Thank you for standing by. This is the conference operator. Welcome to Zymeworks 2022 ASCO Analyst and Investor Webcast. As a reminder, all participants are in a listen-only mode, and the webcast is being recorded. After the presentation, there will be an opportunity to ask questions. To join the question queue, press star then the number one on your telephone keypad. Should you need assistance during the conference call, you may signal an operator by pressing star and then zero. I would now like to turn the conference over to Ken Galbraith, Chair and CEO of Zymeworks. Ken, please go ahead. Thank you. Good afternoon and welcome, everyone. Thank you for joining. My name is Ken Galbraith, Chair and CEO of Zymeworks. We wanted to take the time with you today to review and discuss the results from the first line of study presented at ASCO over the previous few days, as well as provide an overview and update on the Zanidatamab program. In short order, I will hand over the call to Dr. Neil Josephson, our Chief Medical Officer. I also want to note that Neil and I will both be available after the prepared remarks for Q&A. Before we begin, I wanna remind you that we will be making forward-looking statements during the call. Forward-looking statements can be identified by words such as will continue may potential initiate look forward to respectfully plan anticipate enable and similar words. Forward-looking statements are based upon our current expectations with various assumptions and are subject to the usual risks and uncertainties associated with companies in our industry and at our stage of development. For discussion of these risks and uncertainties, we refer you to our latest SEC filings as found on our website and as filed with the SEC. As a reminder, the audio and slides from today's event will be available on the Zymeworks website later today. Before I turn the call over to Dr. Josephson, I wanted to say what a pleasure it has been for our Zymeworks team to be back in person in Chicago with the other members of the global oncology community. We've had the opportunity once again to interact with researchers, KOLs, patient advocacy organizations, collaborators, potential new partners to discuss Zanidatamab, ZW49, and our early-stage oncology pipeline. We are committed to contributing to the next wave of antibody-drug conjugates and multi-specific antibodies to make further advancements for patients. It was a privilege to be here as a part of our global oncology community for the presentation of pivotal clinical data for DESTINY-Breast04, which has the potential to transform the classification and treatment of breast cancer patients with HER2-positive tumors. As a company with two novel biologics in clinical studies for HER2-targeted therapy, we are excited about the potential for further expansion of the potential treatable population in breast cancer and further advancements for patients driven by novel treatments in HER2-targeted therapy, including with Zanidatamab and ZW49. For their time today, we hope to explain the rationale, supporting clinical data, and value proposition for Zanidatamab, which are all highly important to the potential commercialization of this unique, innovative, HER2-targeted bispecific antibody. Second, we'd like to highlight the near-term opportunity for Zanidatamab in HER2-positive biliary tract cancer. This indication has an addressable patient population of approximately 9,000 patients per year, with China being the largest market. Given the recent completion of enrollment in our first pivotal trial, HORIZON-BTC-01, and the potential to be the first HER2-targeted therapy in this indication, we think it's important to further speak to this opportunity today. Third, we'd like to review some of the ongoing clinical studies for Zanidatamab and potential opportunities for additional data disclosures in 2022 and 2023. Finally, we would like to highlight the potential future clinical development opportunities for Zanidatamab beyond BTC and GEA, including the potential use of Zanidatamab to treat advanced metastatic breast cancer patients. With that, I'd now like to turn the call over to Dr. Josephson. Thanks, Ken, and good afternoon, everyone. Thank you for joining us today. My name is Neil Josephson, and I am the Chief Medical Officer here at Zymeworks. Today, I will provide a review of recent data presented at this ASCO meeting by our partner BeiGene, evaluating zanidatamab plus chemotherapy in first-line populations of HER2-positive gastroesophageal adenocarcinoma and HER2-positive breast cancer. In addition to this new data, I will be reviewing other important clinical data presented previously that support future clinical development plans for zanidatamab. On this slide, you can see waterfall plots generated from multiple different studies with zanidatamab. From monotherapy in late-line gastroesophageal adenocarcinoma, breast cancer, and biliary tract cancer, and a variety of other HER2-expressing cancers, to combinations with chemotherapy in earlier lines of therapy, including in front-line treatments, zanidatamab is an extremely active molecule. We are evaluating zanidatamab in a wide range of HER2-expressing cancers. This slide shows most of the cancers that are known to express HER2 and the incidence of HER2 expression and gene amplification for each. The green checks show the cancers where we have clinical data to show that zanidatamab has activity. On the right, we list the indications that are being evaluated in Phase II and III studies. Biliary tract cancer, or BTC, is the indication furthest along in development, with the HORIZON-BTC-01 registrational study evaluating single-agent zanidatamab in patients with relapsed or refractory amplified BTC. This study is now fully enrolled. First-line gastroesophageal adenocarcinoma, or GEA, is our second registrational indication, and the pivotal HORIZON-GEA-01 study is open and enrolling globally. We are also evaluating a role for zanidatamab in breast cancer and have a growing body of clinical data that will help inform our development plans with potential indications in both late-line and early-line disease. Finally, we are actively enrolling frontline colorectal cancer and frontline BTC patients in a phase 2 study. This