Thank you for standing by. This is the conference operator. Welcome to Zymeworks' 2021 ESMO Conference Webcast and Conference Call. As a reminder, all participants are in listen-only mode, and the conference is being recorded. After the presentation, there will be an opportunity to ask questions. I would now like to turn the conference over to Ryan Dercho, Senior Director, Corporate Affairs at Zymeworks. Ryan, please go ahead. Good morning and welcome, everyone. My name is Ryan Dercho, senior director of corporate affairs at Zymeworks. Today, we will review and discuss results from our first-line phase II study of zanidatamab in HER2-expressing gastroesophageal adenocarcinoma, or GEA for short. The call will begin with an introduction from Dr. Ali Tehrani, Zymeworks' president and CEO, and a brief background on zanidatamab and HER2 positive GEA from Dr. Neil Josephson, Zymeworks' interim chief medical officer and senior vice president, clinical research. We are pleased to have principal investigator and lead author on the study, Dr. Geoffrey Ku of Memorial Sloan Kettering Cancer Center, here to present the data. This will be followed by closing remarks from doctors Josephson and Tehrani. The speakers will be available for Q&A after the prepared remarks. Before we begin, I would like to 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 of, initiate, look forward to, expect, believe, plan, anticipate, enable, and similar words. Forward-looking statements are based upon our current expectations and various assumptions and are subject to the usual risks and uncertainties associated with companies in our industry and at our stage of development. For a discussion of these risks and uncertainties, we refer you to the 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 Zymeworks' website later today. I will now turn the call over to Ali. Thank you, Ryan. Good morning, everyone. Thank you for joining us at such an early hour. My name is Ali Tehrani, President and CEO of Zymeworks. Today, we will provide an overview of the data from our phase II study of zanidatamab plus chemotherapy in first-line HER2-expressing GEA. While we are excited to get to the data, I would like to take a moment to review our strategic development objectives for zanidatamab. Then Neil Josephson will provide a brief overview of zanidatamab's unique mechanism of action in HER2-positive GEA landscape. Currently, zanidatamab has multiple ongoing phase I, phase II, and registration-enabling clinical trials across several indications, including biliary tract cancer, gastroesophageal adenocarcinoma, breast cancer, and colorectal cancer. These trials are underpinned by our development strategy for zanidatamab, which is focused on three specific strategies. First, we have our faster market strategy. Here, our goal was to identify the fastest path to potential approval to get zanidatamab into the hands of a broad group of physicians globally and expand access for patients in need. Based on the encouraging results as a monotherapy and a large unmet medical need in the setting, we selected advanced HER2-amplified biliary tract cancer as the indication for our first pivotal trial called HERIZON-BTC-01, which has been granted breakthrough designation by the FDA and is currently recruiting at over 50 sites globally. We have our displace strategy, where our goal is to displace Herceptin as the standard of care in GEA, and similarly, Herceptin plus Perjeta in breast cancer. We believe the data presented today represent key validation on route to accomplishing this goal. Third, we aim to expand the use of zanidatamab into other HER2-expressing indications such as colorectal and endometrial cancer, as well as expand potential combinations with other targeted and IO therapeutics such as BeiGene's anti-PD-1, tislelizumab, ALX CD47 blocker, evorpacept, Seagen's HER2 TKI, tucatinib, and Pfizer's anti-CDK4/6 IBRANCE. We will look to continue doing this moving forward as we execute on the development of zanidatamab. With that, I would like to hand the call over to Dr. Neil Josephson, our interim Chief Medical Officer and Senior Vice President of Clinical Research, to provide you with a brief overview of zanidatamab's unique mechanism of action and the current HER2-positive GEA landscape. Neil? Thanks, Ali. Continuing on slide 7. Zanidatamab is a bispecific antibody that targets 2 specific domains on the HER2 protein, the extracellular domain 2 and extracellular domain 4. Signaling through the HER2 receptor is a mechanism that promotes cell growth and proliferation in a variety of cancers, including a subset of GEA and breast cancer. Because of its configuration, zanidatamab can simultaneously bind 2 distinct HER2 domains in a trans fashion, meaning that each arm of a zanidatamab antibody binds to a different HER2 molecule. Since each HER2 molecule can be bound by 2 different antibodies, this unique binding geometry enables cross-linking of neighboring HER2 proteins, creating large clusters of zanidatamab on the surface of a tumor cell. This clustering results in multiple mechanisms of action, which differentiate zanidatamab from monospecific antibodies like trastuzumab and pertuzumab, which each can bind to only one site on HER2. When zanidatamab binds to HER2, it prevents the formation of HER2 homodimers, as well as heterodimers of HER2 with other HER family members, such as HER3. Preventing dimerization leads to a reduction in HER2 signaling and cell