I'm Erica, and welcome to Gritstone bio's first quarter 2023 earnings conference call. Please note this event is being recorded. At this time, I'd like to introduce George MacDougall, Director, Investor Relations and Corporate Communications at Gritstone. Please go ahead, sir. Thank you, Erica. Thank you everyone for joining us for Gritstone bio's conference call to discuss our financial results, clinical and business updates for the first quarter of 2023. With me on the call today from Gritstone bio are Andrew Allen, Co-founder, President, and CEO, and Celia Economides, Executive Vice President and Chief Financial Officer. Today, after the market closed, we issued a press release providing our first quarter 2023 financial results, as well as clinical and business updates. The press release is available on our website. I'd like to remind you that today's call is being webcast live via a link on Gritstone's investor relations website, where a replay will be available after its completion. After our prepared remarks, we will open up the call for Q&A. During the course of this call, we will make forward-looking statements that are based on current expectations. These forward-looking statements are subject to a number of significant risks and uncertainties. Our actual results may differ materially from those described. We encourage you to review the risk factors in our most recent Form 10-K filed with the U.S. Securities and Exchange Commission and available on our website. All statements on this call are made as of today based on information currently available to us. Except as required by law, we disclaim any obligation to update such statements, even if our views change. With that, let me turn the call over to Andrew. Andrew? Thanks, George. Good afternoon, everybody. Thanks for joining us for our first quarter 2023 conference call. This is a really exciting time for Gritstone. Significant momentum has been established for our personalized cancer vaccine or PCV program called GRANITE, which is driving towards randomized clinical trial data. With infectious disease, we're making great strides in realizing the untapped potential of self-amplifying mRNA. I'll begin today's call with a review of recent clinical and corporate developments, including the expansion of the GRANITE study we announced today. Celia will then present her financials, and I'll come back to share closing remarks. Okay, let's dive right in. Most important to share with you today is the update regarding GRANITE, which is currently in the phase II part phase II/III study in patients with newly diagnosed metastatic microsatellite stable colorectal cancer. I'll refer to this as MSS-CRC. This morning, we shared an enrollment update from the study, and I'm delighted to tell you that we're enrolling at a rapid pace and very close to achieving our initial target enrollment of 80 patients. We also announced that we've made the strategic decision to expand phase II portion phase II/III study to 100 total patients. In order to do this, we'll be shifting near-term funds from our off-the-shelf neoantigen program, SLATE. SLATE is a key part of the future, but our planned randomized trial is not expected to deliver data near-term, of course, and thus must play second fiddle to GRANITE as we maximize the potential of this high-value PCV opportunity. Now, over the years, you've heard me speak of our strong belief that our PCV approach could be uniquely capable of unlocking the power of immunotherapy for patients with immunologically cold tumors. Our phase I/II data from GRANITE in advanced cancer patients that included immunologically cold tumors, published in Nature Medicine last summer, provided strong clinical data in support of the therapeutic hypothesis. Moderna's recent phase IIb data presented at AACR in April provided further evidence supporting the PCV approach, in Moderna's case, in the immunologically hot context of adjuvant melanoma. Just yesterday in Nature, Vinod Balachandran and his team from Memorial Sloan Kettering published data in the adjuvant therapy of pancreatic ductal adenocarcinoma with some provocative immunology and clinical data, potentially further supporting PCV, this time in the cold context of pancreatic cancer. Our current GRANITE trial is how this all comes together, with phase II study potentially being the first to deliver randomized data supporting a neoantigen-based PCV against MSS-CRC. I think it's widely recognized that if GRANITE delivers benefit in metastatic MSS-CRC, a notoriously cold tumor that is difficult to treat with immunotherapy, the opportunity for further application is enormous and potentially encompasses all solid tumors, both hot and cold. There are several reasons why we elected to expand the phase II study. Let me detail them. Firstly, a larger number of patients will provide a better estimate of treatment effect size, which will in turn inform an optimal phase III study sample size. To drill down on that point, the current study is designed as a phase II/III. To remind you, the primary efficacy endpoint for the phase II component is molecular response or ctDNA response, with secondary endpoints including progression-free survival or PFS and overall survival or OS. We anticipate discussing phase II data with regulatory authorities in the first half of 2024 and then moving into phase III. The phase III primary efficacy endpoint is to be determined based on our interaction with regulators, but it is likely to be a traditional endpoint such as PFS or OS. Powering the phase III study for a time-to-event endpoint will be done using phase II data, since phase II and III components are statistically separate. The greater the precision of the estimate of treatment effect size phase II data, the easier it is to power phase III appropriately. Secondly, momentum behind study enrollment has been very strong. As of May 10th, 2023, we've randomized 71 of the initially planned 80 patients, and that number's already gone up, and approximately half of these were randomized in 2023. All sites are screening and consenting enthusiastically. We expect this strong enrollment trend to continue for the foreseeable future. We anticipate completing enrollment of the full 100 subjects in the third quarter of 2023. Sadly, and worth reflecting on, this momentum arises in part from the high unmet clinical