slide highlights our development strategy for our lead indications. There are currently no approved HER2-targeted therapies in BTC, with the greatest need being the development of new treatments for relapsed refractory disease. Therefore, for BTC, we are pursuing a fast development plan with a first to market strategy for a HER2-targeted therapy based on an accelerated approval study in a patient population with a significant unmet need. For frontline HER2-positive GEA, trastuzumab is the only approved HER2-targeted agent. Our strategy is to go head-to-head with trastuzumab in the HORIZON-GEA-01 study, the goal being to displace trastuzumab by showing that zanidatamab is a superior HER2-targeted antibody in first-line GEA. HER2-positive breast cancer has become more of a chronic disease, with many patients deriving clinical benefit over multiple lines of therapy. The growing number of patients in later lines translates to a need for new active agents like zanidatamab that are well tolerated when given in combination with single agent chemotherapy or in chemo-free regimens. There is also potential for zanidatamab to make an impact in earlier lines of breast cancer, as highlighted by the frontline data BeiGene just presented at ASCO. In relapsed BTC, targeted therapies are beginning to make an impact in disease management, as evidenced by the recent approvals of FGFR and IDH1 inhibitors for patients with relapsed disease. Our first pivotal study, HORIZON-BTC-01, is designed to enable accelerated approval for zanidatamab monotherapy in patients with relapsed HER2 amplified or expressing disease. At the same time, we have a phase 2 study that is actively evaluating patients in the frontline setting with zanidatamab in combination with gemcitabine and cisplatin. The results of this phase 2 study will inform development plans for a potential future frontline registrational study. As presented at ASCO GI in January 2021, zanidatamab monotherapy in heavily pretreated patients with HER2 overexpressing BTC produced a 40% confirmed objective response rate and a median duration of response of 7.4 months. Monotherapy treatment was also very well tolerated, with no grade three or higher zanidatamab-related adverse events. Most common treatment-related adverse events were diarrhea, seen in 43% of patients, and infusion-related reactions seen in about a third of patients, with all events being grade one and two and easily managed in the outpatient setting. The phase 1 data informed the registrational HORIZON-BTC-01 study in relapsed HER2 amplified BTC that have now completed enrollment. We project that top line data from this study will be available by early 2023. This study has two cohorts. Cohort 1 is the primary efficacy cohort and consists of patients with HER2 amplified disease and an expression level at IHC 2+ or 3+. The target enrollment for this cohort is 75 patients. Cohort 2 is an exploratory cohort of up to 25 patients with HER2 amplified disease and expressing at IHC 0 or 1+. This global study being conducted with our partner BeiGene enroll patients in North America, South America, Europe and Asia, with patients from China representing less than 30% of the total enrollment. There is no standard of care therapy for relapsed BTC, a disease that is the absence of a targetable FGFR2 or IDH1 mutation. In the relapsed setting, response rates with single agent chemotherapy and combination chemotherapy are less than 10%, and in the randomized ABC06 study, FOLFOX chemotherapy resulted in less than a one-month prolongation of median overall survival versus supportive care. In this setting, the marginal benefits of chemotherapy are largely offset by treatment-related toxicities. For the sample size of 75 patients in the primary efficacy cohort for HORIZON-BTC-01, the lower bound of the 95% confidence interval for an observed response rate of 20% or higher is well above the activity seen in studies with chemotherapy. Another important factor for evaluating the benefit in this study is the duration of response. As previously noted in relapsed disease in our phase 1 study, we observed an ORR of 40% and a median duration of response of 7.4 months. Similar activity and response durability data supported approvals of pemigatinib and infigratinib in FGFR2 rearranged relapsed BTC. Now let's move on to discussing development in gastroesophageal adenocarcinoma. The HORIZON-GEA-01 study is our pivotal phase 3 study in frontline HER2-positive GEA. This global study is also being conducted with our partner Daiichi Sankyo. It has a target sample size of 714 patients and is currently enrolling. Patients are randomized into one of three arms. Arm A is the control arm with trastuzumab plus physician's choice of either CAPOX or FP chemotherapy. Arm B is zanidatamab plus physician's choice of chemotherapy. Arm C is zanidatamab plus the PD-1 inhibitor tislelizumab and physician's choice of chemotherapy. CAPOX and FP are both global standard care regimens for frontline GEA. We anticipate that the majority of patients enrolled will receive CAPOX, though FP is an all-intravenous regimen and may be more suitable for some patients who cannot take oral medications. The study has dual primary endpoints of PFS and OS. Both endpoints are alpha controlled, and positive results in PFS or positive results in both PFS and OS could support regulatory approval. Pathology samples will be evaluated by central review and must be HER2-positive per ASCO/CAP guidelines. In addition to primary malignancies of the stomach and gastroesophageal junction, this study allows enrollment of HER2-positive esophageal adenocarcinomas. Current approvals for HER2-targeted agents are limited to gastric and gastroesophageal adenocarcinomas. We estimate that approximately 15%-20% of patients enrolled on this study will have esophageal adenocarcinoma. Patients are enrolled regardless of PD-L1 status and response assessments are adjudicated by a blinded independent central review. The three-arm study design allows for evaluation of the contributions of both zanidatamab and tislelizumab and supports a potential label of zanidatamab and chemotherapy with or without tislelizumab as first-line treatment for HER2-positive gastric, esophageal and gastroesophageal junction