Thank you and welcome to the call. Following prepared remarks from the company, we will open the call for questions. To ask a question, please press star 1 on your telephone keypad. To withdraw your question, press star 2. This call is being recorded and will be available on the investors section of the Arcus website. I will now turn the meeting over to Pia Eves, Head of Investor Relations and Strategy.

Hello, everyone, and thank you for joining us on today's conference call to discuss ARCIS' third quarter 2023 financial results and pipeline updates, including today's presentation of data from our EDGE-GASTRIC trial at the ASCO Monthly Funnery. Today, you will hear from Terry Rosen, Chief Executive Officer, Dimitri Nautin, Chief Medical Officer, Jennifer Jarrett, Chief Operating Officer, and Bob Geltz, Chief Financial Officer. For Q&A, we will also be joined by Juan Haiyan, President and Head of Research. I'd like to remind you that on this call, management will be making forward-looking statements, including statements about our cash runway, our investigational products, our expected clinical development milestones and timelines, and the potential market opportunity and drug-treatable population of any indications being pursued by our program. All statements other than historical facts involve risks and uncertainties that may cause our actual results to differ. Those risks and uncertainties are described in our most recent quarterly report on Form 10-Q that has been filed with the SEC. We strongly encourage you to review the filing. For today's call, please refer to our latest corporate deck, which can be found on the Investor's section of our website. With that, I'll turn the call over to Terry.

Thank you very much, Pian. Thank you all for those who are on the line. This is the first quarterly earnings call we've had in some time. So in addition to the Domvenomab data that was just presented at ASCOPLINARY, we're also going to discuss our other upcoming data readouts. Specifically for AB521, our potentially best-in-class HIF2-alpha inhibitor, and Quemin-Klustat, our first-in-class small-molecule CD73 inhibitor, both of which we'll be sharing data with you just in the next few months. So just a few hours ago, many of you likely watched Dr. Jan Jigian present initial data from our Phase II study, EDGASTRIC, for DOM vanillimab and first-line metastatic upper GI adenocarcinomas. As a reminder, DOM is the only FC-silent anti-TIGIT antibody in late-stage development, and we and our partner, Gilead, are pursuing a very broad development program that includes four phase three studies in non-small cell lung and upper GI cancers. Today's data are extremely encouraging on all fronts. ORR for the PD-L1 high population clearly exceeded historical benchmarks in this setting. Data in the overall patient population appears differentiated, particularly relative to the most contemporary phase three studies in this patient population, WERC's Keynote 859 and Dave Jean's Rationale 305. Most importantly, six-month landmark PFS data for both the PD-L1 high and overall patient population appear to be quite differentiated from benchmarks. These data are very supportive of our ongoing phase three study, STAR 221, which is evaluating DOM in the same combination, same setting underlying today's dataset. STAR 221 is enrolling extraordinarily well, and we expect that today's data will further enhance interest and actually accelerate recruitment in the study. In addition to DOM, we continue to execute on the remainder of our pipeline, including our HIF2-alpha and adenosine pathway programs. Regarding our HIF2-alpha inhibitor, AB521, early next year we will be sharing detailed safety, pharmacokinetic, pharmacodynamic, and preliminary efficacy data from the dose escalation portion of ARC20, which is a Phase I, 1B trial for AB521. We're close to completing enrollment, in fact, of the dose expansion cohort that's evaluating 100 milligram daily of AB521, the dose that we believe will hit the target substantially harder than the approved 120 milligram dose of Merck's Belzutifan. Merck's most recent data sets for Belzutifan presented at ESMO continue to enhance our conviction around the opportunity for AB521. Those data were just what we've been expecting for months, if not the past year. Later in this call, we'll describe this program in much more detail. With respect to our adenosine programs, we'll discuss our ARC-8 trial evaluating our CD73 inhibitor, Quemley. This is in combination with gemcitabine and AMPAC-plotaxel with or without our anti-PD-1 zimbrelumab in first-line pancreatic cancer. As you may recall, ARC-8 completed enrollment way back in November of 2021. So the median follow-up, the most recent data cutoff, exceeded 21 months, and we just now achieved a sufficient number of events for a mature median OS estimate. These data show clear differentiation from contemporary benchmarks for gemabraxan in this setting, one with huge medical need. Furthermore, we've generated a rigorous synthetic-controlled data set for gemabraxane, which also shows very meaningful differentiation from our combination therapy. We also continue to work tirelessly to advance new molecules into the clinic. We just initiated our phase one study for AB801, our highly selective Axel inhibitor, and we expect to select the development candidate with potential best-in-class properties for our kit program for allergic diseases by year end. So I'll now turn the call over to Dimitri to describe in more detail the edge gastric data that were presented earlier today.