growth. Clustering also induces HER2 receptor internalization, leading to a decrease in the number of HER2 molecules present on the cell surface and further decreases HER2 signaling. In addition, the zanidatamab HER2 clusters promote immune cell recruitment to tumors, leading to tumor cell killing through antibody-dependent cellular cytotoxicity, or ADCC, and antibody-dependent cellular phagocytosis, or ADCP. Finally, the orientation of the Fc region of zanidatamab in the clusters allows for binding of complement proteins, which can promote killing of HER2-expressing cells via complement-dependent cytotoxicity, or CDC. Zanidatamab's multiple mechanisms of action have been elucidated by our own preclinical research, and now there is a growing body of clinical data demonstrating zanidatamab's potential for improving outcomes for patients with HER2-expressing cancers. Slide 8. The data that Dr. Ku will describe shortly was generated in the first-line treatment of patients with advanced unresectable or metastatic HER2-expressing GEA. As shown on this slide, GEA, or gastroesophageal adenocarcinoma, is a disease that has worldwide impact, with the highest incidence being noted in Asia. Globally, gastric cancer is the second leading cause of cancer deaths, and about 20% of GEA cases are HER2 positive. Given the high morbidity and mortality and limited treatment options for patients with GEA, there is a significant unmet need. Slide 9. trastuzumab in combination with chemotherapy is the accepted global standard of care for the first-line treatment of HER2 positive gastric cancer, based on results from the ToGA trial that was reported out in 2010. The JACOB trial that was subsequently performed failed to show a statistically significant benefit by adding pertuzumab to trastuzumab and chemotherapy. Slide 10. While this has been the approved standard of care, that is, trastuzumab and chemotherapy, for over a decade, in May, the FDA granted conditional approval to pembrolizumab in combination with chemotherapy and trastuzumab based on interim data from the KEYNOTE-811 study. The approval is relatively new. We understand, however, that this has the possibility to change the standard of care landscape. For those reasons, we ensured our upcoming pivotal study included a comparator arm using BeiGene's anti-PD-1 inhibitor, tislelizumab. In summary, we see zanidatamab's phase II results, which Dr. Ku will speak to momentarily, as important to patient outcomes, providing not only another treatment option for physicians and patients, but one that is well-tolerated with high rates of durable antitumor activity relative to the benchmarks set by current standard of care for first-line GEA patients. Slide 11. I will be turning the call over to Dr. Geoffrey Ku. Dr. Ku is an assistant attending physician and head of the esophageal gastric section in the gastrointestinal oncology service at Memorial Sloan Kettering Cancer Center in N.Y. He is a renowned physician scientist with expertise in the development of novel therapies for the treatment of gastric and esophageal cancers. We are pleased to have him here today to present this newly released data with zanidatamab for the frontline treatment of HER2-positive GEA. Thanks, Neil, for the very kind introduction. On behalf of my co-investigators, it's my pleasure to present these data. Let me start with a summary of the current study on slide 12. It is an ongoing global phase II study of zanidatamab with chemotherapy in the first-line setting for HER2 positive gastroesophageal adenocarcinoma, or GEA. Zanidatamab was initially administered on a weight-based regimen. Subsequently, this was changed to a two-tiered flattened dosing schedule. On the slide, you will see the three chemotherapy regimens that are evaluated are CAPOX or 5-FU cisplatin every three weeks, along with an every three-week administration of zanidatamab, as well as FOLFOX and zanidatamab every two weeks. There are two parts to this study. The primary endpoint in part 1 was to establish safety, while the primary endpoint in part 2 is the objective response rate of each combination. Next slide. The current data analysis is from a data cutoff on July 28th and includes 36 patients. This table shows the demographics and baseline characteristics. Consistent with a global study, about one-third of patients are Asian. You will note that 11% of patients are not considered HER2 positive. In part 1, patients with tumors that are not considered HER2 positive by standard criteria could enroll. There was also some discrepancy between local versus central testing. Next slide, please. This table shows treatment-related adverse events. Overall treatment-related serious adverse events occurred in 19 patients, all grade 3 or more. 11% of patients discontinued treatment because of an adverse event. The most notable toxicity was diarrhea. 94% of patients experienced diarrhea, 42% with Grade 3 or more toxicity. Other toxicities are in line with standard chemotherapy combinations. Pre-medication was mandated on the study for zanidatamab, and 15% of patients experienced a Grade 1/2 infusion-related reaction. 