cancers. The decision to rapidly move development of zanidatamab into frontline GEA was based on the promising results seen with monotherapy and in combination with single-agent chemotherapy in heavily pretreated patients, almost all having progressed after prior treatment with trastuzumab. The results in late line with single-agent chemo are similar to benchmarks set by multi-agent chemo combined with trastuzumab in the frontline setting, as reported by the ToGA study. At the most recent annual ESMO conference, we presented data for the zanidatamab plus standard of care chemotherapy in first-line HER2-positive patients. As shown in the waterfall plot, nearly all patients experienced a decrease in the size of their target lesions. Across all three cohorts evaluated, we saw a confirmed objective response rate of 75%. The responses were durable. As shown on this spider plot, the median duration of response was 16.4 months, and the median PFS was 12 months. It's important to realize that patients typically either come off of all chemotherapy or are maintained only on a fluoropyrimidine without a platinum agent after 6 cycles of chemotherapy, which translates to 4.5-6 months, depending on which chemotherapy backbone is used. This is shown in the red and blue areas on the spider plot. In fact, in this dataset, all 7 of the patients who have been followed for more than a year discontinued all of their chemotherapy by 7 months into treatment. The prolonged benefits of these responders comes from zanidatamab monotherapy, which we know is extremely well-tolerated. Since this data cut, the data has continued to mature and more patients have been added to the study. We plan to present the final analysis of the study data, including an overall survival readout, in the first half of 2023. On this study, the most common treatment-related adverse event was diarrhea, with 42% of patients overall experiencing grade 3 diarrhea. The majority of grade 3 diarrhea was seen in the first cycle. As a mitigation measure, we instituted a mandatory 7-day prophylaxis of twice-daily loperamide just during the first treatment cycle. With this intervention, the rate of grade three diarrhea in cycle 1 dropped from 44% to 18%. Otherwise, the regimen was well-tolerated with few grade three events. We look forward to updating the safety data as part of our final presentation of study results in the first half of 2023. As presented by our partner, BeiGene at ASCO on Saturday. This is data in frontline HER2-positive GEA from patients treated in China and South Korea with zanidatamab in combination with the PD-1 inhibitor tislelizumab and CAPOX chemotherapy. Nearly all patients on study experienced a reduction in the size of their target lesions and 76% or 25 of 33 enrolled had a confirmed response with many deep responses seen, including 1 complete response. At the time of the data cut, the median study follow-up was 9 months and 20 of 33 patients were still on study. The data set is not mature enough to provide a stable estimate of duration of response or progression-free survival, but there are multiple responding patients now out for more than a year. The safety profile was similar to what we reported at ESMO for the zanidatamab chemotherapy combination in front-line HER2-positive GEA. Diarrhea was the most common grade 3 treatment-related adverse event, and with the institution of 1 week of mandatory loperamide prophylaxis, the rate of grade 3 diarrhea dropped from 33% to 21%. Additionally, there was some immune-mediated adverse events, as would be expected for a treatment regimen containing a PD-1 inhibitor. Overall, the adverse event profile of this regimen is consistent with each of its individual agents and is manageable. Now let's move on to discussing breast cancer, where I'll start by reviewing data previously presented at the most recent San Antonio Breast Cancer Symposium. Patients with HER2-positive breast cancer who had received prior treatment with trastuzumab, pertuzumab, and T-DM1 in the advanced setting were treated in an expansion cohort of our original phase 1 study with the regimen of zanidatamab plus physician's choice of single-agent chemotherapy. The confirmed objective response rate in 23 efficacy evaluable patients was 36.4% with a median PFS of 7.3 months. This regimen was well-tolerated. The most common grade three treatment-related adverse events are neutrophil count decrease and neutropenia, as expected with chemotherapy. There were no events of febrile neutropenia and few other grade three events. Now I will move on to data presented earlier today by our partner BeiGene, evaluating the combination of zanidatamab and docetaxel for the front-line treatment of advanced or metastatic HER2-positive breast cancer. This Phase 1b/2 study, which enrolled patients in South Korea and China, evaluated a patient population that is usually treated with docetaxel in combination with trastuzumab and pertuzumab a regimen that was established as standard of care by the CLEOPATRA study. The primary endpoint for BeiGene's frontline study are safety and objective response rates, with secondary endpoints that include duration of response, progression-free survival, and overall survival. At the time of this interim data cut, 24 patients with HER2-positive advanced or metastatic breast cancer were enrolled, including 21 response evaluable patients. This is a first look at a mature data set, a maturing data set. At this interim point, the study was continuing to enroll patients, and the median follow-up time on study was 7 months, with 16 patients still on therapy. 29% of patients had received prior trastuzumab as part of neoadjuvant or adjuvant treatment, including one patient who had received both trastuzumab and pertuzumab. This rate of prior treatment with trastuzumab was about three times the rate reported on the CLEOPATRA study. The safety profile is similar to that of the regimen of trastuzumab and pertuzumab in combination with docetaxel. The most frequent grade 3 or higher treatment-related adverse event was neutropenia, with 1 patient experiencing an episode of febrile neutropenia and 1 patient coming off study because of a treatment-related adverse event. As shown, all but 1 patient demonstrated a reduction in the size of their target lesions. 