Thank you, Terry. I'll start by directing our audience to slide 9 of our updated corporate deck. The data presented today are from cohort A1 from our phase 2 edge gastric platform study, which is evaluating DOM-based combinations in both the first and second line setting. The AVON cohort is evaluating DOM plus SIM plus Folfox chemotherapy in first-line gastric, gastroesophageal junction, and esophageal adenocarcinomas. As Terry mentioned earlier, this is the same setting and setting we are evaluating in our phase 3 study, STAR-221. This cohort was specifically designed to generate safety and efficacy data to support regulatory requirements for the initiation of STAR-221 in certain countries outside of the U.S. Turning to slide 11, we described the baseline characteristics of this cohort. 41 patients were enrolled, and all patients are included in the efficacy analysis. The cohort enrolled a relatively diverse patient population from 20 different sites in the U.S., France, and South Korea. There was an even distribution of patients included in Asia versus the rest of the world, and 63 percent of patients had gastric cancer, 24 had junction tumors, and 12 percent esophageal adenocarcinomas. PD-L1 status was evaluated using the TEP scoring method, with 24 patients having TEP less than 5, and 15 patients, or 37%, with a TEP greater than or equal to 5. Two of the 41 patients included in the overall population did not have tumor samples available for PD-L1 testing. Note that the CPS and TEP are two methods for PD-L1 assessment, and both are are used in gastric cancer. We'll show you later on this call some of these methods, sorry, that these methods have a high concordance. BMS and Merck have historically used CPS for their phase three studies of anti-PD-1 plus chemotherapy while Beijing is using TEP, including in the phase three gastric cancer trial, rationale 305. The following slide describes the overall response rates of the data cutoff of September 4, 2023. In the TAP high population, we observed a 73% confirmed overall response rate and an 80% best overall response rate. These results exceed historical phase three benchmarks for anti-PD-1 and chemotherapy. For example, in Checkmate 649 and Keynote 859, the overall response rate was 60 or 61% for anti-PD-1 plus chemotherapy in the CPS high arms of the study. And in rationale 305, Beijing study in gastric cancer, which is the most contemporary phase 3 data set in this setting, there's a 50% overall response rate in the TEP high population. For the overall population in F-gastric, the confirmed overall response rate was 59%, which is very encouraging, particular given that approximately 60% of our patients are TEP low, which is higher than the 40% PD-L1 low patients in Checkmate 649. The overall response rate in Merck's Keynote 859 trial was 51%. I'd also note that we have seen two confirmed complete responses so far. The median duration of response has not been reached. And given the time it takes to get to a complete response and the fact that many of our patients are still on treatment, the CR rate might go up over time. We believe that the overall response rate results seen in ad castrate demonstrate the additive benefit that an anti-digit agent can provide, but both and beyond PD-1 chemotherapy, PD-1, excuse me, and chemotherapy in upper GI cancers. On slide 13, we show the waterfall plot, and as you can see, the vast majority of patients experiences tumor volume reduction. While there is a difference in the overall response rates between the TAP high and low tumors, you can see in the chart that we have observed very deep responses in both patients patients with high and low expression. You can also see that in addition to the two complete responders, there are other patients with very significant tumor volume reductions that could convert to CRs over time. The next slide shows the time on treatment by patient. You can see here that there are six patients, both with PD-L1 high and low status, who continue to have stable disease and remain on treatment. On slide 15, we show the overall response rate table again, but here we show the data using both the TEP and the CPS method, and as you can see, there is strong concordance between these two methods. The next slide, slide 16, shows the Kaplan-Meier curves for progression-free survival. Here we call out the landmark six-month PFS, which is mature in our trial with a minimum follow-up of six months for all patients. These data are extremely promising for both the high and the low patient population. Specifically, we observe a 77 percent in the overall population and a very impressive 93 percent in the TEP-high population for six-month landmark PFS. While we recognize that these are small numbers, these six-month PFS numbers compare very favorable to the benchmark Phase III studies, which have been in the 50 to 60 percent range. You can see here in the curves that we have not reached the medium PFS for either the TEP high or overall population, with a medium follow-up of 8.1 months. Given that the historical benchmarks have shown a PFS in the range of 7 to 7.5 months, we believe these data put us on track to exceed those benchmarks. And importantly, a substantial number, specifically 24 out of 41 patients enrolled in our study, continue to be on treatment at time of the data cutoff. Lastly, I will cover the safety and tolerability profile we've seen so far in edge gastric. The most common treatment emergent adverse events, which are shown on slide 17, were neutropenia, nausea, and anemia, which is very consistent with what we would expect from chemotherapy alone. In fact, the vast majority of grade 3 or higher drug-related treatment emergent adverse events were contributed to chemotherapy, and only 12% were contributed to DOM or SIM. No serious treatment emergent adverse events were related to DOM or SIM. Of note, all infusion-related reactions shown on slide 18 were deemed related to oxaliplatin. Overall, the regimen was well-tolerated with a similar AE profile to that expected from Folfox plus anti-PD-1. These results add to the growing body of evidence supporting a potentially differentiated safety and tolerability profile for DOM relative to FC-enabled anti-digit antibodies. Before I turn it over to Jen, I wanted to spend a minute on some key elements of the design of our Phase 3 study, START 221, which is shown on slide number 20. First, we are stratifying by TEP greater than 5 or less than 5%, so this is well balanced between the two treatment arms. We are also closely monitoring the percentage of patients who have tumors with a TEP score of more than 5% to ensure that the percentage of these patients in our study meets the pre-specified percentage per our statistical analysis plan. Second, the study has dual primary endpoints of overall survival, one for the TEP more than 5% and the other one for the ITT population. So we have two opportunities to win in this study. With that, I'll turn it over to Jed to talk about the market opportunity for TIGIT.

