Zymeworks Inc. (ZYME) Earnings Call Transcript & Summary

Thank you for standing by. This is the conference operator. Welcome to Zymeworks 2021 ESMO Conference Webcast and Conference Call. [Operator Instructions] And the conference is being recorded. [Operator Instructions] 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 in HER2-positive GEA from Dr. Neil Josephson, Zymeworks Interim Chief Medical Officer and Senior Vice President, Clinical Research. Then 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 Dr. Josephson and Tehrani. The speakers will be available for Q&A after the prepared remarks. And 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 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, and 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 and then Neil Josephson will provide a brief overview of zanidatamab's unique mechanism of action and 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 3 specific strategies: First, we have our fast-to-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 the 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. Second, we have our display 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 onward 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, trastuzumab, ALX-CD47 blocker, [ Evoprocept ] Celgene HER2 TK1, 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 buy -- simultaneously buy 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 differentiates zanidatamab from monospecific antibodies like trastuzumab and pertuzumab, which combined to only one site, which each combined to only one side 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 service and further decreases HER2 signaling. In addition, 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 by a 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 incidents 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. However, 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 -- Well, 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 and 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. Now I will be turning the call over to Dr. Geoffrey Ku. Dr. Ku is an assistant attending physician and head of esophagogastric -- of the esophagogastric section in the gastrointestinal oncology service at Memorial Sloan Kettering Cancer Center in New York. He is a renowned physician scientist with expertise in the development of novel therapies for the treatment of gastric in esophageal cancers, and 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 the 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. Pembrolizumab was initially administered on a weight-based regimen. Subsequently, this was changed to a 2-tiered flat and dosing schedule. On this slide, you will see the 3 chemotherapy regimens that are evaluated are CAPOX or 5-FU cisplatin every 3 weeks, along with an every 3-week administration of zanidatamab as well as FOLFOX and zanidatamab every 2 weeks. There are 2 parts to this study. The primary end point 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 28 and includes 36 patients. This table shows the demographics and baseline characteristics. Consistent with a global study, about 1/3 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. Premedication 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 2 patients receiving FP and accrual to this arm in Part 1 continues. In the FOLFOX arm, 2 DLTs were noted and 62% of patients developed grade 3 diarrhea. As such, the Safety monitoring committee recommended modification of a FOLFOX regimen with the mission of the bolus 5-FU. Around this time, a prophylactic anti-diarrheal regimen was also introduced. With these measures, one DLT was noted in 7 patients and the modified FOLFOX6-2 was confirmed for Part 2. Next slide, please. Turning to efficacy analysis. 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 or with discontinued study treatment due to death or clinical progression. Of the 8 patients who are not efficacy evaluable, 4 were HER2-negative, 3 did not have measurable disease and 1 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 1 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 [ suresh ] plot, and it highlights the durability of the responses. Approximately 25% of patients have been on treatment longer than 12 months with the responses ongoing and 2 patients continue on treatment more than 20 months later. Next slide. This slide of 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 continue to experience a deepening response over time. Next slide. And finally, here, we have the Kaplan-Meier curve, which shows the median progression-free survival, which is 12.0 months. Next slide. In conclusion, zanidatamab plus chemotherapy is refined therapy for HER2-positive GEA is encouraging antitumor activity. Specifically, the confirmed objective response rate in the CAPOX and FP arm are 92% and 100%, respectively. Most recent 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. And with that, I would like to turn the call back over to Dr. Neil Josephson.

Continuing on Slide 23. A. 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 in chemotherapy. And 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.

We will begin the question-and-answer session. [Operator Instructions] Our first question comes from David Novak of Raymond James.

Congratulations on these class-leading results. And I guess to kick things off from 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 [ TRAEs ], specifically diarrhea across all chemo arms. This does seem to be well managed by prophylaxis in the [ pyrimide ]. I guess my question is, does diarrhea persist past cycle one? And 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?

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 the 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, that allows patients to stay on therapy. And through the course of the Phase II study, that's what we've done. So if you look at what we did with the FOLFOX regimen, that meant making small adjustments to the chemotherapy regimen by emitting 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. But more importantly, as you discussed, the management across all treatment arms is improved by the institution of prophylaxis of diarrhea. So we've instituted a 1-week mandatory diarrhea prophylaxis with twice daily dosing of oral loperamide on cycle 1, and that's very effective in preventing the onset of diarrhea. So in this 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%. And no patients discontinued treatment due to diarrhea after we instituted prophylaxis. So it has been an effective management tool and will be employed in our Phase III study.

Great. That's helpful. And I guess just moving on to durability, you're showing here in a median duration of response in 16.4 months with a number of patients still on therapy. 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 that [ TH3RESA triplet ] in this context?