19 of 21, or 90.5%, of the efficacy evaluable patients had a confirmed objective response at the time of the data cut, and their 6-month progression-free survival rate was 95.2%. At the time of this interim data cut, 16 of 24 patients remained on treatment. Additional patients have been enrolled in this study, and over time, this larger data set will mature to allow us to evaluate the durability of responses, progression-free survival, and finally, overall survival. This data will inform the potential for performing a future registrational study with zanidatamab in an early line of breast cancer. Zanidatamab is an active agent in breast cancer. Our current focus in development is to identify what lines of therapy and treatment regimens hold the most promise for making a significant impact to disease outcomes. As shown, based on maturing data, we see three potential development opportunities. The first is the combination of zanidatamab with single-agent chemotherapy for later-line patients who have been previously treated for advanced disease with trastuzumab, pertuzumab, and trastuzumab deruxtecan. The second opportunity is in early line setting in combination with a taxane as a replacement for trastuzumab and pertuzumab. The third opportunity is in later-line therapy as part of a chemo-free regimen with zanidatamab given in combination with a CDK4/6 inhibitor like palbociclib and fulvestrant for the hormone receptor-positive subset of patients who have previously been treated with trastuzumab, pertuzumab, and trastuzumab deruxtecan. We anticipate presenting data from our phase two study evaluating this regimen at a medical meeting by the end of this year. I will now turn the call over to Ken. Ken? Thanks, Neil. I will just briefly touch on the upcoming data we expect to present over the remainder of 2022 or in 2023. As you can see from this slide, we have multiple upcoming data sets across our lead candidates and potential R&D candidates. In the second half this year, we will present data on the weekly and every 3-week cohorts for ZW49, the first look at best clinical data for this molecule. In the fourth quarter this year, we plan to present potential clinical candidates that are early R&D data, as well as data in late line breast cancer for HER2-positive and hormone receptor-positive patients. Early next year, we plan to announce top-line data from our recently enrolled pivotal study, HORIZON-BTC-01, with the study completion and full data set planned to be presented later that year. Additionally, in the first half of 2023, we will present a follow-up of our phase 2 data in frontline GEA, where we continue to see complete responses across patients being followed in this study. We're also targeting completion of enrollment by the end of next year in our second pivotal study, the HORIZON-GEA-01 study, looking at frontline GEA patients. In exciting upcoming 18 months, we remain eager to continue to provide further updates for zanidatamab as we continue to progress towards initial commercialization and further clinical development of therapeutics to potentially expand the treatable patient population. I'd like to conclude with some important items about zanidatamab. We've seen some recent significant advancements in treatment regimens available to physicians for their HER2 patient populations in multiple clinical indications driven both by ADCs and other advanced biologics. It's exciting to be in a position to participate in further advances for patients in HER2-targeted therapy with both zanidatamab and ZW49. Based on zanidatamab's unique mechanism of action in HER2-targeted therapies, we believe that we have a differentiated value proposition from current and expected future standards of care in specific HER2-positive patient populations. With two ongoing registration-enabling studies, one in second-line biliary tract cancer and one in first-line GEA, we will have opportunities for initial market investment in global markets with the potential to expand into further clinical development opportunities that are currently being explored. Today, that is in colorectal cancer and breast cancer. We continue to believe that zanidatamab has the potential to be effective in combination and in early lines of therapy, and we'll continue to pursue its use across other indications as additional clinical data and partner interactions inform our path forward. With CMC activities for zanidatamab expected to be complete by the end of 2022, we believe that we'll be prepared and ready for any potential regulatory filings in 2023 and beyond. We'll be working very closely with BeiGene to execute regulatory filings and commercialization of zanidatamab in their Asia Pacific region, and we'll be looking to potential future partners in markets outside of the Asia Pacific region to provide resources for future clinical development and commercialization. We also expect to retain a role for regional commercialization or co-commercialization in specific markets for zanidatamab. We are excited about the future of zanidatamab in the rapidly evolving and growing market for HER2-targeted therapies and believe in the value proposition of zanidatamab for patients in specific clinical indications we're working in to provide supporting clinical data for our various treatment regimens. We also look forward to reporting on our clinical development work on our other clinical-stage HER2-targeted therapy, ZW49, and our future potential clinical candidates from our technology platform during the second half of 2022. Thank you all for listening to our prepared remarks. I will now pass the call back to the operator for a Q&A session where both Neil Josephson and myself will be available on the line to answer your questions. Operator? Thank you. We'll now begin the question-and-answer session. If you do have a question, please press star then one on your telephone keypad. If you are using a speakerphone, please pick up your handset before pressing any keys. To withdraw the question, press the hash key. We'll pause a moment as callers join in the queue. Your first question comes from Yigal Nochomovitz with Citigroup. Please go ahead. Hi. Great. Thank you. Thank you very much for taking the questions. I had a