Thanks, Dimitri. I'd like to start by talking about the TIGIT field overall. Our most recent feedback from KOLs indicates a clear and growing data-driven enthusiasm for anti-TIGIT as an innovative therapy. Following the release of data from the second interim analysis of Roche's Skyscraper I, we engaged a third party to conduct a survey of 30 oncology KOLs regarding their sentiment on anti-TIGIT. You can see these results on slide 35 bar investor deck. Approximately 80 percent of respondents believe it is likely that Tarago plus Atezo, Roche's anti-TIGIT and PD-L1 combination will receive FDA approval. Additionally, based on data they've seen to date, 83 percent expect anti-TIGIT to play a moderate or larger role in the treatment of first-line PD-L1 high non-small cell lung cancer. These survey results are telling. As the evidence on anti-TIGIT accumulates, physicians are increasingly convinced of the potential for this mechanism to change the treatment paradigm in lung cancer. Since we are combining DOM with the current standard of care, chemo plus anti-PD-1, and adding almost no toxicity, this is a very easy value proposition for physicians. Today's results continue to demonstrate the potential for anti-TIGIT to improve outcomes and indications where anti-PD-1 is successful. As Terry mentioned, gastric, GE junction, and esophageal adenocarcinomas represent a $3 billion-plus market opportunity, with approximately 25,000 patients in the U.S. alone and over 100,000 patients across the G7 countries. Note that we are pursuing adenocarcinomas, a different histology than that which is being pursued by Roche and Beijing and their respective Phase III and II studies. In fact, we in Gilead have the only anti-Tiget and Phase III development for first-line upper GI genetic carcinomas, which is one of the fastest-growing cancer types in the U.S. and Western Europe. Many of you are aware that there is another class of agents being developed in gastric cancer, directed against clodin 18.2s, which were also discussed in today's plenary session. While the efficacy data are encouraging, published literature estimates that only anywhere from 20 to 40% of patients are high expressors of clodin 18.2, and these molecules are associated with significant GI toxicities. We also expect it will take several years for clodin 18.2 testing to be successfully rolled out. With anti-TIGIT, we believe we have the potential to achieve similar efficacy without the toxicity associated with anti-clodins and potentially avoid the need for any testing, allowing patients to go directly to treatment. Today's data set will support both steady recruitment and regulatory filings for a combination, and we are moving aggressively to secure our position as first to market and best in class in this indication. I'll now turn it back to Terry to discuss our HIF-2-alpha and CD73 programs.

Thanks very much, Jen. So first let me start by level setting a bit on HIF-2-alpha. It's a transcription factor. It has no ligand binding domain, and as a result, it's proven very difficult to create molecules that are high-quality inhibitors, but also that have ideal drug properties against the target. That's why there are very few other HIF2-alpha blockers in clinical development today. Belzutafan is the first and only HIF2-alpha inhibitor to be approved today, and it's only approved for BHL-associated cancers, although Merck recently filed for Belzutafan's first approval in clear cell RCC. Slide 47 of our corporate deck describes the value proposition for AB521. It's really pretty simple. The primary limitation of belzutafan is substantial. Its oral absorption saturates at a dose of 120 milligrams. So what does that mean? Even when higher doses of belzutafan are administered, systemic drug exposure does not meaningfully increase. In fact, it's very clear from the published data for Belzutafan that the approved dose of 120 milligrams was chosen because doses beyond 120 milligrams did not result in meaningfully higher plasma levels. This had nothing to do with dose-limiting toxicity. Merck, in fact, just released results for LightSpark 13 at ESMO, which evaluated doses of 120 milligrams versus 200 milligrams of Belzutafam. No surprises. They concluded that there was no difference in ORR between these two doses and that the results support their dose selection of 120 milligrams for their trials. However, it's super important to note that they made no mention of whether they were achieving higher levels of drug exposure with a 200 milligram dose, and they did not share any PK or PD data for this study. So consistent with the previous literature, we just view this as more evidence of belzudepan's PK and PD limitations and the inability, in fact, to achieve meaningfully greater plasma concentrations with doses that are above 120 milligrams, our fundamental thesis going into this program. The primary objective of our HIF2-ELPA program, then, was to create a molecule without this pharmacokinetic liability, enabling us to hit the target harder. In a Phase I-B study in second-line clear-cell RCC, valzutafan demonstrated an ORR of about 25%, and approximately half of these responses were not achieved until six months or more of treatment. These ORR data were essentially recapitulated in the Phase III LightSpark O5 study, which showed a 22% ORR for belzudephan versus 3.5% for everolimus in a 5.6-month median PFS. While these results are actually quite encouraging, we believe they show clearly room for improvement. And with AB521, we could observe a higher response rate, deeper responses, or faster response kinetics, all of which should translate into longer PFS. In our healthy volunteer study, we demonstrated that AB521 has an ideal profile, including dose-proportional pharmacokinetics. That's important. Dose-proportional pharmacokinetics is the huge differentiator here. In our dose escalation study in patients, we replicated the pharmacokinetics that we observed in Healthy Volunteers and now have dosed up to a daily dose of 100 milligrams, which we believe has the potential to achieve at least three times higher levels of AB521 than those equivalent to the approved dose of Belzutafan. Importantly, and this is a key finding, we have not seen any dose-limiting toxicities. So based on these data, we've initiated our 30-patient expansion cohort with a dose of 100 milligrams daily in clear cell RCC patients. There's been a great deal of investigator enthusiasm around the study, and in fact, the cohort is almost fully enrolled. Early next year, we're very excited to have the opportunity to present PK pharmacodynamic safety data, as well as the initial efficacy data from the 12 patients in the dose escalation portion of the study. Approximately half of these patients have RCC, and all were treated at a dose of 50 milligrams or 100 milligrams daily. So both of these doses are pharmacologically relevant. The safety data support our view that the enhanced target coverage by AB521 relative to that obtained by belzutafan does not result in increased safety liability. We also expect to present data from the expansion cohort next year. We're progressing the molecule rapidly and expect to start a Phase II TKI combination study in second-line clear cell RCC by year end with the goal of getting a Phase III study for AB521 as quickly as possible. So now let me shift over to our gate. Really excited to talk about this study, our Phase I 1B study that's evaluating QEMLI in first-line metastatic pancreatic cancer. QEMLI is a highly selective and extraordinarily potent small molecule inhibitor of CD73. A key differentiator of QEMLI compared to the most advanced CD73 antibody in clinical development is that it blocks both the membrane-bound and the soluble forms of CD73, enabling it to achieve complete inhibition of the enzymatic activity. This is a huge difference because CD73 is readily shed from cells, resulting in significant levels of soluble CD73. So, in contrast, the most advanced CD73 antibody is only partially effective in inhibiting the enzymatic activity of either membrane-bound or soluble CD73. So I think an important concept here is that although they share the same target, CD73, QEMLE is highly differentiated by its mechanism of action, which, as I said, enables it to fully inhibit both forms of the enzyme. We also believe that a small molecule may penetrate tumors better than an antibody. Pancreatic tumors are notorious for being very fibrotic. What does fibrotic mean? Think of it like scar-like tissue. This makes it hard for drugs to infiltrate the tumor, and therefore, a small molecule approach may be particularly advantageous in this setting. We chose pancreatic cancer as the first indication for QEMLI because this tumor type is associated with extremely high CD73 levels, and in fact, high CD73 expression has been shown to result in poor overall survival outcomes in patients. Slide 42 highlights the design of our gaze. We enrolled approximately 30 patients evaluating 100 milligrams of Quimli plus Zim plus Gemabraxane in the dose escalation and expansion portions of the study. Subsequently, we enrolled the randomized portion of the study, and this evaluated Quimli plus Gemabraxane with and without Zimbrelumab in 90 patients with the goal of determining whether anti-PD-1 therapy provides any clinical benefit on top of what we're seeing from QEMLI in this setting. We've already disclosed that zimbrelumab did not add any benefit to QEMLI plus gemabraxan in this study. We completed enrollment of this randomized portion in November of 2021. At the most recent data cutout, median follow-up was 21 months. The data set we will share early next year will therefore include mature overall survival data for all 122 patients enrolled in the study. This is a substantial data set. They're all at the 100 milligram dose of Quenly. There have been several recent data sets, good data sets, that provide benchmarks for how geminobranxane performs in this setting. And overall survival for these contemporary data sets falls in the 9- to 11-month range. The data are really pretty tight. The NAPOLI-3 study, which was just presented at ASCO this year, demonstrated 9.2 months overall survival for the gemabraxane arm. Fofirinox is also used in this setting, but it's often reserved for healthier patients given its toxicity profile. Fofirinox demonstrated a median overall survival around 11 months in the NAPOL E3 study. We plan to share the full data set from ARC-8 early next year. The disclosure will be comprehensive. It's going to include ORR, TFS and OS, Landmark 12, and Landmark 18-month OS. We also plan, and this is an important update, we plan to share data from an externally generated synthetic control arm of gemabrioxane, which we believe will further validate the clear benefit that was observed with QEMLI. We'll also spend more time on the mechanism for QEMLI in pancreatic cancer and why we might be seeing such a meaningful benefit in overall survival. Briefly, we believe that there are two mechanisms at play, both of which are very well supported by extensive literature on the role of CD73 in pancreatic cancer. First, by inhibiting adenosine formation in response to chemotherapy and essentially blowing up cancer cells, we may be enhancing a T-cell response in the tumor. And second, by interfering with the effects of adenosine on well-known fibroblast biology and tumor fibrosis. We're really very excited about the data, and we believe these results support further development of Plimley for patients with this devastating cancer. There's really been no advances in this field for the better part of a decade. As you know, pancreatic cancer is a disease with extremely high unmet need. It affects 37,000 patients in the United States alone, and we believe the global market opportunity could easily exceed $3 billion. I'd like to turn it over to Bob now to review our financials from the quarter. Thanks, Terry.