Yes. So I mean, you're right, the durability of this regimen is -- looks very good. This is -- this is ongoing data. As we've mentioned, we still have many patients that are on treatment. So the data is evolving. And -- but what we're seeing looks quite promising. And as Dr. Ku showed in the Spire 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. So the data here is from a global a study that we believe is represented in the type of study that we're going to do in -- 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. And again, as you mentioned, and adding the PD-1 inhibitor, in the Phase III study, we have -- we're still arising that data's actually going to improve the results not only from the standpoint of increasing response rate, perhaps, but also increasing the durability.

Great. And just finally, lastly for 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? And I'll hop back in the queue.

Yes. And I think we're -- it is true that if you look at the study on the CAPOX and FP, which are the 2 regimens that we are taking forward in the Phase II study, we saw of the 14 patients, 13 of the 14 patients had a partial response. So 93% of the patients treated with the regimen that we're taking forward into the Phase III study had a response. But we're also seeing good responses in FOLFOX as well. So that I think that in total, the data looks very promising, but I don't think that we have enough data to be able to say that necessarily one regimen is -- works better with zanidatamab than another. But 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. And congratulations again.

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?

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 -- the [indiscernible] that were treated at Memorial actually had maintenance zanidatamab alone. Frequently with oxaliplatin-based regimens, we stopped the oxaliplatin but continued the [indiscernible]. But 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. But again, many of these responses are occurring with zanidatamab alone. So really as kind of a chemotherapy-free maintenance option. The toxicity profile is very favorable and the durability really speaks for itself. So I think that's something that is also worth noting. And I think the -- and then 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. But one thing I would add also is that patients who received CAPOX were much more likely to be Asian. And I think there continues to be a debate about gastric cancer in Asia versus rest of world, even in the HER2-positive subset. But 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.

A couple for me. So 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. So 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. So maybe you can just help me understand if there's anything specific to this study with respect to just how drugs being administered or whatnot that would explain the differences that we're seeing between the 2 studies?

So 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 in -- with HER2-targeting therapy with gastric cancer in combination with the 2 agents, the fluoropyrimidine and the platin agent. So there is a difference in the backbone chemotherapy. And as we pointed out in this presentation, risk property 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?

Yes. So flat or fixed dosing is a more convenient, a way of dosing zanidatamab, it also leads to less wastage of the product. And we've chosen a dosing scheme, 2-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. So 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. And so we will be going with the flat dosing, the 2-tier flat dosing regimen in the Phase III study.

Okay. And then just lastly, and 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 trastuzumab here. I'm just curious as to when we might expect to see that data?

I'll take that, Ali. Neil, I'll take that. So 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 proceed the start of the Phase III in Q4 as we noted.

Our next question comes from Nick Abbott of Wells Fargo.

It's -- I won't even say it's bright now here, Ali, on the West Coast, but it's certainly less but congratulations on a terrific set of data. And question for Dr. Ku. Dr. Ku, one of the authors listed on the 2020 [ lantho ] Oncology paper describing it a Memorial experience with Keytruda plus CAPOX? And so you've had obviously direct experience of both these regimens. Can you compare your observations from the 2 trials? How easy these regimens are? How tolerated they are? and then I have a follow-up.

Sure. I mean, 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. So I think that as investigators on the study, there certainly was a learning curve I think we're simply recognizing the fact that the diarrhea exists. But I think the prophylactic Imodium regimen in combination with patient awareness and physician awareness has ultimately made it manageable. So again, I mean, the 2 regimens are slightly different because one has PD-1 inhibitors and 1 does not. But 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 antidiarrheal 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. And -- but I think with a -- I mean 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. And I think in general, all of the toxicities are actually very manageable as first-line regimens go.

And then from your prior comments that you have any maintenance, presumably when you have pembro, you're using tempo maintenance. So think of the Phase III, do you consider that patients will be receiving PD-1 and any maintenance?

Yes. I mean I'll definitely have Neil -- yes, exactly. I mean the one thing I would clarify is that even with -- even based on the KEYNOTE-811 paradigm, I think a 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 maintenance strategy. And that's really kind of historical and something that's commonly done in upper GI as well as colon cancer. But the Neil can address the Phase III study.

Yes. So 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.

Our next question comes from Gena Wang of Barclays.

Congrats on the great data. So I have 2 questions for Dr. Ku. First, my question is regarding the FOLFOX arm. Just wondering, what is the percentage of IHC 3+. And then the second question is, and you comment before, it could be a small number of patients. But on the other hand, we did see zani dosing regimen are different between FOLFOX and CAPOX. So do you think the response rate differences beyond the small number of patients, also partially due to zani any dosing or the chemo itself?