need. Colorectal cancer is the second leading cause of cancer death in the United States. Over 150,000 people are expected to be diagnosed with CRC this year alone. Median survival for patients with metastatic disease is around two years. Better therapeutics are desperately needed. Innovation is needed. We aim to deliver both. Thirdly, GRANITE is the tip of the spear for our neoantigen programs. The basic idea is that delivering many neoantigens to solid tumor patients in a potent vaccine that drives strong CD8 T cell responses will drive clinical benefit. GRANITE seeks to do exactly that, leveraging our neural network epitope identification platform, EDGE, to accurately predict which subset of tumor DNA mutations forms true neoantigens that will stimulate an effective antitumor immune response. Our published clinical data show that patients mount strong T cell responses to most of the administered neoantigens, with T cells trafficking into their tumors and killing tumor cells, as evidenced by the approximately 50% molecular response rate that we've observed. As you are well aware, our data further show that those patients with molecular responses experience extended overall survival versus those without. However, a PCV approach will always take more time and cost than an off-the-shelf approach. We're rapidly building out our off-the-shelf program, SLATE, which delivers shared tumor-specific antigens to each patient, but it is temporarily behind GRANITE in development. It takes work and time to identify high-quality, shared tumor-specific antigens that can be combined into a single vaccine that delivers multiple relevant antigens to each patient. Where GRANITE leads, SLATE will likely follow. However, showing that GRANITE delivers efficacy in a randomized controlled trial is our highest near-term priority. Before we move on from GRANITE and oncology, I'd like to draw your attention to the value of circulating tumor DNA or ctDNA as an efficacy biomarker. Reduction in ctDNA, referred to as a molecular response, is rapidly emerging as a likely superior surrogate biomarker of efficacy over radiology in the early assessment of solid tumor immunotherapy. It makes particular sense for us at Gritstone to assess molecular response in our studies because we aim to drive T cells into tumor lesions, where we have shown that they can meet cognate antigen and proliferate, potentially making the lesions appear bigger. This obviously makes radiology-based tools susceptible to errors of mislabeling. Lesions that increase or remain stable in size are labeled as progressive disease or stable disease respectively, when in fact the patient's immune system may be newly at war with their tumor, i.e. anything but stable. ctDNA dynamics are casting light on the key issue of what's actually going on in those complex lesions. Tumor cell destruction is reflected by a decrease in ctDNA over time. Now, molecular response is defined as a 30% reduction in ctDNA as the primary endpoint for phase II portion of our GRANITE study. We originally powered the study for this endpoint, we've waited for mature clinical data from our phase I/II study in advanced cancer patients to allow us to carefully define molecular response in a data-driven manner that is expected to best predict overall survival in colorectal cancer. To remind you, no one's done this before, we've had to build the framework ourselves. No one's ever generated strong de novo neoantigen-specific T cell responses in cold tumor patients before. No one's combined this with checkpoint inhibition. There is no off-the-shelf answer to the question, what's the best surrogate endpoint for overall survival? We've had to find the answer, that's exactly what we've done. We've generated data in phase I/II, we're now deploying a data-driven definition to establish efficacy in a randomized phase II trial. Once efficacy has been demonstrated phase II, we'll proceed into a pivotal phase III. As I've already noted, we anticipate using a traditional efficacy endpoint, such as PFS or OS, in the pivotal trial. There is a possibility that molecular response will have accrued enough support by 2024 to be used as a surrogate endpoint for accelerated approval. We would like that, but we are not dependent on it. We're very excited by the phase II trial, the momentum it's gained, and its potential to serve as a major advance in cancer immunotherapy as we seek to extend the emerging benefits of PCV to cold tumors. We will update you further on enrollment once complete, and we look forward to sharing preliminary data in the first quarter of 2024. Now let's move over to infectious disease, where data demonstrating potential advantages of self-amplifying mRNA or samRNA over first-generation mRNA vaccines continue to flow from our clinical stage CORAL program centered on SARS-CoV-2. The differentiation of samRNA from mRNA is now becoming clearer. The prolonged antigen expression associated with samRNA vaccines appears to be translating into a more durable neutralizing antibody response, potentially reducing the need for frequent booster vaccinations. The replication of the RNA, once in the cell, appears to enable similar immunogenicity as non-amplifying mRNA at a fraction of the dose, offering a cost of goods benefit. In April of this year, we presented new six month neutralizing antibody data from our ongoing phase I CORAL-BOOST and CORAL-CEPI studies at the 33rd European Congress of Clinical Microbiology and Infectious Diseases, also known as ECCMID. These presentations in Copenhagen demonstrated that the robust neutralizing antibody responses driven by our samRNA vaccine candidates persist for at least six months, regardless of setting and across multiple subject populations. Of note, in the CORAL-CEPI presentation, we reported high neutralizing antibody levels and persistence at six months in over 100 vaccine naive subjects, a meaningful increase in subject numbers versus our prior data reports. samRNA is rapidly emerging as a tolerable, immunogenic, and flexible next generation platform for vaccines against infectious diseases, including COVID-19. The induction of broad, long-term and potentially variant proof immune responses that we're seeing in our phase I studies is highly promising for the field. We look forward to continuing to work with collaborators to demonstrate the full potential