Arcus continues to be in a very strong financial position. Our cash at the end of September 30th, 2023 was $950 million, and our net cash utilization through three-quarters of 2023 has been $188 million. Importantly, we share costs 50-50 with our partner Gilead on a large portion of our portfolio, including all of our ongoing Phase III studies. We now expect cash utilization for full year 2023 to be between $265 and $290 million, down from our prior guidance of $295 to $325 million. And we continue to expect our cash balance to fund operations into 2026. Our cash runway guidance excludes potential opt-in payments and approval milestones from our partners. Turning to our P&L, we recognize gap revenue for this quarter of $32 million, which compares to $29 million for the second quarter of this year. Our revenue is primarily driven by our collaboration with Gilead, and we expect to maintain similar levels of revenue in the near term, with small fluctuations due to updates to our clinical development plans and timelines. In addition to our partnership with Gilead, Taiho is our partner for DOM in Japan. In the fourth quarter, we received a milestone payment of $14 million from Taiho related to their participation in our STAR 221 pivotal study and will receive another $14 million in the first quarter of 2024. We are also eligible for additional milestone payments from Taiho related to STAR 121. Our R&D expenses for the third quarter are stated net of reimbursements from Gilead and were $82 million as compared to $84 million in the second quarter of this year. In the current quarter, non-cash stock-based compensation represented $8 million of our R&D expenses. We expect modest increases in our R&D expenses as our Phase III studies mature. However, spend may fluctuate based on the timing of clinical manufacturing activities and the purchase of standard of care therapeutics for our clinical trials. For example, in the third quarter, spend in these areas was lower than in the preceding quarters of this year. G&A expenses were $30 million for the third quarter of 2023 compared to $28 million in the second quarter of this year. Non-cash stock compensation represented $10 million of our G&A expenses for this quarter, and we expect G&A to remain stable over the remainder of 2023 and through 2024. For more details regarding our financial results, please refer to our earnings press release from earlier today and our 10Q. I'll now turn the call back over to Terry for

some closing remarks. Thanks very much, Bob. So to wrap up, first off, we're really excited about today's data set. It provides evidence that supports DOM as potential best-in-class anti-TIGIT and first-line upper GI adenocarcinomas, a setting we're well on track to be first to market and and first to mark it by a distance with an anti-Tiget antibody. I think it's also important that if you elevate a bit, it really continues to support DomZim as a best-of-class anti-Tiget, anti-PD-1 doublet, the combined holistic profile of efficacy and safety profile. As we execute on our four phase three trials for Dom, we continue to advance the remainder of our pipeline, And we're really looking forward to sharing more data in the very near term on QEMLI and pancreatic cancer in our HIF2-alpha program. Both of these programs have been ongoing for some time. I think we're going to have some data that you can really look at as inflections for So with that, I'd like to thank you for your continued support as we work to develop, we believe, very innovative combination cancer therapies for patients that are in need. And with that, I'll open up the floor for questions.

