benefit. As you said, not just keeping their numbers lower or their scans better, but in them actually feeling better, which is of course the goal. - And then you just mentioned Ben has talked about the side effect with the rash and the bleeding on his face. What are other adverse events that come with the stroke and how significantly do they affect patients quality of life? - Yeah, I mean, so he presented that. Obviously it's not surprising that a new medicine, especially targeting a new pathway is going to have unintended or maybe intended, but off-target consequences. I think the data that we have is incomplete. So the company revolution medicine has had presentations of their own data and some peer review presentations of the early phase, the phase one studies and some expansion cohorts. The exciting news on Monday came from the phase three study which really all the news that's public that we know is what you saw in that press release, which is that it was positive on every metric that there was a survival benefit. I think that data is going to come out very soon, right? There's tremendous urgency to get it out there. And so I don't think I know or we really are able to talk about what was seen in that study. I think though in the earlier studies and other experience, rash has been something that's been reported quite commonly, but is very manageable for most patients or maybe almost everyone. There are other side effects they report or are other sort of GI side effects like mouth inflammation, mucusitis or sometimes trouble eating or diarrhea. But I'd say for the most part, it's been GI and rash. So GI and skin toxicity for most patients and overall in the early studies, especially it's been manageable. It's not necessarily pleasant and somebody will have a harder time than others, but it's been able to be managed and people can stay on study and get this treatment. - You know, Paul, I want to ask about some of the reaction that we've seen over the last couple of days. There was one doctor who was on Twitter/X saying that this excitement around the drug had was kind of hype and kind of criticizing the fact that six to seven months of additional survival, of improvement and survival, that was being presented as a revolution in oncology. You know, these patients unfortunately, we should note, their cancer is not being cured, but his comments got pretty immediate blowback on social media. What do you say to somebody like him who's looking at this data and is not impressed by it? - So I didn't, I can't say I know the exact comment. I mean, I think the reality is that we're talking about a treatment for second-line metastatic pancreas cancer and we haven't seen the final data, right? We don't know if the median survival is 13 months, there are probably some people who are alive at 18 months or 24 months or hopefully one day at 36 months, right? So I don't think we have the data to say too much about it yet. I would just say, you know, pancreas cancer is a third leading cause of cancer death in the United States and in many other countries. It's a huge problem for many, many people. And this is the best data we've ever seen in a phase three trial for pancreatic cancer. So certainly there's room to do better, but it's a pretty good start and I do think it's a revolution. And I'd say that, you know, the company name chooses that, but it partly just cause it's such good data. I mean, it's not just that it's a new therapy, it's that it came out with such impressive benefit over what we currently do, which is chemo. And more so because it's a new pathway. So it's, you know, there's so many potential ways that this will evolve and be combined and get better over time. So there's no question, again, I don't know the Twitter comment that there's room for a lot of improvement. And we need to figure out how to do that, but I do think this is quite revolutionary. - So Paul, you know, just diving into that a little deeper. As you mentioned, you know, this study that was run, this was run in patients who had advanced pancreatic cancer with that was no longer responsive to their initial or frontline treatment. So this was a second line study, but yet it was noted also that the 13 month survival benefit here in second line was actually longer than what you typically see in a frontline treatment setting for pancreatic cancer. I wonder, like your comment about your thoughts about that and how maybe you see this drug moving up into a first line treatment setting. - Yeah, so I did make that comment and I just say the first line regimens that we currently have approved for pancreas cancer are two or three regimens. They're all associated in the phase three trials with survival times that were less on median than 13 months. So this is better, again, it wasn't done in first line, but better than what we had seen. Now that's not a trial, right? So I think things have evolved. It could very well be that first line survival's better than it was 10 years ago when those trials were done. So I think we definitely need to evaluate that in clinical trials. I think one of our challenges here is that every single person in pancreas cancer who saw this press release is calling us up and saying we wanna get this drug and it's not available, right? They've gotta get it FDA approved. But even if it, when it gets FDA approved, I think we still have to understand when the best context is to give it. And so it's certainly intuitive and the company's already started a trial and I think that dose their first patient in the last month looking at this as a first line treatment. So that, to me, makes sense as a clinical trial that has to be done, Deroxin RASIB is for patients with untreated metastatic pancreas cancer, but just because it worked in second line doesn't automatically mean it's gonna be superior in first line and doesn't tell us whether we should do it first or second or in combination with chemo. And then of course, as I alluded to a few times, there are many, many other drugs that are coming in development that are looking at this pathway. And we don't know if they will somehow have an advantage over time. - Paul, so the initial data that we have from this trial was in the press release this week. It's anticipated that Revolution Medicine is while you presenting the study at the ASCO meeting that's coming up at the end of May. What do you wanna see when the data are presented? What outstanding questions would you like to see answer when we get the full data? - Yeah, so I think a lot of data points, survival is really important and to me, it's the most important metric 'cause that's really what matters. But usually when we do a trial, we look at several things along the way, including response rate, progression of free survival, duration of response. And the reason you look for those is you're looking for anomalies, right? If something is a very low response rate but a long survival, there's something unusual going on there. So I think we just wanna see the whole package of data to make sure that this is so revolutionary in my opinion that you wanna make sure you're not somehow making a mistake in what you're looking at. So that's the full data set. But at the end of the day, you also wanna make sure the patients in the study are typical and that this is translatable so that whoever was enrolled is a representative population so they'll present that data. And then I'd say of all the things that most important to me is looking at quality of life and toxicity, right? So.