of our samRNA platform against both SARS-CoV-2 and other important viruses. We expect to share additional data from our CORAL program this fall. These data will relate to different immunogen designs, illustrating the flexibility of the platform to accommodate both B-cell and T-cell epitopes in efficient formats. It is clear that there is still need for next generation solutions against COVID-19. The recent actions by the White House and BARDA are encouraging signals that the pursuit of enhanced breadth and durability of protection is not going to the wayside. Outside of our PCV and SARS-CoV-2 programs, our forward-looking efforts to identify and develop potentially transformative vaccines continues. Our partnership with Gilead to develop a vaccine-based curative immunotherapy treatment for HIV remains active and ongoing in a phase I study. Promising results from a preclinical study in non-human primates within this program were presented at the Conference on Retroviruses and Opportunistic Infections in January. Our preclinical projects against human papillomavirus, influenza, and a new combination vaccine against multiple respiratory viruses continue to progress well. I'll now turn it over to Celia, who will provide more color on our financial results for the first quarter of 2023. Celia. Thank you, Andrew. Good afternoon, everyone. We maintained a strong cash position in the first quarter of 2023 and have been able to extend our runway through multiple sources. Ending this recent quarter with $153.2 million in cash equivalents, marketable securities, and restricted cash. Our runway has now been extended into mid-2024. In addition to utilizing our ATM program from time to time, you'll recall we also have an $80 million credit facility with Hercules Capital and Silicon Valley Bank, a division of First Citizens Bank. During the first quarter, we drew an additional $10 million from the facility, totaling $30 million to date. We also have the option to draw an additional $10 million before the end of 2023. The remaining $40 million will be available through June 15th, 2024, upon achievement of certain milestones by Gritstone. While we have taken steps to extend our runway so far in 2023, we also have multiple potential avenues to secure additional capital. These include, but are not limited to, drawing down additional funds from our existing credit facility, establishing new or expanding existing collaborations and other non-dilutive funding sources, such as a potential $40 million milestone payment from Gilead on our HIV cure partnership. Turning now to our first quarter 2023 operating results, we reported a net loss of $34 million compared with $28.9 million for the same period last year. Our research and development expenses were $30.5 million for the three months ended March 31st, 2023, compared with $28.2 million for the same period in 2022. The increase in R&D costs was primarily due to increases in personnel-related costs and laboratory supplies. Specifically, for our GRANITE program-related expenses, we incurred $5.4 million in the first quarter of 2023, compared to $2.7 million for the same period last year. The increase was primarily due to the continued execution of phase II/III trial in first-line maintenance MSS-CRC. For the period ending March 31, 2023, we were able to reduce general and administrative expenses to $6.7 million from $8 million for the same period in 2022 by managing our spend on outside services and facilities-related costs. You may recall that the establishment of collaborations and partnerships is a core part of our business strategy as we continue to leverage our unique platforms and capabilities. Gritstone's collaboration, license, and grant revenue for the first quarter ending March 31, 2023 totaled $2.4 million compared to $7.2 million for the same period in 2022. These also include collaboration revenue of $0.1 million related to the Gilead agreement and $0.4 million related to the 2seventy bio agreement. This also includes grant revenue of $1.5 million from the CEPI funding agreement and $0.4 million from the Gates Foundation. Finally, as of the end of the first quarter 2023, Gritstone had 87,848,417 shares of common stock outstanding and pre-funded warrants outstanding to purchase 13,573,704 shares of common stock at a nominal exercise price of $0.01 per share and 13,274,923 shares of common stock at a nominal exercise price of $0.0001 per share. In summary, we are pleased to have maintained a strong cash position and extended our runway during the first quarter of this year and are confident in our ability to execute on our strategic objectives. I'll now turn the call back over to Andrew for some closing remarks. Andrew? Thanks, Celia. As described today, happily, Gritstone is in a period of significant momentum. Robust enrollment within our PCV program, GRANITE, has enabled study expansion and the generation of additional clinical and scientific data to inform the future development of GRANITE and further validate our approach to solid tumors. Within infectious disease, we're pioneering a novel technology that could represent the next RNA platform approach against SARS-CoV-2 and beyond. We look forward to continuing to share our findings with you as progress continues. With that, I'd like to thank you all for joining us today, and I'll now turn the call over to the operator for questions. Erica? If you would like to ask a question, please press star one on your telephone keypad now. You'll be placed into the queue in the order received. Please be prepared to ask your question when prompted. Once again, to ask a question, please press star one on your phone now. Our first question comes from Marc Frahm from Cowen. Please state your question. Thanks for taking my question, and congrats on all the progress. It sounds like some pretty exciting enrollment numbers that you're seeing these days. Maybe just to start off on the change in trial size, can you talk through the kind of the process that led to that decision? Was this initiated entirely by Gritstone, or is this something, you know, maybe regulators ask you to think about? Then can you walk through the kind of powering assumptions that are now built into the trial, given the new trial size? Yeah. Thanks, Marc. This was a Gritstone-generated decision. phase II basically is up to us. Obviously, what