9% of patients experienced a cardiac event, but only one patient had a decreased ejection fraction. Next slide. In terms of dose-limiting toxicities identified during Part 1, there was no DLT in the CAPOX group, and dosing was confirmed for Part 2. DLT occurred in one of the two patients receiving FP, and accrual to this arm in Part 1 continues. In the FOLFOX arm, two DLTs were noted, and 62% of patients developed Grade 3 diarrhea. The Safety Monitoring Committee recommended modification of a FOLFOX regimen with omission of the bolus 5-FU. Around this time, a prophylactic anti-diarrhea regimen was also introduced. With these measures, one DLT was noted in seven patients, and the modified FOLFOX dosing was confirmed for Part 2. Next slide, please. Turning to efficacy analyses, 28 patients were evaluable for efficacy. This efficacy evaluable population was defined as all HER2-positive subjects with at least one evaluable post-baseline disease assessment, all who discontinued study treatment due to death or clinical progression. Of the eight patients who were not efficacy evaluable, four were HER2 negative, three did not have measurable disease, and one withdrew before having their first scan. Of the 28 patients, 17 remain on treatment. The confirmed objective response rate is 75%, with confirmed complete response in one patient. Disease control rate is 89%, and the median duration of response is 16.4 months. Next slide, please. This is the waterfall plot. As you can see, 27 of 28 patients had some tumor shrinkage. Next slide. This is the Suros plot, and it highlights the durability of the responses. Approximately 25% of patients have been on treatment longer than 12 months, with responses ongoing, and two patients continue on treatment more than 20 months later. Next slide. This spider plot is another way to visualize these data. In addition to, again, seeing the durability of some of the responses, we also note that several patients with durable responses continued to experience a deepening response over time. Next slide. Finally, here we have a Kaplan-Meier curve, which shows the median progression-free survival, which is 12.0 months. Next slide. In conclusion, zanidatamab plus chemotherapy as first-line therapy for HER2-positive GEA is encouraging anti-tumor activity. Specifically, the confirmed objective response rate in the CAPOX and FP arms are 92% and 100%, respectively. Most frequent toxicity is diarrhea, which is manageable with a prophylactic anti-diarrhea regimen. Final slide. Lastly, I would like to express our gratitude to the patients and the family members who have participated in the study. I also thank the team at Zymeworks for preparing these slides. Thank you very much for your kind attention. With that, I would like to turn the call back over to Dr. Neil Josephson. Continuing on slide 23. Thank you, Dr. Ku, for reviewing the data. All of this data builds on work that we've done previously. Go to slide 24 now. Previously in late-line GEA, evaluating zanidatamab first as monotherapy in late-line GEA, followed by a study or data with zanidatamab plus chemotherapy in late-line GEA. The data presented by Dr. Ku today represents key validation of zanidatamab in early line of therapy, as we continue to observe the high rates of durable activity of our molecule. Next slide. In parallel to this study that we presented today, we have been running a phase II study with our partner, BeiGene, of zanidatamab in combination with tislelizumab and chemotherapy. We'll be starting a global phase III study that will begin enrollment in 2021, the fourth quarter of 2021, so by the end of this year. Slide 26. This study plans to evaluate zanidatamab and chemotherapy with or without the PD-1 inhibitor, tislelizumab, for the first-line treatment of locally advanced, unresectable, or metastatic HER2-positive GEA. With that, I would like to turn the call back over to Ali. Thank you, Neil. As we think about the future of zanidatamab, I want to make sure that everyone that is listening understands that we see zanidatamab as a treatment option, not only for patients suffering from biliary tract cancer or gastric cancers, but that we believe that zanidatamab's differentiated mechanism of action that Neil described earlier may enable it to displace Herceptin and Herceptin plus Perjeta across the entire HER2-targeted therapeutic space. This has the potential to change the standard of care in first-line metastatic GEA, as well as metastatic, neoadjuvant, and even adjuvant breast cancer. We see these data as thesis-defining and look forward to continuing along this trajectory as we march towards our ultimate goal of sending patients home disease-free. With that, I would like to open the line for questions. Thank you. We will begin the question and answer session. To join the question queue, you may press star then 1 on your telephone keypad. You will hear a tone acknowledging your request. If you are using a speakerphone, please pick up your handset before pressing any keys. To withdraw your question, please press star then 2. We will pause for a moment as callers join the queue. Our first question comes from David Novak of Raymond James. Please go ahead. Good morning, folks. Thanks for taking my questions this morning, and congratulations on these class-leading results. I guess to kick things off for me, looking at the safety profile, things look pretty good considering you're outperforming KEYNOTE-811 on both activity and durability without any neutropenia or thrombocytopenia. However, you do call out an increased rate of GIAE, specifically diarrhea, across all chemo arms. This does seem to be well managed by prophylactic loperamide. I guess my question is, does diarrhea persist past cycle 1? Further, could you provide us some insight into how you're thinking