question on the GEA study in first-line GEA, the phase 1b/2, the triplet. You had very good data, obviously, with the 76% ORR and a 100% disease control rate and a good DOR range. Obviously, this is very similar to what we saw in KEYNOTE-811, which showed approximately the same ORR and about a 10-month DOR. When you look ahead to the HORIZON-GEA-01, which is also evaluating the triplet in the first-line GEA setting, I'd just like to get a better understanding, you know, as to how you see yourself differentiating potentially on what metrics, for example, PFS or OS, if you could just elaborate on that. Thank you. Sure. This is Neil Josephson, and I'm happy to take the question. I think that one thing to realize is that this is a maturing data set, so this is an early data set on a relatively small number of patients, and it's relatively early on. While we can talk about the response rate being 76%, which is really quite good, it's a little harder for us to know what the true duration of response and what the PFS is because the majority of patients, about two-thirds of the patients have yet to have had a PFS event and certainly less with an OS event, at the time of this data cut. We'll have to wait for the data to mature to be able to see how it pans out. I also wanna point out that you know when you're looking at studies you have to you know when you're trying to do cross-study comparisons you have to realize that not all the patient populations are the same. This is a population of patients that's all in Asia. There was a relatively high rate of patients who had ECOG performance status one, more than you would expect, rather than ECOG performance zero. This study was enrolled based on a local determination of Of HER2 status, not by central review. Comparing it to KEYNOTE-811 or comparing it to data that we previously presented at ESMO, I think there are a lot of caveats in terms of trying to draw conclusions. It certainly is an impressive data set and we're pleased with the outcome. I think that we have to wait for the full data to pan out. I think what I would say in terms of why I'm really excited about the triplet is because I think that there is role for both a better HER2-targeted agent like zanidatamab, which we believe is a more active agent than trastuzumab. We believe that there's a role for that. Some patients may benefit in addition to having a better HER2-targeted therapy to having a PD-1 inhibitor, because of the immunotherapy component. What I would say is this, where this study differentiates itself and where our pivotal study differentiates itself from KEYNOTE-811 is that we have both. We have a better HER2-targeted agent, we believe in zanidatamab and that's what we intend to show. Then we also have an active PD-1 inhibitor. Okay. That makes sense. Thanks. Just one quick follow-up based on what you just said. Should we assume that in HORIZON-GEA-01 will have a higher contribution of the ECOG 0 patients relative to the phase 1b/2? I think what I can say is that ECOG performance status and region are both stratified factors so that when you look at the data from the HORIZON-GEA-01 study and you're looking at the three arms, they should be very similar in terms of patients that are enrolled across different regions and very similar in terms of performance status across agents. I mean across the cohorts. What I'm saying to you is now you're looking at two different studies where those kinds of things were not controlled or stratified. Got it. Okay. Thanks very much. Thank you. Your next question comes from Charles Hsu with Guggenheim. Please go ahead. Hey, good afternoon, everyone, and thanks for hosting this call and for presenting all the data that you have at this conference. One thing I had, you know, you have cited the need for a potential development partner for zanidatamab and, you know, some of the particularly larger indications out there. I guess on this front, how much data do you think you may need to generate with how much follow-up in order for some of those potential development partners perhaps to feel like you're perhaps ready to make some form of agreement? Thanks. Yeah, thanks, Charles. I don't think additional data is required to strike a collaboration. Obviously it's good in these discussions that we continue to generate additional data and the data that we have that we share under confidentiality with potential partners continues to mature. So they have access to that information. So I think as we have a very strong data set right now, we're continuing to add to the potential data set that partners are allowed to review for Zanidatamab and ZW49 and our early-stage pipeline because we have an active program across the company's portfolio. But I don't think additional data is a gaining factor to completing a partnership with a good party who wants to help us beyond BeiGene territory. Got it. Great. Perhaps one additional question if I could squeeze it in. In biliary I was wondering if you had an established bar for regulatory approval by ORR and duration of response and perhaps why you specifically called out two objective response levels at 20% and 30% with their associated 95% confidence intervals. What's the significance of having those two distinct bars? Thanks. The reason I pointed that out was not because I'm making any claims about a regulatory bar. I'm trying to point out that the sample size is 75. What can it tell us when we think about what we know about standard of care? We know that standard of care, there really isn't a standard of care for these patients. We know that the data shows that these patients who are treated with combination chemotherapy or single agent chemotherapy, you know, have response rates in the single digits. With 75 patients, you know, even a response rate as low as 20% which is lower than what we saw in the phase 1 study that we reported out, even that is above what you'd expect the historical control. I just wanted to point out that how much information we can get out of these 75 patients. I'm not making any claims about a bar that needs to be met for regulatory approval. I'm just pointing out that other agents also that got accelerated approval in relapsed biliary tract cancer had response rates and durations of response, you