As a reminder, to ask a question, please press star 1 on your telephone keypad or press star 2 if you'd like to withdraw your question. Our first question comes from Jigal Natromovic from Citigroup. Please go ahead.

Yeah, hi. Thanks very much for taking the questions. I just wanted to follow up on a comment Dimitri made around the design for star 221. Dimitri, you mentioned that you, in the plan for the stats, it's a pre-specified percentage of TAP high and TAP low. Can you comment on what that is, and is it similar to what you've seen in the edge gastric?

Thanks for the question. So, as my standard answer around statistical analysis plans is, we don't comment on the exact details. I made the comment specifically because I want people to be sure that the trial is designed to look at both the overall population and the high population. In order to do that, we have specific criteria about the number of patients, number of events, and thereby the power for the survival analysis in those groups. What I can say in general is what I've said before. We are expecting a slightly lower number of PD-L1 high patients. As you can see in our current data set, we are at about 40% PD-L1 high. That's something that we were expecting to be lower than Checkmate, given that Checkmate changed the standard of care more for high expressor than low-expressing tumors, and thereby we anticipate that patients with PD-L1 low disease disproportionately would want to be on a clinical trial. That's why we've done comprehensive planning to make sure that both of the primary populations have a good shot on goal for success.

And the primary endpoint is on the overall, or do you have a – how does it work? Do you have a primary on the PD-L1 high?

both so we have dual primary endpoints for overall survival in both the high expresses and in the full population the attention to tree population so both can be tested independently and the study will be declared positive if either one

of those is positive okay and then the discussion today mentioned the that FC silent might potentially be the reason why you saw the higher efficacy in the tap high population that had more immune sensitive just can you comment on that Do you agree with that hypothesis?

I think so. I'll take that. I think it's number of patients, et cetera. The one thing that we would comment on the FC silent is clearly that safety profile, you know, is something that enables patients to stay on better, et cetera. So we think that manifests itself in, you know, a better overall profile. I think it's a little too nuanced to get into differences with respect to the PD-L1 status of those patients.

Okay, got it. And then one on 521, Terry, I'm just interested that you've made the argument that you have better PK than the Merck compound for several quarters. Can you comment a little bit on what's driving that? I mean some of the hypotheses I was thinking about was maybe less protein binding or engineered to avoid certain metabolic pathways or better gastrointestinal absorption can you comment at all as to what what design features you've introduced that are giving you that that edge you keep you

refer to thanks yes so what we know in a black box sense is simply their absorption you know is limited and if they go actually if you look at the data closely there's very little difference between 80 milligrams 120 milligrams 160 milligrams and 240 milligrams you you have a an issue with absorption in their case it probably relates more likely than not simply to solubility our molecule doesn't have that liability and our molecules simply well behaved like Like most small molecule, organic molecules, and we don't have that problem. So it's probably something as simple as that, physical chemical properties.

Okay, thank you.

Our next question comes from Jonathan Miller at Evercore ISI. Please go ahead.

Hey, guys. Yeah, hey, guys. Thanks for taking the question. I'll follow up on HIFT2. I guess it makes sense that you've got better exposure than Merck does. Let's take that as red. But I guess what we don't know yet is if hitting the target harder really does result in better outcomes that Terry mentioned during the call. So I guess my question is, what data gives us that clear signal of additional efficacy in addition to better PD? Is it likely that we could get something in escalation that does that, or do we have to wait for expansion data later in the year?

Thanks, John. It's a great question, and, of course, that's the key question. I think the arguments that we make are a combination of factors from, you know, our own data as well as the data with the Merck molecule. So I'll start with the latter. What's clear from their data is that if you look, you know, the vast majority of the patients, for example, in their earlier study, and you see this 20-some-odd percent response rate, you see tumor reduction, but you see slow kinetics, you don't see the sort of response rate that you might envision, particularly in a setting that is known to be driven very strongly by HIF2-alpha. So you might expect that you would see stronger results. So, for example, if you had an ORR that was 90% and you could hit the target much harder, that probably wouldn't buy you much. Now, if you come to what we know about our molecule, and first of all, let me finish on their molecule, we know that they can't hit the target harder. So, as you know, usually in oncology, you've either modeled something or you've hit an MTD. In their case, they simply can't get to a higher exposure, and in fact, that's been demonstrated in multiple ways by them. What we have shown, in fact, is that basically if you look at the pharmacodynamic endpoint that's easily detectable, we can get the same effect that Merck gets with their clinically used dose at about one-third to one-quarter the dose. And the dose that we're using now go forward is four-fold. That should be hitting the target harder. And then you said, you know, the obvious question will be now going to a randomized study in a large trial. You know, do we see that manifest itself? Certainly from the escalation data, you'll get a good feel that the molecule is behaving well, that roughly half or a little more than half of that 12 patients that has RCC. Keep in mind that's a very late-line group of patients. It's heterogeneous, but you'll be able to pick those patients out and see that it looks like the drug is working. So I think that what we would say is that the Phase II data in the cohort will be one that we will get the real true sense of how much better we might be doing by hitting the target harder.

Great, great. That makes sense. And then I guess on Tidget, it seemed like the plenary discussant this afternoon wasn't very excited about the edge results, I think because of how early the PFS curve is at this point. So your PR suggests that mature PFS is coming second half. But I know that the virtual plenary series usually comes with ASCO presentation. Is it fair to expect we'll get updated PFS at ASCO next year as well?