about a prophylaxis regimen in the pivotal trial and maybe some insight into how you're thinking about this in the context of other indications such as breast cancer? Is this a regimen-specific or indication-specific effect? Thank you. This is Neil Josephson. Diarrhea is a described and manageable adverse event that's associated with zanidatamab, and it's also described in general with HER2-targeted therapies when given in combination with fluoropyrimidine and platinum agents in frontline treatment of HER2-positive GEA. For us, the key in developing an effective regimen of zanidatamab in frontline HER2-positive GEA is to come up with a management plan for diarrhea that controls the diarrhea and allows patients to stay on therapy. Through the course of the phase II study, that's what we've done. If you look at what we did with the FOLFOX regimen, that meant making small adjustments to the chemotherapy regimen by omitting the 5-FU bolus. It was not necessary for us to make any changes to the backbone chemotherapy, CAPOX, and that's the chemotherapy regimen that's going to be the primary chemo regimen used in our pivotal phase III study. More importantly, as you discussed, the management across all treatment arms is improved by the institution of prophylaxis of diarrhea. We've instituted a 1-week mandatory diarrhea prophylaxis with a twice-daily dosing of oral loperamide on cycle 1, and that's very effective in preventing the onset of diarrhea. In this study, prior to the institution of prophylaxis, the rate of grade 3 diarrhea was 44% in cycle 1, and after the institution, it was 18%. No patients discontinued treatment due to diarrhea after we instituted prophylaxis. It has been an effective management tool and will be employed in our phase III study. Thank you. Great. That's helpful. Thanks so much. I guess just moving on to durability. You're showing here a median duration of response of 16.4 months with a number of patients still on therapy. Now, that significantly outperforms ToGA at 6.9 months, JACOB at 10.2 months, and even KEYNOTE-811 at 10.6 months. Can you talk a little bit about the durability advantage you're seeing here, specifically versus KEYNOTE-811, and maybe some insight into how you're thinking about the tislelizumab triplet in this context? Yeah. You're right. The durability of this regimen looks very good. This is ongoing data. As we've mentioned, we still have many patients that are on treatment. The data is evolving, but what we're seeing looks quite promising, and as Dr. Ku showed in the spiral plot, many of the patients that respond have prolonged responses that deepen over time. With the PD-1 inhibitor, we're hoping that not only would that contribute to an increase in response rate, but would also contribute to durability. We know that that's what has been seen with PD-1 inhibitors in other studies. The data here is from a global study that we believe is representative of the type of study that we're going to do as our phase III study. We're very pleased with the data that we have obtained so far. It is evolving, so we can't say exactly what the durability will be, but it looks quite promising right now. Again, as you mentioned, and adding the PD-1 inhibitor in the phase III study, we're theorizing that that's actually going to improve the results, not only from the standpoint of increasing the response rate, perhaps, but also increasing the durability. Great. Just finally, lastly from me on activity, could you talk a bit about the response variability between the CAPOX and the FOLFOX arm? Is this simply a sample size effect, or how are you thinking about these results? I'll hop back in the queue. I think it is true that if you look at the study in the CAPOX and FP, which are the two regimens that we are taking forward in the phase II study, we saw 13 of the 14 patients had a partial response. 93% of the patients treated with the regimen that we're taking forward into the phase II study had a response. We're also seeing good responses in FOLFOX as well. I think that in total, the data looks very promising. I don't think that we have enough data to be able to say that necessarily one regimen works better with zanidatamab than another. Again, what we have here from this entire body of data is an overall excellent response rate and, in particular, when you look at the regimens that we're taking forward, a response rate that we're really excited about. Great. Thanks, Neil, and congratulations again. Oh, thank you. Hi, everyone. This is Ali Tehrani. Before we take the next question, I just wanted to turn the mic over to Dr. Ku to see if he had also any additional thoughts on the response and the duration of response. Yeah. Thanks, Ali. I think one thing I did want to add is that I think what's particularly impressive to me about the durability of the response is that many patients on the study, or the 20 patients that were treated at Memorial, actually had maintenance zanidatamab alone. Frequently with oxaliplatin-based regimens, we stop the oxaliplatin but continue the fluoropyrimidine. The protocol allowed for the possibility of stopping all cytotoxic chemotherapy entirely, and I think it was something that we did with trepidation early on. Again, many of these responses are occurring with zanidatamab alone. Really, as kind of a chemotherapy-free maintenance option. The toxicity profile is very favorable, and the durability really speaks for itself. I think that's something that's also