we're trying to do is optimize for phase III now. We, you know, are in the fortunate position that just a short period of extended open enrollment will put in a meaningful number of incremental patients. It's that really that combination that drove us to make this decision. Now, the primary endpoint for phase II, as you're aware, is molecular response. That's a binary outcome, and we are extremely well-powered to detect at least a 20% difference between the two arms of the study. You know, we're in the high 90s power for that endpoint. What we're now more interested in actually is looking beyond the primary efficacy endpoint phase II and starting to think about planning for phase III. Of course, phase III will all be about the size of the study. The current thinking, and let's recognize we have not yet discussed this with the agency, the way we approach this is to assume conservatively that we'll be using a traditional endpoint. The most traditional will be OS. Obviously, PFS has a good history in colorectal cancer, we may be able to use PFS if we don't see too much pseudo-progression. The data will help us make that decision. You have to think about the powering of the phase III study. Obviously, more is always good from a power perspective, but more is slower and more expensive. You want to size it appropriately. You don't want to overpower, but you don't want to underpower phase III. The best way to gauge that is to have a good estimate of that endpoint from phase II study. Really, that's what we're trying to accomplish here. By putting on this incremental 20 patients, we both increase the power against PFS and OS, although those are only secondary endpoints. Perhaps more importantly, we'll have a more accurate estimate of treatment effect size, which then feeds directly into the sample size for the phase III study. The way to think about it, I think, is that you can make a reasonable assessment early on, and then as you launch the phase III study, as phase II data mature, you could then do a sample size reassessment based on phase II data to modify the phase III sample size to more fully reflect phase II data. Obviously, because these are statistically independent elements, there is no problem, statistically speaking, with doing that. This is the journey we're on now. This is all really about optimizing the phase III study, assuming we use a traditional endpoint. That's all very, very helpful. Can you remind us exactly how have you changed the definition of molecular response, or is it still the same response you were using before? I know there's a lot of debate in the field as to exactly where to set that threshold. Yeah. We have, we basically had a straw man that we put in, with very little data. Our intention was always to do the following: to collect samples from the phase II study, but just bank them, so not analyze them. We've not analyzed a single sample from our ongoing study for ctDNA. What we were waiting for was the data from our phase I/II study to mature. Obviously, what we're trying to do is use ctDNA response as a surrogate for overall survival, and to do that with our therapy in the context of colorectal cancer. We have, not a huge amount of data, but we have data from that phase I/II study to help us optimize that definition of molecular response in service of the goal of best predicting overall survival. We've done all that work now. We have mature data from the phase I/II study, we've set the definition, which is a 30% reduction in ctDNA from the baseline. Using our data, that is best associated with prediction of overall survival. Obviously, you could set a lower threshold or you could set a higher threshold. We've been data-driven, and it's all about just optimizing the sensitivity and the specificity. Great. Thanks. That's very helpful. Yep. Thanks for the good questions. Our next question comes from Ted Tenthoff from Piper Sandler. Please state your question. Hi, guys, and thanks for the update on GRANITE and very clear in terms of the increase in number of patients. Wanted to ask on SLATE and understand, as you said, this takes backseat, what does it take to really accelerate that or get that moving in the future? In other words, what does the pause cost us? Thanks. Thanks, Ted. I think obviously any delay pushes things back. Let's be clear-eyed about that. The momentum is building in the field. We've obviously seen, as I mentioned in our prepared remarks, the Moderna data. Yesterday, Nature published the data from the Memorial Sloan Kettering team, and that's using the BioNTech vaccine approach. Those data were presented at ASCO, but they were published yesterday. Then we have our own data published in Nature Medicine. The biology, I think actually holds together remarkably well. What we're seeing across all of these different platforms, we have a little bit less data with Moderna 'cause we're waiting on T cell data from Moderna, although we are told to expect that maybe at ASCO sometime around middle of the year. What we can see from our data and from the BioNTech data is this common biological theme, which is that if you drive good, strong neoantigen-specific T cell responses measured using a traditional, not very sensitive assay, typically it's ELISpot, then those patients that develop neoantigen-specific T cell responses of good number experience clinical benefit. That's the common thread that spans our disparate datasets, you know, raised with different products in different tumor types. If you read the Nature paper carefully, which obviously I've had the chance to do, then you can see that the patients in whom they were able to generate a T cell response did then appear to derive clinical benefit, which is obviously consistent with our data. We drive a good T cell response in just about everybody we vaccinate, that's not true with the BioNTech data. They get a measurable T cell response in about half of their vaccinated subjects. They see benefit in half. There are some differences, and one can't tell from the published data whether the differences relate to the neoantigen prediction or the power of the vaccine vector or both. You know, the outcomes are highly consistent, and these are both cold tumors. I think the notion that this platform, this approach has now matured to a point where it's really starting to deliver clinical benefit. I think that