So first let me just come back to the actual data. We think the data actually look quite encouraging. High PD-L1 as well as the totality of the patient population. So if you think about it, clearly that 93% landmark PFS for the high PD-L1 is quite meaningful. And even the 70-some-odd percent is quite meaningful. If you go back and, for example, look at the Checkmate study, what you've got is a median PF on the order of six and a half months. And that's in the PD-L1 high. So in our total population, we're still at 73% landmark at six months, which bodes pretty well if you even start to compare it to like what would be 100% high PD-L1 and we're diluted. With that said, insofar as expectations, we do not know. Our guidance has made medium PFS to be mature in the second half of next year. So we'll just have to see. Obviously, that's event-driven. We had a large, as you saw, a large number of patients remain on the study. So we'll see how that plays out as the year goes along.

But do you have a presentation at ASCO in the summer as well?

Oh, yes. Absolutely.

Okay, thanks.

If you could please keep it to one question as much as possible, we'd like to get to everybody.

Oh, Pia, I was liking the multiple questions. It's a bonding experience.

So if you can call the next person.

Thank you. Our next question is from Peter Lawson at Barclays. Please go ahead. Great.

Thanks for taking my question. I'll try and make it a multi-part of you. Just on your HIF2 alpha, the data we're going to see early 2024, do you think that differentiation starts emerging, whether it's in ORR, or do you think we have to wait to see that emerging in PFS? Go ahead, Jen.

Yeah, I mean, I think, so first of all, Terry started to talk about this, but maybe just, again, to tell you exactly what that data set is going to be. So the dose escalation is going to be 12 patients. Approximately half of those patients, you know, so approximately six of those patients do have RCC. All of those RCC patients were treated at a pharmacologically active dose. As far as, like, will the ORR be differentiated relative to, you know, sort of the 20 to 24 percent you see in cells, I think the problem is the denominator is still going to be really small. So, you know, whether it's really high ORR, really low ORR, I think the denominator is too small to really tell you much, which is why Terry was saying we wouldn't rely on the ORR from the dose escalation. So I think from the dose escalation, what's going to be most interesting to see is, one, just what does the waterfall cloud look like? And then, while are you seeing patients, are you seeing activity? You know, and two, are there any signs, you know, that maybe the responses are happening a little bit faster? Because, as we know, it's called Zutafan. For a lot of patients, it can take six months or more to get a response. And then once we get to the expansion cohort, so that'll be sometime in 2024, that will be a higher end in the denominator, and so the ORR will start to be more meaningful. Does that answer very much over here?

Our next question is from Robin Karnowskas from Truist. Please go ahead.

I have 10 questions. I hope you can do them all in a very short period of time. Robin, you can have 100 questions. All right. I just was noticing, given the curves, like Bill and I were talking about, like how patients who experienced tumor reductions were PD-L1 negative. And that's so unusual in the waterfall plot. So how do we think about that? How do we put that in perspective for PD-L1 high? And can you help us with the median 21 months of follow-up in pancreatic cancer and put that into context? Like those are three. I'm sorry I got three, but like I'm just putting my out there. You can cut one off and give it to another person. It's fine. But I thought the waterfall

plots are very interesting. So one thing to keep in mind with PD-L1 levels is that once you introduce chemo, you sort of have a dynamic situation, and that's an important aspect of this therapy. So it's not surprising if you heard one of the discussions talk about immunogenic chemotherapy and what that does. And so if you get an immune response, now having an immunotherapy, you can generate what might be a surprisingly good response. And I think, you know, it's something we talk about this since we work on a number of immunotherapies and we talk about this a lot in the context of QEMLI. you can have a patient who that much of a tumor reduction, but from a survival standpoint can really benefit because if they can mount a T cell response, you can enhance it. So we just feel that that's certainly amongst the rationales for when you start bringing in chemo together with immunotherapy be that the PD-L1 levels don't tell 100% of the story. What was your second question, Robin?

So if you, you know, for the pancreatic trial, like, you know, with the median follow-up of 21 months, how do I put that into context? Is that a long time? That seems like a long time for pancreatic cancer.

Yeah, it's a long time. and to be clear when we think about what the median OS readout is that tends to range somewhere between like 9 to 11 months on the high end you know if you talk to clinicians given this is so devastating even something that was two to three months longer than that would be meaningful so we we think we're gonna have something that really looks like it's moving the needle all right I'll

put my another eight questions back in the queue enjoy our next question is

from Kaveri Polman at BTIG please go ahead yeah good evening and congrats on

the edge gastric trial results for pdl1 expression can you provide any color on rationale for using TAP assessment and how different it is from the CPS score that was used for the 6-4-9 trial. Also, if you could tell us about your rationale for using cutoff of 5 versus 1 or 10 like some other trials have used.

Dimitri will take that. Yeah, so relational use TAP, there's a couple of different things, right? So there's the scoring method which is TAP or CPS and then there's the different essays and we need a combination of those for regulatory purposes, and we need to have the work done as companion diagnostic to use it as a stratification factor in a trial. That work cannot be done on every single essay. That's why we work with SB 263. When it comes to TEP and CPS, my simplest way of answering the question is, as the discussant said, the TEP is kind of a visual scoring method. She didn't use those words, but it's easier for pathologists to do. CPS has a strong scientific rationale, but if you look at BMS's initiated trial that was published, looking at 13 pathologists who have been in practice for 20-plus years and got training, the concordance of the inter-observer variability for the CPS assays is not great in the 50% to 60% range. So I think CPS is somewhat challenging in implementation in a larger setting, and TEP has the benefit that it's easier to implement the 5% threshold is a reasonable threshold extrapolated from the data for CPS in in the public domain we think it's it's a good threshold and then lastly there was one more so part of the question no that was it okay we get everything to burn no sorry no and I wanted to make the point, we showed the concordance, right? So TEP is easier. I think that that makes it easier to implement it on a larger scale, also beyond clinical trials. But we have provided, let's say, the CPS data on our own data set in the corporate deck as well to provide confidence that the number of patients captured by both assays is not widely different. There's a high concordance between these two methods.