worth noting. Also, I guess on a related note, I think I would also agree with Neil's point that this is a small sample size, and I don't know that we should overread into activity between FOLFOX and CAPOX. The one thing I would add also is that patients who received CAPOX were much more likely to be Asian. I think there continues to be a debate about gastric cancer in Asia versus the rest of the world, even in the HER2-positive subset. I think the big-picture top-line results are certainly what are extremely impressive to me. Thank you, Dr. Ku. Why don't we go to the next question, operator? Our next question comes from Stephen Willey of Stifel. Please go ahead. A couple from me. The first, I guess I'm just trying to rationalize the difference here in the incidence rate of grade 3 diarrhea that was observed in this study relative to what was seen previously in the second-line plus trial when combined with chemo, whereby I believe there was a 0% incidence rate of grade 3. I guess just given the high rates that you're seeing after cycle 1, it doesn't appear to be a function of duration of therapy. Maybe you can just help me understand if there's anything specific to this study with respect to just how drug's being administered or whatnot that would explain the differences that we're seeing between the two studies. I'll take that. We've covered the issue of diarrhea, but I'll just say that diarrhea is more of an issue in frontline regimens with HER2-targeting therapy with gastric cancer in combination with the two agents, the fluoropyrimidine and the platinum agent. There is a difference in the backbone chemotherapy. As we pointed out in this presentation, with proper management, this diarrhea can be managed. Thank you. Okay, and then maybe you can also just explain, I guess, what the intention was behind the fixed dosing regimen, and is it safe to assume that you'll be pursuing weight-based dosing in the phase III? Yeah. Flat or fixed dosing is a more convenient way of dosing zanidatamab. It also leads to less wastage of the product. We've chosen a dosing scheme, a two-tiered flat dosing scheme that gives the same coverage in terms of dose density or dose coverage over a variety of weights that we would see in patients. There's really, over the population of patients, there's really no difference in terms of weight-based and flat dosing in terms of the population coverage of the drug. It's a more convenient, less wasteful way of giving it, we will be going with the two-tiered flat dosing regimen in the phase III study. Okay, just lastly, forgive me if I missed it, but I know that you have the pilot study that's being conducted with BeiGene with the addition of tislelizumab here, just curious as to when we might expect to see that data? Thanks. Yeah. Maybe I'll take that. This is Ali. Neil, I'll take that. Thank you very much. Yeah. That study is underway, and we're working with our partner BeiGene to bring that data out. We're currently looking at maturing the data set. We believe right now, that data set will come in the first half of 2022, which would precede the start of the phase III in Q4, as we noted. Great. Thanks for taking the question, guys. Our next question. Next question. comes from Nick Abbott of Wells Fargo. Please go ahead. Good morning. I won't even say it's bright and early here, Ali, on the West Coast, but it's certainly early. Congratulations on a terrific set of data. A question for Dr. Ku. Dr. Ku, you're one of the authors listed on the 2020 The Lancet Oncology paper describing Memorial's experience with KEYTRUDA plus CAPOX. You've had obviously direct experience of both these regimens. Can you compare your observations from the two trials, how easy these regimens are, how tolerated they are? I have a follow-up. Sure. I would say that I think pembrolizumab with trastuzumab and chemotherapy is well-tolerated. I think the results of the KEYNOTE-811 study really kind of bear that out. Again, I would say that the major difference that we're seeing with zanidatamab and chemotherapy without a PD-1 or PD-L1 inhibitor, is the diarrhea. I think that, as investigators on this study, there certainly was a learning curve, I think, with simply recognizing the fact that the diarrhea exists. I think the prophylactic IMODIUM regimen, in combination with patient awareness and physician awareness, has ultimately made it manageable. Again, the two regimens are slightly different because one has a PD-1 inhibitor and one does not. I think that would be the major difference that emerges. I know there have been questions about the diarrhea toxicity. I would say that patients who are on zanidatamab monotherapy have very minimal diarrhea and certainly don't require any anti-diarrhea medications. Similarly, FOLFOX chemotherapy has a relatively low incidence of diarrhea that, in general, is easily managed. I think there clearly is an additive or even synergistic component when we bring zanidatamab together with a fluoropyrimidine-based regimen. I think it's certainly manageable with a prophylactic regimen moving forward. Beyond that, I think other toxicities are certainly very comparable between both of these combinations. I think in general, all other toxicities are actually very manageable as first-line regimens. Thank you. Then, from your prior comment that you have zani maintenance, presumably when you have pembro, you're using pembro maintenance. As you think of the phase III, do you consider that patients will