know, that were in the same range. Some, you know, run lower and, you know, than what we've seen. Just to, you know, provide some insight into other agents in the same, you know, line of therapy. I am not claiming or saying that there is a specific bar that we have to get over. Got it. Great and fully understood. Thanks again for taking the questions, and congrats on presenting the data. Thank you. Thanks, Charles Hsu. Your next question comes from Jessica Fye with J.P. Morgan. Please go ahead. Hey, guys. Good afternoon. Thanks for taking my questions. I've got three. First, with enrollment completion by year-end 2023 for the pivotal frontline gastric trial, when should we expect top line results? Second, for the third line plus HER2-positive, HR-positive data expected later this year, what benchmarks, if any, should we consider when assessing those data? Third, in the phase 1/2 frontline breast cancer dataset presented at ASCO, can you walk through the reasons that each of the three patients without post-baseline scans did not have them? Thank you. I'll try to answer all three of those questions. You know, the GEA study is an event-driven study. I can't tell you exactly when we will have the number of events to allow us to read out that study. You know, I think that we have provided some really high-level guidance, you know, that we anticipate that there would be a readout sometime, you know, in 2024 in terms of top-line data. I can't give you guidance as to exactly when because it's determined by the number of events and depending on how long it takes for those events to accrue, that's how long the study will go. In terms of the benchmarks for the late line or third line HER2 positive, HR positive, I think that there are two things to think about. One is this is a you know a phase 1b/2 study, and it's gonna be looking at safety. Certainly we wanna report out safety data which will be important to show that this combination is safe. In terms of benchmarks to think about, I think that you can basically look at what late line, you know, data in HER2-positive breast cancer gives you with chemo and either, you know, trastuzumab or margetuximab. I mean, you know, just as sort of a general idea, where you're seeing, you know, response rates maybe in the 20%-30% range in PFS in the five- or six-month range as just a general rule of thumb. The patients that we're seeing are gonna be even more heavily pretreated than those patients because, you know, we're now seeing patients that have had Enhertu on our study, so it we can't really compare apples to apples in that sense. That's what's been seen at really late line in really late line patient populations. As for the specifics of the patients in the BeiGene study, you know, that study is being performed by BeiGene, so I don't have insight into exactly what those two patients that you are referring to or three patients, I'm not sure, you know, why there was no post baseline scan on those patients. Okay, got it. If I could just ask a couple follow-ups. On the grade three diarrhea that you see, even with prophylaxis, what's the KOL feedback on that, and your expectations for whether that, you know, will be tolerated or lead to discontinuation? Last one, can you talk a little bit about the new TOPO1 platform and the possibility of coming up with an upgraded version of Enhertu using zanidatamab instead of Herceptin as the binder? In terms of the grade 3 diarrhea, I think that the feedback that we have from our PIs who are treating these patients is that the regimen is better tolerated with the prophylaxis. I also want people to understand that, you know, if you look at our spider plot, you know, we're talking about grade 3 diarrhea in some patients in cycle 1. We're not talking about grade 3 diarrhea through the course of therapy. You know, the reason why we put the prophylaxis in was to prevent even that initial grade 3 diarrhea. Docs are very good at managing diarrhea in this setting. They're good at managing it with antidiarrheals. They're good at managing it with chemo modification. When you look at the spider plot that I showed, those patients who are you know out you know very long ways on in terms of their course, they haven't seen chemotherapy for months. You know even those that are on chemotherapy cycle two, cycle three, cycle four, they're not having high rates of diarrhea. I think that we can do a better job of showing you know adverse events by cycle maybe in a future presentation. Even more than that, I just you know we're not having patients go off study. These patients are staying on study, and it's manageable. I think the feedback that we're getting from our PIs who are treating our patients is that this is a manageable regimen, and that the institution of prophylaxis on the first cycle makes it even more manageable early on. To your second question, I'll let Ken answer. Yeah. Sorry. On the second question on the TOPO1 platform, we're you know Razi starts talking a little bit about our next-generation ADC platform. We're not gonna talk about specific strategies or targets, until we get to our early R&D day in the fourth quarter. That question will have to wait until later in the year. Okay. Thank you. Thank you. Your next question comes from Stephen Wiley with Stifel. Please go ahead. Yeah, good afternoon. Thanks for taking the questions. Just a point of clarification, I guess, on the HORIZON-GEA-01 study. Did you say that you were expecting to enroll 20% esophageal adenocarcinomas? And I guess I just ask the question because I know that I think when you look at, like, some of the ToGA and the JACOB data, there's a little bit of a suggestion in the data that those esophageal cancers and junction cancers actually do a bit better than gastric specifically. Is 20% the kind of the non-gastric number that you're expecting, or are you expecting 20% of esophageal, some number of gastroesophageal? Is there a cap on that, or is that just based upon where you're gonna be enrolling patients geographically? Yeah. There's no cap. Maybe I should make the point that ToGA and JACOB studies and other studies, and KEYNOTE-811, only enroll patients with gastric and GEJ. Historically, the diseases have been thought of as very anatomical, and gastric and GEJ have