Got it. And if I can just squeeze one more. For ARC-8 trial, the comments you made about sharing data from externally generated synthetic control with gen-abraxane, can you give us some color around that?

I'll give you minimal. I mean, what I'll say is it was done with metadata. It was done in an extremely rigorous way, very much to get matched patients. And quite frankly, when you start to think about, particularly in trials that aren't like 1,000 patients or 800 patients, the reality is you actually, from a control standpoint, get a better patient population that's more matched to your data set, assuming that they have a large enough, well-annotated data set, which they do. And that was even, that took a couple months to just even do that part of the analysis to make sure that they could do it. So I think everyone's going to be very pleasantly surprised by the quality of that data set. And I think it's going to bring a lot of confidence. It's the type of data set that you can certainly even take to regulatory agencies in discussing your plans going forward. So we think that's going to be a big deal and part of our, you know, total package for that program.

That's helpful. Thank you.

Question comes from Mara Goldstein from Mizuho. Please go ahead.

Thanks so much. During the plenary today, there was a comment along the lines of the presentation of this data. There's a hope that this would also help facilitate STAR 221 enrollment. So can you talk a little bit about where that trial is from an, you know, from enrollment characteristics perspective and what the timing looks like from here?

Yeah, so I love the question. Even though we can't give you a bottom line answer, the trial is enrolling gangbusters. So when we talk about help, it isn't so much like, oh, it's in need of help. incredibly well. In fact, you know, I would go and say that more likely than not, if you ask us to bet, I think that's probably going to be our first trial to read out. Our guidance has been that our trials will, you know, be, let's say, 20, 25 plus. We're not changing our guidance, but it's enrolling well ahead of schedule. A couple comments on the, you know, reasons. I think there's been a lot of enthusiasm that's, you know, data-driven what's going on just in the TIGIT field. In this particular setting, as you can tell from the discussions, there's also a lot of clinical trial need. There's simply not a whole lot happening in an innovative sense, And we believe this data set unquestionably, so all of the investigators we've spoken to are really excited about the data, and we think it's just going to accelerate things further. So I keep an eye on this. I think what's interesting about this, when you think holistically about the field, for us, this trial is going to help us, you know, close the distance on, you know, who and what ends up being the first doublet that comes to market in the field.

Okay. Thanks a lot. I appreciate it.

The next question comes from Dana Grabash from Leerink Partners. Please go ahead.

Hi, this is Jeff. Do you think you could share your thoughts on the potential differentiating characteristics of DOMP relative to the various antibodies beyond F-C function to these points? What else do you think could explain the arguably disappointing Phase II data that we saw from osaprilimab, the competing skin antibody that was recently presented to ESMO? Thank you.

yeah so i mean i think primarily we're going to you know come to that fc um as being a key differentiator so um you know it'll anti-tigets and you wouldn't know this until you get the empirical data but they do deplete t-regs and so by definition um that's not going to be a good If you deplete Tregs in the periphery, you're going to see enhanced immune AEs. But secondarily, dose is different. I think it's telling. For the FC-enabled anti-Tiget, what you have to realize is when you think about it, because one of the fundamental, it's not a shock that anti-Tiget is turning out to have the safe mechanism that we see, because it's a tumor where you have that high CD155 is just being way overexpressed as a survival advantage by the tumor. So people keep asking questions about TIGIT expression. The key thing is CD155 expression. If you want to draw an analogy, you know how everybody focuses on PDL1? PD-L1 is the correlate of CD-155, so it's not the PD-1 that's the driver, it's not TIGIT that's the driver. But that component of then the higher dose, particularly with an FC-enabled anti-TIGIT, you're simply getting, don't forget that that depletion of T cells, that's an on-target mechanism. So by going a higher dose, you would expect it is on the higher end of the spectrum. What's telling, as far as not just this setting, 200 milligram dose of VEBO, they explored a 700 milligram dose of VEBO, and in the coform, they're using 200 milligrams.

Talking about Ocprolimab, particularly the data that was just printed and sent at ESMO was in very different settings than anything that we're doing. You know, and they tended to be going after the second-line setting, so their data was presented second-line cervical, second-line esophageal squamous cell carcinoma, so a different histology that we're pursuing with gastric esophageal. But like I said, going after the second-line setting without chemo and tumors that are progressing very rapidly where you have a PFS of sort of two to four months. So not only is their antibody different when you look at a superior lab, but their development plan and the tumor types that they've been pursuing and settings have been very different than ours. Our next question

comes from Lee Watsack from Cantor Fitzgerald. Please go ahead. Hi, this is Rosemary on for Lee.

Thanks so much for taking your question. So for SAR 221, hypothetically, if you were to hit the survival endpoint for the PD-L1 high patients, but not for all comers, do you think you still have a chance to get approved in that patient subset, given that the PD-L1 status is a stratification factor?

So, we don't just think that. We know that. The study is set up for exactly that. It was designed to detect both, and that when Demetra was talking about the co-primary endpoints, both of those are opportunities for the way the trial is designed and both opportunities for approval. And, you know, we think it's a very meaningful opportunity.

Thank you so much.

Our next question is from Salveen Richter from Goldman Sachs. Go ahead.