Ultimately, you hope that if you double survival, people have better quality of life during that time. You hope that it's manageable toxicity, that they don't have to stop this drug because of side effects. But that data is going to be very granular. I don't think we're going to get it all at the presentation and ask if that happens in the next six weeks. But I do think in the manuscript and over time, we're going to see a lot more of that data. And that's really important to know how to use this in practice. I was just wondering, as we mentioned, this is a drug that works by targeting these K-RAS mutations. But as you noted, the data that we got in overall survival was in all comers. So patients who both had the K-RAS mutations and those who don't. I mean, will that be important? I mean, if we sort of separate one, to parse out the data by patients with the mutations or not, how do you see that sort of playing out? Yeah, so I mentioned that because it's really important. Every time we have a therapy and we say, well, it helps people, but it's only the few percent that have that. It's a good thing for those people, but it does limit the applicability. So it's a little tricky here because K-RAS is a common commin mutation. So it's somewhere between 90 and 95 percent. And so it's not a rare mutation, but it's not 100 percent. And I think the question is, how do the people who don't have K-RAS get pancreatic cancer? And so there are a lot of answers to that because there's a lot of different people. But some of it is through other mutations in the same pathway that leads to K-RAS activation. And so it's conceivable that this RAS on inhibitor will actually inhibit other things or inhibit even wild type RAS in the pathway and lead to benefit. And so we're going to want to see that data. I don't know if it's going to be large enough because it's going to be a small, you know, 400 patients, probably a small number or K-RAS wild type. But if they present and have that data, I agree it will be very eager to see that. Also curious to see what FDA does in terms of the approval, right? So the study, like I said, was all comers. And whether they'll approve it for all pancreas cancer patients. Well, Paul, Dr. Overseen, we are going to be looking at that data right alongside you. Thank you so much for joining us on the podcast. My pleasure. Thank you for highlighting this and really excited to talk more about this and learn more about this exciting pathway. I'm Jesse McHorters, Editor of StepRinth Studio. And today, I'm joined by two oncology research leaders from Kiliad Sciences and Kite. Jackson Egan is Senior Vice President of Research on Kology at Kiliad Sciences, where he leads early stage discovery efforts, spending solid tumors and blood cancers. Priti Hegda is Senior Vice President and Global Head of Research at Kite, a Kiliad Company, and a recognized leader in Cancer Immunotherapy Research and Translational Science. Jackson, Priti, thank you so much for being here. Great to be joining you today. Thank you for having us. All right, so let's start with you, Jackson. With so much happening across the oncology landscape right now, where do you see the greatest unmet need? And how does that inform Kiliad's research priorities? I think it's really important first to acknowledge the tremendous progress that has been made in cancer treatment prevention over the past few decades. Patients are living longer, and I think importantly, we now have clear demonstrations of durable, even curative responses that can be achieved with treatment, at least in some settings. Of course, the problem and the challenge is that these examples are too few and far between. There's still a tremendous unmet need. Many cancer patients, particularly those with advanced metastatic disease, still won't have adequate treatment options available to them. So our priorities at Kiliad and Kite are driven first and foremost by that unmet medical need, asking ourselves, what are the cancer types, who are the patients that are underserved by existing treatments, with that North Star of Unmet need in mind, we then focus on the disease biology, applying the expertise we have in cancer cell biology and immunology to ask ourselves, what are the key mechanisms or the pathways that are actually underlying unrestrained cancer cell growth or preventing the immune system from making an effective response to cancer? And then if we were to actually develop a successful therapeutic that targets these pathways, what would have the biggest benefit to cancer patients? So finally, we then look to apply the unique drug development expertise that we have at Kiliad and Kite and the breadth of therapeutic modalities. We have a data disposal from small molecules to large