theme is now becoming widely accepted. That, of course, will help enrollment. Yes, we'll lose a bit of time on the front end, but as momentum continues to build behind these programs and this concept, I think, you know, a delay of a quarter or two quarters is not really insurmountable. That will shrink, given I think the momentum benefits, and maybe you'll end up with data a quarter later. Of course, if we're able to secure additional capital, you just put a few more sites on, and you'll basically end up back where you started, as it were. Yes 'cause you'll just enroll that certain number at a faster rate. I think. Sure ... it's not a huge blow for the program. Obviously, today, we're in capital conservation mode like every biotech company pretty much. This for us was a rational prioritization of our resources. I think it makes a lot of sense. I know that you guys were doing some optimization work on the antigens. Is there any update there? Does that work continue, or is that sort of put on hold now, or have you even finished sort of that optimization? Thank you. No, great question. The optimization continues. Our research team in Cambridge, Mass, this is a big effort for our company because, as I think most people anticipate, having multiple relevant antigens in an off-the-shelf vaccine is highly desirable. If you step back, you know, we treat viral infection with combination drugs because. Yeah A virus can mutate around a single drug. It has a problem mutating around three different drugs all being used in concept. The same is true in cancer, of course. We use combination chemotherapy for the same reasons. The general belief is that having a single antigen in a vaccine, while it may be effective, is likely to lead to some degree of acquired resistance where tumors can mutate around and edit that antigen. Therefore, delivering multiple antigens is highly desirable. With GRANITE, we do that because these are personalized products, so it's 20 customized neoantigens for that patient. With an off-the-shelf product, of course, you can't do that. The truth is there aren't very many shared classical driver mutations. There are very Right few, in fact. With our KRAS product, if you're just delivering KRAS, then basically you're giving a single neoantigen to each patient. We saw clear evidence of efficacy in so doing. If you just compare it with our GRANITE data, the extension in observed overall survival in molecular responders was of a lower magnitude than we saw in the GRANITE program, which is consistent with that notion I just articulated. You wanna put other antigens in. Well, it's not super obvious what those are, and that's where the interesting research comes in. There are all kinds of classes of additional antigens. They're not what people think of as classical mutated neoantigens, where a single amino acid changes between the wild type and the mutant protein. These are things like fusions, atypical or non-canonical splicing that creates novel junctional sequences, inclusion of things that are normally excluded as introns suddenly get retained in tumor cells. These are things like re-expressed endogenous retroviruses. There are lots of interesting things that tumors, because of their dysregulated genomes, display on the surface, which can act as targets for the immune system. It's harvesting from that big library of novel candidate antigens. That's the work we're doing right now, and that will go into the next SLATE product. We're absolutely using this time profitably, but we're excited to get going, but today is not the day. Understood. Awesome. Thanks for the update, Andrew. Yep. Thanks, Ted. Our next question comes from Jonathan Miller. Please state your question. Hi, guys. Maybe just a quick one before I get to the meat. When should we expect to hear something about the Gilead opt-in in HIV? That's something I didn't notice in the press release. Maybe more specifically about the GRANITE program. Can you talk a little bit more about the powering of that phase III endpoint off of ctDNA from phase II portion? I mean, are you gonna have enough PFS or OS data by 1Q 2024 from phase II portion to make powering assumptions on those traditional endpoints in phase III? I'm just trying to get a sense for how that ctDNA data will get from phase II is going to inform powering for a traditional endpoint in the phase III. Hey, John. I'll take the first part of your question with respect to Gilead. We haven't provided any specific guidance at this time as to when that option payment could occur. I will point to the fact that the partnership has gone well for quite some time. They were very motivated, and we went from signing the deal to an IND cleared in about 11 months, and the program is ongoing and in phase I. We presented that data along with Gilead, the preclinical non-human primate data at CROI recently. That's essentially the best I can guide you at this point, which is not very much. Okay. Thanks, Celia. Let me take the second part, John. I wanna be very clear about this. The ctDNA endpoint, the molecular response endpoint, is used for proof of concept phase II, and that is the gateway for us to then say, "This looks very effective. Let's move now into the phase III setting." On the assumption that we are using a traditional time to event endpoint such as PFS or OS, the powering obviously becomes the key issue as you well know. Our PFS data will be reasonable, by, you know, mid-next year. If you think about it, assuming we're putting on our last patient sometime around middle of this year, the median PFS for the standard of care for the control arm is 11 months. Even the very last patient we put on the study has a good chance of having achieved a progression event by mid-2024. The PFS data, I think, will actually be pretty good as we begin that study. The OS data, however, will be immature. If we're doing an OS primary endpoint for phase III, we will begin with a placeholder powering, and then we will let the data from phase II component mature. As those data mature, we will then do a sample size reassessment that's pre-specified and obviously legitimate statistically because we're phase II data to inform the phase III sample size. We're not in any way interrogating phase III data to modify the phase III sample size. That obviously is a much harder thing to do. We're phase II data to