be receiving PD-1 and zani maintenance? Yeah. I'll definitely have Neil. I see. Yeah, exactly. The one thing I would clarify is that, even based on the KEYNOTE-811 paradigm, I think few of us actually are completely omitting the chemotherapy. With the exception of patients with exceptional response and minimal disease, most of us still typically continue a fluoropyrimidine chemotherapy as a maintenance strategy. That's really kind of historical and something that's commonly done in upper GI as well as colon cancer. Neil certainly can address the phase III study. Yeah. Thank you. In the phase III study, patients who are randomized to the arm with the PD-1 will continue with tislelizumab and zanidatamab. Details of the phase III study will be reviewed at the time of first patient in. Okay, thanks. I'll hop back in the queue. Our next question comes from Gena Wang of Barclays. Please go ahead. Thank you for taking my questions, also congrats on the great data. I have two questions for Dr. Ku. First, my question is regarding the FOLFOX arm. Just wondering, what is the percentage of IHC 3+? The second question is, you commented before, it could be small number of patient, but on the other hand, we did see zani dosing regimen are different between FOLFOX and CAPOX. Do you think the response rate difference is beyond the small number of patients also partially due to zani dosing or the chemo itself? Yeah. Those are both great questions. I don't have the breakdown of HER2, whether it's 3+ or 2+ FISH positive based on the regimen. Neil may have that information. I'll address your second question. Again, I think it's absolutely a hypothesis that potentially, the schedule and the dosing of the fluoropyrimidine plus the dosing of zanidatamab could. One can certainly hypothesize that that has an effect both on toxicity and efficacy. I think ultimately, we don't know. Again, I would also throw in that there is also the confounder of ethnicity with most patients receiving CAPOX being Asian. It's also pretty well established that toxicities of capecitabine clearly vary based on ethnicity and based on geographic location. I think to answer your question, essentially, I think we don't know. I think certainly, it's fortuitous and it's encouraging that the regimens that are moving forward in phase III include CAPOX, where I think seemingly the most favorable toxicity profile and the highest response rates were seen. In terms of IHC status between the CAPOX and the FP, I don't have it tallied or broken down, but there's not any significant difference in terms of the IHC status in what we're seeing in the different arms. I would just echo what Geoffrey Ku said previously, that this is a small data set. It's hard to parse out differences between the arms. I would also point out that there are some patients here, 1 patient that I think Geoffrey Ku can talk about, that technically is a progressive disease based on an early diagnosis of a brain met, but is now 2 years into therapy with fantastic management of his systemic disease and doing well. While that patient may count as a PD in the FOLFOX arm, I think by all measures, that patient has had tremendous benefit from FOLFOX plus zanidatamab. Yeah. Sure. I think just to briefly add to that. This is a patient who was having symptoms prior to start of treatment. Clinically, certainly it was not progression. Shortly after initiation of therapy, was found to have a brain metastasis. By RECIST, that was considered progression. That patient is getting close to the 2-year mark of being on treatment. To Neil's point, that patient is treated on the FOLFOX arm. I think there's always the temptation to kind of read into the tea leaves. I think sometimes there's a risk of reading too much into the tea leaves. Thank you very much. Our next question comes from Jessica Fye of JP Morgan. Please go ahead. Hey, guys. Good morning. Thanks for taking my question. There's been a little discussion about geographic and ethnic differences as it relates to response. I'm curious whether the geographic mix in this trial is comparable to what you would anticipate in phase III, and also how it compares to the geographic mix in other large HER2 gastric trials. Sure. I'm happy to take that question. This is a global study. It was performed in Canada, U.S., and South Korea. About a third of the patients are Asian. This is probably pretty similar to what we'd expect in the phase III study. It's similar to what's been seen in other phase III studies. There was some difference. I think that we saw more FOLFOX given in North America. The CAPOX treated patients were pretty much split between North America and South Korea. Overall, the mix of patients that we're seeing here is similar to what we expect to see in the phase III. Okay, great. Any comparison to other trials? Again, I think that if you look at other large phase III trials that have been done in gastric cancer, you see somewhere between 30%-50% of the patients are typically Asian, so I'd say that this is similar as well. Okay, great. And then. Geoffrey Ku, do you have anything to add to that? No. I think part of that is that I think many studies deliberately limit the number of Asian patients just to make sure that there's equal representation. It's one of these things that GI medical oncologists like to talk about as to whether there really is truly a difference between gastric cancer in the East and West. I think that really remains also kind of an