molecules, antibody drug conjugates to cell therapy to then develop a therapeutic that is going to have the biggest impact and hopefully transformational impact for cancer patients. Priti, how does this unmet need that Jackson talked about? Shape the research and the research questions that your team is focusing on? At Kite, we've seen what transformative benefit really looks like for patients. And so that's given us a sense for what the molecular and cellular drivers of response are in lymphoma and multiple myeloma. And as Jackson pointed out, we're really interested in exploring how do we then take these learnings from human trials and say, how can we now make that difference for patients in other diseases? Where the bar for efficacy, unfortunately, is low. And I'll give you an example, glioblastoma, really devastating disease, patients who get diagnosed with glioblastoma tend to have very poor five-year survival outcomes less than 5% of patients survive up to five years. That's a solid tumor indication or a disease where they're collectively really interested in exploring how do we tackle this disease? Now that we know what responses should look like for cell therapies from hematologic malignancies and take those learnings now to more difficult to tackle diseases in solid tumors, we're doing it with cell therapies. Jackson's team has small molecule inhibitors that address certain tumor intrinsic properties in glioblastoma. And then as we sit at the table together, we say, what can that future look like for patients where we can potentially combine these agents together for maximum transformative benefit for patients? Prety to get specific, I know you're doing some work around a need-ocell research. What is this signal about where Giliad and Kite are headed? The acquisition of our cell X-release signals, a deep commitment that Giliad and Kite have towards cell therapy as a platform. And it's not just based on what we see as its potential today, but truly where this science can lead us. Kite and our cell X started working together sometime in 2022 on the Anita Cell program. That is a BCMA targeted CARTI that's being developed in multiple myeloma. And through that collaboration and partnership, we got a really good sense for the potential for their platform. It's essentially a platform that identifies these small synthetic proteins called D domains. And you can imagine these patients with multiple myeloma who gone through many rounds of therapy. If you can provide them with a therapeutic option that has potential, it really democratizes the access of cell therapies beyond just these niche centers to more patients globally. And that's what we saw as the true benefit of this partnership and this platform with D domains. Our cell X has a really nice repository of D domains that we could leverage for a variety of applications both within Jackson's organization and Kite oncology as well as beyond oncology to other therapeutic areas. So I think what this acquisition signals is that sentiment of deep commitment to cell therapies. From the Gilead perspective, Kite has really led the way in advancing both in lymphoma and myeloma, these truly transformational therapies. I think it's given us at Gilead quite a bit of impetus to continue pushing into that space even more, developing complementary therapeutics beyond cell therapy into myeloma space and the lymphoma space that again could be ultimately part of a regimen of therapeutics that can make impact. Well Jackson and Prety, before we wrap up, how can people stay connected with this fantastic work that you're doing at Gilead and Kite? Well for Gilead, I would encourage folks to visit the oncology page at gilead.com. And for cell therapy, please visit guidefama.com. The science is moving quickly so we'd really love for people to follow along and stay tuned. Jackson Egan, Senior Vice President of Research on Ecology at Gilead Sciences, and Prety Hector, Senior Vice President and Global Head of Research at Kite. Thank you both so much for taking the time to talk with me today. Thank you, Jessen. Thank you. It's pleasure. And that does it for another episode of The Read Out Loud. Thank you to Hyacinth and Bonato for producing this week's episode. Our Senior Producer is Alissa Ambrose. Our Executive Producer is Rick Burke and our theme music is by Brian Joel. And we'd love to hear from you. Tell us what you like about this week's episode, what you didn't like and your reaction to this stunning pancreatic survival benefit. You can do all that by sending us an email at
[email protected]. And if you like what we do, leave a review or rating on Apple podcasts or whichever platform you use to get your podcasts. See you next week.
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