modify phase III. That is a very legitimate and reasonable approach. Obviously, we'll discuss all of this with the regulatory authorities in the first part of 2024. Thanks. That makes sense. Maybe one more about that interim there. Given that you're gonna have a little bit more data, you're getting more data already from the phase I, and you'll have more data from phase II by next year, given the upside. Do you have any progress in developing a prospective biomarker to help you select responders from non-responders? Simple answer is no. We've looked at the baseline molecular genetics and phenotypes of all the patients we've treated in the phase I/II study, and the responders and the non-responders look the same. There's nothing obvious that we've yet identified. I will note that some of those patients, you know, progressed and died within a few weeks of starting the study. They're included obviously in the data that we've put out there. The thing about moving to the first-line setting, the newly diagnosed setting, is that those patients obviously will not exist. A 50% molecular response rate in late-line end-stage patients, I expect to go up as we move into a first-line setting. Once you're over 50%, I don't think anyone worries too much about trying to weed out the, whatever it is, the 30% that don't get immediate benefit from the study. Obviously, we're always interested in that question 'cause we're always looking to do better, but that would not be a strategic priority for us. If you ask me my thoughts around hypothesis, there are some data suggesting that Treg infiltration after vaccination, after treatment may be driving some of these disparate outcomes, and that there are some people who, for reasons that we don't fully understand today, do accumulate T-regs in their tumors over time that are obviously antithetical to a good outcome. That's probably the leading hypothesis today. Over time, I think we'll have some therapeutics that might be useful, and interesting to add in. As of today, that's just a scientific hypothesis and not something we're spending a lot of time or energy on. okay. Fair enough. Great. Thank you. Our next question comes from Kaveri Pohlman with BTIG. Please state your question. Hey, good afternoon. This is Christian on for Kaveri. Our first question is in regard to GRANITE. Sorry. Can you just talk about your rationale for selecting the iPFS as the primary endpoint for the phase III part and how this endpoint has been used historically? We have not selected iPFS as the primary efficacy endpoint for phase III. That is a possibility, but we have not selected any endpoint yet for the phase III part of the study. On the list would be in reverse order, OS, very traditional, widely accepted, no debates there, and actually obviously historically very good with vaccines. I'll just note that the interesting thing about vaccines is that the benefits, those T cells that you elicit do not go away just because the patient has some form of progressive disease. So it is possible, and we've certainly seen evidence of this in our earlier stage studies, that OS actually is a really good endpoint for a study with a vaccine such as ours. Anyway, OS is the most traditional option. PFS would be next. If we see a lot of pseudoprogression, meaning lesions get bigger because of T-cell infiltration, then typically that's a good thing for the patient, but they will be labeled by RECIST criteria as progressive disease, and they are mislabeled. That's obviously a problem. If we see evidence of abundant pseudoprogression in the phase II study, then obviously we will not be using PFS as the endpoint for phase III. That's where iPFS or immunologic PFS defined using the immune response PFS criteria potentially becomes interesting and valuable. We're evaluating both PFS and the iPFS in our ongoing phase II study. You'll see those data next year. As I mentioned, there is a small chance that ctDNA response may have accrued enough evidence to be used as an accelerated approval surrogate endpoint. Obviously because we're running a randomized study that will continue to deliver OS data with no crossover, this actually fits nicely with the FDA's recent guidance around accelerated approval trial designs, where they're trying to move away from single-arm trials. I think the study design is good. The question on the table is whether ctDNA has become sufficiently accepted as a useful surrogate, quote, "reasonably likely to predict overall survival." That's the key question. Today, the FDA has clearly not made the determination that the answer is yes. That is obviously subject to change as data continue to accumulate. Oh, okay. Thank you. That's very insightful. Just one more. For KRAS, there's a lot of next-generation inhibitors for different mutations being tested as single agent and in combination. Where do you see the use of immunotherapies in this space? Yeah, it's a great question. The earliest data that were published, I'll go back three years ago, I think it was now, when Amgen's sotorasib was published in Nature with preclinical data, what they showed was very interesting. In nude mice that have no functioning immune systems, using standard xenografts, the efficacy of the drug was clear, but it was finite, the tumors typically actually grew through drug therapy. When they repeated similar experiments in immunologically competent mice using a syngeneic tumor system, there was a much better outcome. For those mice, the tumors seemed to respond much better, more durably to the small molecule KRAS G12C inhibitor. They actually did a study where they added in a PD-1 antibody and showed clear evidence of synergy, again, in a murine system. We took these drugs obviously into humans and two have been approved. What we've seen certainly from sotorasib is that clinical benefit is often relatively transient and acquired resistance is complex. This is not as simple as something like EGFR mutations where there is a dominant resistance mutation T790M, and therefore I develop a drug that binds T790M. The acquired resistance to sotorasib, much more complex, very heterogeneous, and much harder to sort of simply drug around. I think the combination of these drugs with immunotherapy is likely to be really important to drive the durability of clinical benefit. It's been somewhat challenging for some of those companies