been lumped together. It's really clear from a biologic standpoint that if you just move a few centimeters up from the GE junction and have esophageal adenocarcinoma, that's HER2-positive, that it is essentially the same disease, and that's how docs manage it. They manage it the same way. There's no approved agent for HER2-positive esophageal. There's no approved companion diagnostic. What we've done is we've developed a companion diagnostic that will allow us to include esophageal, because it is included in the same treatment paradigm as gastric and GEJ. Just from a standpoint of epidemiology, we're anticipating that 15%-20% of the patients enrolled in the study will have esophageal. You know, as you alluded to, in Asia, there's more gastric cancer, and in the West, there's more GE junction and esophageal cancer. So I don't know exactly what it's gonna turn out to be. It's gonna turn out to be whatever, you know, the international distribution is and the distribution of patients. It's just a speculation that we are going to have, you know, some esophageal cancer patients here in this, in this indication, and that there really is no other drug that or other HER2-targeted drug for HER2-positive esophageal that has an approval. There's not a companion diagnostic that has approval. That one of the unique aspects of our study is that it is including this patient population, which historically has been treated the same as GE junction, HER2-positive GE junction and gastric adenocarcinoma HER2 positive. Okay. That's actually very helpful. On the frontline breast cancer study, I know that this was an Asian study. I know that a lot of these patients or the majority of patients didn't see any neoadjuvant or adjuvant HER2-targeting therapy. I think those that did didn't see any pertuzumab. Is there just any reason to believe that seeing pertuzumab, I guess, in pre-metastatic disease would somehow impact your ability to confer clinical benefit in frontline metastatic? I’m not exactly sure I understand your question, so maybe you could repeat it again. Yes. I guess the question is, in the frontline study that you presented today, I know that this is an Asian study. There's perhaps not as much HER2-targeted therapy that's deployed in the pre-metastatic setting. I think when it is deployed, it often does not include pertuzumab. So just wondering if you think about the translatability of that frontline data to, I guess, a more Western population or U.S. population, where you do see a lot more pertuzumab pre-metastatic use. Do you think that that would somehow influence the clinical benefit that you're able to confer in frontline metastatic disease? I'll start off by saying that a large percentage of frontline metastatic disease is de novo. Those patients with de novo have not had any you know, neoadjuvant or adjuvant therapy. I'll also say that you know, the CLEOPATRA study that established trastuzumab and pertuzumab as the standard of care, the patients in that study had only 10% of those patients had seen a prior trastuzumab. At least from a historical basis, we're actually seeing a more heavily pretreated patient population with prior HER2-targeted therapy. I guess I, you know, I think that is a small data set, but I wouldn't conclude that this data set should have performed better than what historical data sets in the front line have, because actually this is probably a more heavily pre-treated patient population, actually maybe even a little bit sicker. We had a higher rate of ECOG performance status 1. I don't see this as being anything but positive. There's nothing about this data as being anything but positive. We have a really high response rate, and, you know, based on anything that you wanna think about in terms of a benchmark from historical data, I think this is really, you know, a good result. Yeah. No, agreed. And then maybe just lastly for Ken, I think in the kind of overview of upcoming milestones and catalysts, there wasn't a mention of the frontline breast cancer data. I know that you've added more patients. I know that you're kind of waiting for that data to mature to get a read on duration of response. Should that be something that we expect to see over the course of the next 18 months or so? Thanks. Yeah. I mean, we obviously didn't guide in this call on every data set that we expect to announce in 2022 and 2023. I think where we were fairly certain about the timing of such data announcement, we've guided that which is appropriate. I think if we have other data sets, as you say, such as this one, which have more patients that we're continuing to follow and we have some certainty or at least good probability about the timing of that data being available, then we'll add that to our guidance. I think you should expect it during 2022 and 2023. There will be additional datasets, that one and others, which we will look to present in a peer review setting and we'll guide as soon as we're certain or at least probable about the timing of that. All right. Thanks. Thanks for taking the question. Yep. Thank you. Your next question comes from Nick Abbott with Wells Fargo. Please go ahead. Good afternoon. Thanks for taking our questions. First just going back to the diarrhea because, you know, I noticed when you look at the poster, the rate of grade 3 diarrhea with flat dosing is much lower, so it was 0% versus 30% in breast, 7% versus 37% in gastric. Why is that and is there some kind of correlation here with body surface area perhaps? And then I have a follow-up. Thank you. Well, specifically in the gastric cancer, I think that the institution of prophylaxis came at a similar time as the institution of the flat dosing. Those two things coincided. I don't think that the flat dosing per se has led to a lower rate of diarrhea. I think it's that the flat dosing was instituted at a similar time as the prophylaxis was instituted. You know, if you look across the weights, you know, that patients have, you see a similar, a very similar, you know, distribution of exposure, both on the flat dose and the weight-based dosing. I think of them as being equivalent in terms of, you know, how much drug patients are actually seeing. Okay. Fair enough. You know, can you talk about the data for zani in HER2-low disease