unresolved issue. I think it's part of good trial design to ensure that no one geographic location is over-represented. Okay, great. Lastly, can you maybe walk us through the 3 patients who couldn't be captured in the ORR due to lack of measurable disease. Maybe talk about how they did clinically and if there were other assessments that you used to determine if they were benefiting. Yeah. I think that, as was pointed out, patients who do not have RECIST target lesions are not RECIST evaluable. Those patients can be enrolled to some studies and the progression-free survival of those patients is certainly something that can be assessed. I know, Dr. Ku, you had one of those patients on this study, so maybe you can speak to that patient specifically. Yeah. Is that the patient with the lymph nodes who had surgery? Yes. Yeah, exactly. Yeah. Okay. Yeah, again, it's actually very helpful to have studies that allow patients who have evaluable but not measurable disease by RECIST criteria. It's a little bit of a technical distinction. Typically, the lymph nodes are a little bit smaller. They're less than 1.5 centimeters in the short axis. Still, for all intents and purposes, there is disease that we can follow. Like Neil said, I think in terms of estimating progression-free survival, that's still absolutely something that can be done. In fact, this is exactly the situation with this particular patient. There were lymph nodes that we could clearly see. We could see them getting smaller, but certainly we would've seen them getting bigger. Just that the largest was not big enough to be considered measurable. This patient actually had a very significant response to treatment. Actually radiographically, all of the lymph nodes disappeared, and ultimately his treating physician decided to take him to surgery, where he actually had, I believe it was an esophagectomy, as well as resection of the original lymph nodes that were involved. There was residual disease at the time of the surgery. Then subsequently, his physician elected to continue him on maintenance trastuzumab, as he had come off the study to have surgery. I think it's been, at this point, about eight months since the surgery and the patient remains disease-free on imaging. Thank you. Our next question comes from Yigal Nochomovitz of Citi. Please go ahead. Hi, this is Carly on for Yigal. Thanks so much for taking our questions, and congratulations on the data. We have 2 questions. First, we were just hoping you could expand a bit on the point you made during your prepared remarks about sort of the broader strategy to displace Herceptin and Perjeta, and why you believe there should potentially be read-through from this gastric trial to other tumor types, specifically breast cancer, when you think about the JACOB trial as a proxy. Then the second question is on the phase II study for the triplet being led by BeiGene. Can you just talk about what you see as the bar on ORR for that regimen in light of the data that was presented today? Thank you. Thank you. I'll take that. This is Ali Tehrani. I think you asked a really good question. I'm glad you brought up the JACOB trial. The key pieces of therapeutics in the JACOB trial are Herceptin, Perjeta, and chemo. In the same setting, in the frontline gastroesophageal adenocarcinoma, I believe the data that was generated there had a 57% ORR. We acknowledge the fact that we have a small data set. Certainly in looking at our data, we are headed in the right direction. We believe we are absolutely showcasing the fact that, as I mentioned, we have a thesis-defining piece of data here. Naturally, we have to expand the data set. Naturally, we are excited to see how this data matures over time, and as we begin to showcase the data for our triplet combination in the first half of the year. I would say that we're also on track to showcase the breast cancer data over the course of the next few months this year, and certainly in the first half of the new year, to directly corroborate our thesis that there is a read-through to breast cancer. I want to remind everyone that we have an ongoing first-line metastatic breast cancer study with our partner, BeiGene, where we're looking at the combination of zanidatamab plus chemo. Also we have an ongoing late-line breast cancer study in combination with chemo, which will be presented at a near-term medical conference. I think when that data comes out, there can be a direct sort of a discussion between the read-through of this data to others. We're very excited about showcasing that and having that discussion. From the very beginning, as I mentioned in my prepared remarks, we've always gone into the development of zanidatamab with a viewpoint that this asset has the potential of displacing Herceptin and then Herceptin plus Perjeta across all HER2 positive tumor types. Great. Thank you. Our next question comes from Andrew Berens of SVB Leerink. Please go ahead. Hi. Thanks. Congrats on the update. Very nice data. A lot of my questions have been answered. I guess just a little more color on that first-line breast trial that you just mentioned, Ali. Looks like it's expecting data in 2022 now, I think, is what it looks like on the pipeline graph. What do you think, and I think you probably talked about this a little bit in prepared comments, what does the regulatory pathway look like in GEA in regards to accelerated approval? The last one is, you previously said that you plan to partner zani and was