to successfully and safely combine their small molecule drugs with PD-1 antibodies. I'm sure you're all very well aware of the data I'm referring to. Some of the newer drugs appear to be free of challenge when it comes to combination with PD-1 antibodies. I think there's a really interesting opportunity to combine those small molecule drugs with both PD-1 antibody and vaccine because the preclinical data suggests that there is likely to be meaningful synergy. There's a lot of evidence that KRAS mutation is relatively immunosuppressive, and by vaccinating against the KRAS epitopes, we may essentially bypass that local immunosuppression and really recruit the immune response into the mix to help drive durable clinical benefit. It's a long answer to your short question, but I think we're getting to a point where those studies will begin. Okay. Thank you. I really appreciate the detailed explanation. Yep. Thank you. Our next question comes from Mayank Mamtani from B. Riley Securities. Please state your question. Good afternoon, team. Thanks for taking our question. obviously glad to see the sample size expanded here, you know, It looks like driven by organic investigator interest and also, you know, strategic choice by Gritstone. I was just curious as, you know, you've seen a lot of the patients now in the study, more than we thought. Any learnings or any protocol measures you might be taking to sort of manage the pseudo progressors in the study? I was also curious, like, does this mean that your follow-up period may be longer than what you may have thought initially? In terms of the percentage subjects that do get that, six-month ctDNA boost, you know, do you have an estimate of what that would be now relative to what you may have initially projected for the interim analysis? I have a quick follow-up. Yeah. Thanks for the question, Mayank. I'm not gonna speak in any data-informed manner because I am not aware of data. Let me be very clear. What we observed in the phase I/II was clear evidence of pseudoprogression. We saw that early on, and we also saw it in association with that 2nd dose of the adenovirus, as you astutely noted. Whether iPFS adequately addresses that issue, I don't know. I think it's the best we have, short of just saying, "You know what? PFS is just unreliable here." Let's just go with OS. I don't know the answer to your question, but obviously we are generating those data. In terms of managing the trial, right from the get-go, we knew that this would be all about physician education. This is where it's very helpful to have our phase I/II data, particularly, now it's been published in Nature Medicine, to show to investigators to say, "Look, this is what we're seeing. Just be mindful of this, be aware of it. If a patient has radiologic progression, but they're otherwise doing very well, then we encourage you to consider leaving them on study and performing a follow-up scan per the rules of iRECIST. Per iRECIST, a patient is not labeled as PD if they're able to stay on study and have a follow-up scan, and then it's the outcome of that second scan that determines whether the patient then is labeled as confirmed PD if the lesions continue to enlarge, or if actually the lesions stabilize or get smaller again, they revert to being stable disease, and you then just continue to follow, of course. Education is very important. Our team's done a beautiful job of obviously driving momentum and enthusiasm for the trial, and we're in very close contact with the physicians. Nothing I've said is informed by data from the study, so let me be clear about that. Got it. Thank you. On the obviously the comments you made about the Moderna data and also the BioNTech Nature publication yesterday, I was just curious, you know, based on everything that you're seeing, do you have any preliminary thoughts on where you might go next in terms of additional tumor types or disease settings? Is that... Like, do we expect all of your additional plans beyond this study to sort of be on pause until we hear from you on the GRANITE dataset, including obviously you said the SLATE is also been pushed back. Is that kind of how we should think about the story? No, you should not assume that SLATE won't do anything until GRANITE delivers data. That's not accurate. We are very pleased with the overall platform, the neoantigen-based approach, and so we are very happy to launch SLATE once we have operating capital to begin. We will not gate that on data from GRANITE. Those are dissociated. Today's decision is purely just about redeploying some capital this year, without sort of, you know, driving our burn this year, way north. In answer to your second question about where do we go next, you know, the question we get asked a lot is around adjuvant opportunities and high-risk adjuvant in particular, as Moderna did. When you think about this for a little bit, a patient with high-risk localized disease who is not cured by surgery, that patient obviously has metastatic disease. It just can't be seen on a CT scan, often referred to as micrometastatic disease. This idea that treating patients in the adjuvant setting is completely different from treating patients in the metastatic setting, I think is specious. Because unless you believe that the fact that a lesion cannot be picked up by a CT scan means it behaves in one way, and as soon as it's detectable on a CT scan, the biology behaves in a completely different way, then that position just doesn't make any sense. I've never really thought that that was likely to be operative. Again, you've now got data from Moderna, which is the first randomized dataset showing that their program seems to deliver activity in a hot tumor. But even within that dataset, as you are well aware, if you look at the PD-L1 negative population, the treatment effect with the Moderna PCV was actually stronger than the treatment effect in the overall population. This notion that hot tumors only will respond to this or that adjuvant only will respond to a PCV approach, I think is just wrong-headed. We obviously have shown very nice data, single-arm trial, phase I/II in advanced disease. Obviously, we're now doing the randomized study. BioNTech, obviously again, cold tumor in the adjuvant setting. We're sort of peppering the dartboard, as it were, with these different studies. The biology just looks