beyond the second cohort in BTC? You know, especially given data we had this weekend for Enhertu in HER2-low and triple-negative breast. You know, how much of a data set do you have? Are you able to share with potential partners in HER2-low disease? For zanidatamab, that's not been an area where we've actively developed it at this point. You know, it might be an area where an ADC like ZW49 might be better suited, but it's not an area that we have any data that we're planning to imminently report out. Okay. Thanks. Excuse me. Last one. I think you mentioned earlier, Neil, that you know you have now enrolled some patients who have seen prior Enhertu, but do you have a model of acquired Enhertu resistance and if so, are either zanidatamab or ZW49 active in that setting pre-clinically? Yeah. I think you're gonna have to wait for, you know, additional data releases to come out for us to show you some of the data that we're accruing in patients who've had prior Enhertu. I can just say that it's, you know, it's something we're seeing more and more of on our studies. You know, we will point those out in future presentations in terms of which patients. Just like we point out in all of our studies now, you know, which patients got Traz, Pertuzumab, T-DM1, et cetera. You know, we're now seeing patients who've had Enhertu, and we'll be able to report out that information as well on future presentations. Preclinically, is there a rationale to think that Zanidatamab or ZW49 would be active in those patients? You know, we don't have specific preclinical data in an HER2-resistant model that I know of to be able to answer that question specifically. But we do have some clinical that we can report out in future presentations. Okay, fair enough. Thank you. Thanks, ma'am. All right. Your next question comes from David Martin with Bloomberg. Please go ahead. Yes, thanks for taking my questions. The first one is the two studies reported at ASCO. I know you've mentioned there's more follow-up to do for the PFS and the duration of response. Do you plan to enroll more patients going forward? How many in total do you plan the studies to be? In particular, I'm thinking you've got the HORIZON GEA study going on, but getting more breast cancer patients might be advantageous. Specifically, are you asking in the BeiGene study, the frontline breast study, are we planning on enrolling more patients? Yeah. Yeah. Yes. We have enrolled more patients into that study. You know, and we haven't disclosed exactly how many patients we've enrolled, but I can tell you that we have enrolled more and that we are gonna follow those patients, you know, for data maturity. You know, as has been alluded to before, you know, we need, you know, at this time, we only had, you know, the longest patients in follow-up was, I think, 17 months. We needed significantly more time to be able to see, you know, the duration response in the PFS based on what we know about frontline data in general, where, you know, on CLEOPATRA was an 18-month median PFS. You can think about that in terms of, you know, we've enrolled more patients. We're not enrolling any more at this point, and we're just gonna follow them up, and in time, we'll be able to report that data out. Okay. Second question. You showed a number of options for pursuing breast cancer in potentially pivotal studies. Would any of those be something that you and BeiGene alone would pursue, or do you need another partner in North America to pursue those options for registration? I think, David, one of the things we talked about in getting another partner for zanidatamab beyond BeiGene and their territories is to have the ability to broaden out the clinical development plan for zanidatamab beyond what we have now. Given the fact that those, you know, all of those studies in breast cancer we've identified as opportunities and hopefully we can do not just one of them, but all the ones that make sense to do would require some additional resources and funding of an additional partner to supplement what we and BeiGene would likely be able to do. Okay. Got it. That's it for me. Thanks. Thanks, David. Your next question comes from Gena Wang with Barclays. Please go ahead. Hi. Hey, guys. This is Tong for Gena Wang. We have one question about the, as we can see from different cancer type, we have addressed a different rate of grade three plus diarrhea. I just want to get some color on the rationale underlying the results. The question is why are we seeing different rates of diarrhea in different indications? Right. Yeah. I think it's largely influenced by the combination agents that are being used. You know, fluoropyrimidines and platinum agents alone have some rate of diarrhea. When you combine those with zanidatamab, that's probably why you're seeing more diarrhea than, say, in a frontline breast cancer population, where you're combining with docetaxel. I think it has to do with the combination agents. Then I also think it has something to do with the disease. Patients with GI cancers tend to have more issues with diarrhea than patients with breast cancer. That's not unique to you know zanidatamab. I mean, if you look at you know, the JACOB study, you know, where trab and pert were given, there was a higher rate of grade three diarrhea in that arm than say, you know, like in if you look at the CLEOPATRA study. It's a combination of the combination agents, probably the anatomical relation of the tumor. We do know that HER2-targeted agents do induce some degree of diarrhea. Okay. Thank you. All right. I'm not showing any further questions in the queue. I will turn the call back to Kenneth Galbraith for final remarks. Great. Thank you all for joining us today. I'm very excited about the potential of our employees, partners, and collaborators to make additional advancements for patients in HER2-targeted therapies and beyond in the years ahead. We very much look forward to reporting our continued progress in that mission in the weeks, months, and years ahead. I wanna thank you all for your time and support for our vision at Zymeworks, and hope you have a wonderful rest of the day. Thank you. Thank you. This concludes today's conference call. You may disconnect your lines. Thank you for participating. Have a pleasant day.