wondering if you'd give us some updated thoughts here. Thanks. Congrats again on the good data. Thank you. Good to speak with you again. First, on the first-line metastatic breast cancer study, a good number of patients have been enrolled. We are currently maturing the data set, and as we've showcased here, when we highlight that data for everyone, we want to make sure that we have followed these patients for a sufficient amount of time such that we can have a comprehensive discussion as it relates to comparable trials, especially the CLEOPATRA trial. That's why we are going to bring that data set in the first half of the new year. In terms of the second question, and when it comes to the potential of an accelerated approval in GEA, we'll be happy to elaborate further on the trial design on the specifics of the phase III at the initiation of the study later this year. Last but not least, on the partnership, as I've always mentioned before, we view a partnership critical to accelerating the path to patients for zanidatamab and of course broadening it. Zymeworks is well-positioned for the registrational studies currently underway. However, as we embark on additional registrational studies, especially in breast cancer, we view a partnership as a critical piece to accelerate bringing zanidatamab to patients globally around the world, and that priority remains well within our corporate objectives. Okay. Just to clarify, in terms of the accelerated pathway in GEA, I believe KEYTRUDA did have an accelerated approval, is that something that you guys think is possible here too? Absolutely. Obviously, when there is a precedent set by another therapeutic, it creates the opportunity for other assets to benefit from that. We are aware of that. We have studied that, and as I mentioned, at the initiation of the study, we'll be in a much better position to completely discuss that with everyone. Okay, thanks and congrats again. Thank you. Our next question is a follow-up from Nick Abbott of Wells Fargo. Please go ahead. Great. Thanks for taking the follow-up. For the PD-1 inhibitor, how convinced are you that tislelizumab is equivalent to pembro, why not allow U.S. physicians to choose between tislelizumab and pembro, given that pembro is approved? This is Neil Josephson, and I will answer that question. I'm not aware that there's been head-to-head studies looking at the efficacy of different PD-1 inhibitors. It's hard to point to specific data to say anything in direct comparison. I think what we can say is that from a mechanistic standpoint, BeiGene's PD-1 inhibitor has been shown to be a very effective therapy, tislelizumab. In addition, there are actually reasons to think that it actually may be a better PD-1 inhibitor in terms of its affinity to PD-1 in terms of the way that it engages certain immune cells and that it actually may have a mechanistically a better outcome. In terms of a trial design, I think that as Ali said, we'll get into the specifics of that when the first patient is in. We have to control the elements in the different arms to be able to make an assessment of the regimen and the regimen that we're looking at with the PD-1 inhibitor, specifically with tislelizumab and not with other PD-1 inhibitors. It does not prevent us from doing other studies with other PD-1 inhibitors. For this study that we're talking about, the phase III, it is one where we have to control the regimen so that we can really tell what is the best regimen to take forward. Yeah. No, I understand. I guess it just seems like it's a risk, going with an unknown quantity as far as the PD-1 element goes. Maybe just a follow-up from that. One of your competitors has ZEJULA is now evaluating an anti-HER2 plus a PD-1 in GEA. Is this a strategy you're considering? Say that again. I'm sorry. One of your competitors. PD-1. Yeah PD-1 and alone without chemotherapy? Right. With the two, there's the two biologics. Yeah. That's not currently part of our phase III development plan. Again, we will talk about specifics of the phase III study at first patient in. I'm sorry. I guess I was just saying not as part of the phase III, but as an additional trial concept. I'll jump in with that. Yeah. Nick, this is Ali. I'll jump in. We're constantly in dialogue with physicians and investigators such as Dr. Ku, we will certainly consult with them in terms of what they believe they need to treat their patients best. As necessary, we will consider other studies to meet their needs of treating their patients. Certainly, the potential of additional Phase IIs is within the books. At this time, what I would like to bring everyone's attention to is that we have a set plan for going forward. At this point, I want to turn it back to the operator. This concludes the question and answer session. I would like to turn the conference back over to Zymeworks for any closing remarks. Great, I think this is coming back to me. This is Ali again. I just wanted to conclude the discussion today by saying that we are very excited as ever about the potential of our lead asset, zanidatamab. With what we've been saying all along, that it can be a foundational therapy in the treatment of HER2 expressing cancers. I want to thank all of you again for joining us, and I know everyone is really busy with the ESMO conference, so thank you and have a wonderful rest of day. This concludes today's conference call. You may disconnect your lines. Thank you for participating, and have a pleasant day.