really consistent, and it's all about driving large numbers of neoantigen-specific T cells. If you can do that, you seem to see benefit. I think that's true in our study, and that seems to be true in the BioNTech study. Now, with Moderna, we don't know because they haven't published any T cell data yet. There's this big issue. Why do the curves not separate to nine months? Well, maybe they don't see T cells until nine months. Maybe it takes multiple vaccinations to actually drive that really strong T cell response. I think that's a pretty good hypothesis, and the data will obviously give us the answer. That seems to be unifying. For us, the decision about where to go next is not really hemmed in by notions of hot, cold, adjuvant or metastatic. I think we'll just look for the opportunities where we think there's meaningful unmet need, where we can really add something to those patient populations, where there's a large commercial opportunity, which of course also means trials will enroll quickly. Those are the things that we're excited about, contingent on the GRANITE data. I'm not really answering your question, but I'm saying we're not gonna be you know, hemmed in or penned in by these, I think, rather, artificial and ill-thought-through boundaries that some people try to impose on us. That's helpful. Thank you. Just maybe a quick one on COVID vaccine. Now that the, you know, clinical profile is relatively clear in, you know, in terms of durability, immunogenicity, safety, tolerability, all the things that you discussed, I was just curious how this feedback has been, you know, if you stack this profile against the government funding framework that exists out there for next-generation vaccines. I don't know if you can comment on how you're sort of seeing your profile relative to what maybe the U.S. government RFI that exists out there is looking for. Thanks again for taking our questions. Yeah. Yeah, thank you. We're obviously paying attention to that government initiative, because durability of protection was explicitly called out as something of interest. We obviously have now clinical data demonstrating that. Clearly, we'd be remiss not to be paying attention. Thank you, operator. Next question, if we have one. Our next question comes from Sean Lee from H.C. Wainwright. Please state your question. Good afternoon, guys, thanks for taking my question. Most of my questions have already been answered. I was wondering, would we see any additional updates from the SLATE program later this year based on the existing study? No. We gave a good update at last ESMO. There's really nothing important or particularly novel to show from that program at this stage. No. Okay. Great. My second question is also on the infectious diseases program. I was wondering, beyond COVID, where or what other diseases do you see the learnings from CORAL that could apply well going into the future? Yeah, there's a lot of interest in respiratory viruses, the notion of multiplexing pathogens into a single vaccine. Obviously, a population of subjects, you know, people over 60 are frequently hospitalized with a distressingly high mortality associated with respiratory viral infections. The ones that are often talked about are, of course, SARS-CoV-2, influenza, RSV, parainfluenza, and sometimes the human metapneumovirus. Those are all very interesting pathogens. Several of them have some similar structural features to their surface proteins that obviously we've learned quite a lot about through the prism of SARS-CoV-2. That's an area of high interest for us currently in the research phase. Great. Thanks for your thoughts. That's all I have. Yep. Thanks, Sean. Our next question comes from Corinne Jenkins from Goldman Sachs. Please state your question. Good afternoon. This is Craig on for Corinne. Just a couple for us. First, how should we think about the median time of therapy for the first 50 patients featured within the 1Q 2024 readout of GRANITE-CRC-1L? Yeah. Obviously, we told you how many subjects have been randomized as of yesterday. As I said earlier, the median progression-free survival is 11 months. I think that will give you what you need to know about likely data in Q1 2024. 50 subjects, obviously that antedates May and probably most of April, and you can do the math. Got it. Got it. Just a follow-up here. Given that you're expanding the trial to feature more patients, how should we think about this having potential impacts to the initiation of the phase III portion of study? Yeah. Of course, nothing changes in terms of the kinetic with which we accrue data. We'll get the same amount of data at the same time as we did before. We'll just get a bit more data that follows. As I said earlier, and I won't repeat the answer, what this enables us to do is to power the phase III study more accurately, which obviously is always a good thing. What we're gonna get out of the phase II is a more precise estimate and a more accurate estimate of the treatment effect size. That is what is used to power the phase III study. As I said earlier, you don't have to start this. You don't have to wait for this data to mature to start the study. You can start the study with a placeholder sample size, and then you can revise that based upon observed data from the phase II. you can actually pre-program the whole thing. Literally, it's all baked in before you even start the study. If we ultimately observe a hazard ratio of this, then the sample size will be that, et cetera. The whole thing can be pre-baked. You get going, so there's no delay in the program. You just end up optimizing sample size, which obviously is always a good thing. The move we've taken, again, it's available to us because of the great momentum we've built without compromise really on timelines, and it enables us to design and execute a better phase III study. This is the logic behind the change that we made today. Got it. Thank you. Yep. Thanks very much. At this time, we have no further questions. Great. Thank you, Erica. Thank you, everybody. Appreciate your time and attention today. If you have any further questions, obviously you know where we are. Otherwise, we will update you upon completion of enrollment of the study. Thanks very much and have a great evening. This concludes today's conference call. Thank you for attending. The host has ended this call. Goodbye