Hey, thanks. This is Matt on for Salveen. On the gastric digit data, could you share anything on how median PFS is currently tracking? I know you're going to share more next year. And what do you view as a meaningful improvement over the seven to eight months of standard of care? And then could you share anything on how current standard of care breaks down between Keytruda and Nevo combos? And are most patients actually treated with an IO combo?

That's a lot of questions. So when it comes to are most patients treated with an IO combo, it depends on where you are, what the reimbursement structure is, and what the experience of investigators is. There are plenty of investigators, especially in the U.S., that give NEVO-based regimens to everyone because you don't have to wait for the testing, and there is a modest benefit for low expressing, and there is, of course, significant benefit for high expresses, and the toxicity profile is very manageable. There are definitely markets where reimbursement would come to be an issue, and in that case, typically reimbursement focuses on 5 percent and higher. When your question about the median PFS, we can't really say anything about it, the median hasn't been reached. We need more follow-up to reach a median that requires a number of events for Kepler-Meyer to calculate that so that there's nothing what we can say except that we emphasize the numbers we have right now look very, very promising, and obviously they are significantly away from the medians that we think we should be reaching. When it comes to a meaningful improvement, that to me is actually a question about survival benefit in a Phase III. If the PFS benefit would be in the same range, then let's say a hazard ratio of a bind 0.75 starts to get interesting. For survival, probably a little bit higher. That's as much as I can say. When it comes to absolute differences in months, I think that's very hard to state on a single-arm trial. I would be looking at the hazard ratios in the Phase III setting. I think you had another question in there.

One other question you had was, I think, the mix of Nevo versus Pembro, maybe in Gastric. And today, Nevo is the only PD-1 that's approved. Mark has filed for approval with Keytruda, so their study, Keynote 859, was conducted later, and I think their PDUFA dates in December. But our assumption is that Nevo will continue to have the vast majority of share in the PD-1 market for Gastric. And that is the comparator for our phase three.

You know, one other thing I just probably worth highlighting is something that, like, could somehow, you know, sometimes evaporate, like FC versus non-FC, which, you know, for a year or two was the continuous question and overnight somewhat evaporated. I think another one that's evaporating, but I'd like to address it, is the, you know, Zim-Ketruda comparison. And I think this data set is another one that just, you know, the anti-PD-1 performance clearly looks good. It also got another approval in China recently. But I think that's another example of Zim behaving as you would expect an anti-PD-1 to behave.

Our last question for today comes from Jason Zimansky from Bank of America. Please go ahead.

Thanks. Hey, guys, congrats on the progress this quarter and appreciate taking the question. So I have to ask, during ESMO, one of the big debates was obviously over how the treatment paradigm would evolve in gastric. And I think one of the big kind of takeaways here was that in any cloud and positive patient who was also CPS greater than or equal to one, the algorithm would likely move towards combining both agents to get that potential synergistic benefit. Now, obviously, it's still very early, but I'm curious, how are you working to position TIGIT as the conversation starts to evolve? I mean, if KOLs are already thinking about this type of combination, what do you need to do to enter the discussion in favor of a TIGIT PD-1 combo, you know, particularly as Clowden is biomarker-driven?

Yeah, and I think, I mean, we've spent a lot of time with KOLs talking about anti-clowden, and, you know, we're working with the same KOLs as the anti-clowden companies are. So the first thing that I'd say about anti-clodin, if you look at the prevalence of high clodin 18.2 in patients, I know there was a number cited today, 40%, which was the percentage that was seen in Spotlight, but there's literature out there that puts that number well below 20%. And my hunch is that if you go outside of Asia, the prevalence of high clodin 18.2 is lower. The other thing that's interesting if you look at literature is there seems to be more of a prevalence of high clodin 18.2 in patients that are PD-L1 low for some reason. And we've heard statistics like only 10% of patients that are CPS high are also high clodin 18.2 expressors. So even just looking at that piece, they may not be viewed as directly competitive. But I'd say on top of that, when people look at anti-Tiget versus anti-Claudin, we're obviously much less toxic. So if you look particularly at the Estellus antibody, which is the most advanced antibody in clinical development, there's a lot of GI toxicity in the plenary presentation today. They obviously talked about some of the other toxicities that they're seeing with the ADC. So that's something else to keep in mind. And then the third piece is Claudin 18.2 testing does not happen today. And as we've talked to the KOLs, they think it's going to take, you know, up to five years or more for that to roll out. There's a lot of sites that don't even test for PD-L1 today. And because PD-L1s are relatively safe agents, they just feel like, you know, I'm not going to test. I want to put my patient right on treatment, and so I'm just going to give them a PD-L1 antibody anyway. So we do think the need to roll out testing is going to be another impediment to the uptake of antichlotin. So we're definitely keeping a very close eye on the class. But at least today, I think we feel very, very good about our chances to compete with anti-clotin and maybe, you know, way down the road, there's a potential to combine PD-1, TIGIT, and the anti-clotin as well, anti-clotin ADC.

Yeah, and I do want to add to that, right? So people typically talk about toxicity in grades, but I would encourage you to look up what it actually means. So the clodin antibodies, they have at least 10% or 15% grade 3 nausea and fomiting. If you hit that as a patient, that means you're hospitalized, you're on tube feeding, you get parental feeding. It's a really, really big deal. We talk about grade 1 and 2 toxicities that are obviously a burden on patients, but grade 3 nausea and fomiting is a really, really big deal. So I think that's another uphill battle for the clodin field. Obviously, the efficacy data is absolutely promising, but to the point that Jen made, I think it's going to be a small subset of patients that's funneled into the clot and high, PD-L1 high population. And then, honestly, ask yourself the question, like, could you deal with grade 3 nausea and vomiting? I think that is incredibly, incredibly bad toxicity for patients

to have to deal with. Got it. Thanks so much for the color. This concludes today's conference call. Thank you, everyone, for joining. You may now disconnect.