Yes. I mean those are -- well, those are both great questions. I guess I don't have the breakdown of HER2, whether it's 3-plus or 2-plus-ish positive based on the regimen. Neil may have that information. So I'll address your second question. And again, I think it's absolutely a hypothesis that potentially the schedule and the dosing of the fluoropyrimidine plus the redosing of zanidatamab -- I mean one can certainly have publicize that zanidatamab, has an effect both on toxicity and efficacy. And 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. And it's also pretty well established at toxicities of it's kind of been clearly vary based on ethnicity and based on geographic location. So I think to answer your question, essentially, I think we don't know. But I think certainly -- I think it's fortuitous and it's encouraging that the regimens that are moving forward in Phase III include CAPOX, where I think the -- seemingly the most favorable toxicity profile and the highest response rates we're seeing.

Yes. In terms of IHC status between the CAPOX and FP, I don't have a tally to working down, but there's not any significant difference in terms of the IHC status and what we're seeing in the different arms. And I would just echo what Dr. Ku said previously that this is a small data set. It's hard to parse out differences between the arms. And I would also point out that there are some patients here -- one patient that I think Dr. 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 a fantastic management of his systemic disease and doing well. So while that patient may count as a PV in the FOLFOX arm, I think by all measures, that patient has had tremendous benefit from FOLFOX plus zanidatamab.

Yes. I'm sure. I mean I could just briefly add to that. So this is a patient who was having symptoms prior to start of treatment. So clinically, certainly was not progression. But shortly, after the initiation of therapy was found to have a brain metastasis. So by RECIST it was considered progression. I mean, that patient is getting close to the 2-year mark of being on treatment. And to Neil's point, I mean, that patient is treated on the FOLFOX arm. So 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 leave.

Our next question comes from Jessica Fye of JPMorgan.

There's been a little discussion about geographic and, I think, 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. And I'm happy to take that question. So this is a global study. So it was performed in Canada, U.S. and South Korea, and about 1/3 of the patients are Asian. And 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 was -- treated patients were pretty much split between North America and South Korea. But overall, the mix of patients that we're seeing here is similar to what we expect to see in the Phase III.

Okay. Great. And any comparison to other trials?

Again, I think that if you look at other large Phase III styles, the trials that have been done in gastric cancer. You see somewhere between 30% to 50% the patients are typically Asian. And so I'd say that this is similar as well.

Okay. Great. And then...

Dr. Ku, do you have anything to add to that?

No. And I think part of that is that I think many studies deliberately limit the number of agent patients just to make sure that there's equal representation. Again, I mean, it's one of these things that geomedical oncologists like to talk about as to whether there really is truly a difference between gastric cancer in the East and West, I mean I think that really remains also kind of an unresolved issue. So I think it's part of a good trial design to ensure that no one geographic location is overrepresented.

Okay. Great. And then lastly, can you maybe walk us through the 3 patients who couldn't be kind of captured in the RR 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?

Yes. So I think that as was pointed out, patients who do not have resist target lesions are not response evaluable. But those patients can be enrolled to some studies and can be -- 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.

Yes. Is that the patient with the lymph node to head surgery?

Yes. Yes, exactly.

Yes. Okay. Yes. So I mean, again, I mean, the -- it's actually very helpful to have studies that allow patients who have evaluable but not measurable disease by RECIST criteria. I mean it's a little bit of a technical distinction. -- particularly the lymph nodes are a little bit smaller. They're less than 1.5 centimeters in short axis. But still, for all intents and purposes, there is a disease that we can follow. So like Neil said, I think in terms of estimating progression-free survival, that's still absolutely something that can be done. And so 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, I mean smaller, but certainly, we would have seen them getting bigger. Just that the largest was not big enough to be considered measurable. So this patient actually had a very significant response to treatment. And actually, radiographically, all of the lymph nodes disappeared. And ultimately, his treating physician decided to take in to surgery, where he actually had -- I believe it was in the self-ojectomy as well as resection of the original lymph nodes that were involved there was residual disease at the time of the surgery. And then subsequently, his physician elected to continue him on maintenance trastuzumab as he had come off the study to have surgery. And I think it's been, at this point about 8 months since the surgery and the patient remains disease-free on imaging.

Our next question comes from Yigal Nochomovitz of Citi.

This is Carly on for Yigal. 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 sort of the JACOB trial as a proxy? And 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?

I'll take that. This is Ali Tehrani. I think you asked a really good question, and I'm glad you brought up the JACOB trial. The key pieces of therapeutics in the JACOB trial are Herceptin/PERJETA in chemo. And in the same setting in the front line gastroesophageal adenocarcinoma, I believe the data that was generated there had a 57% ORR. And we acknowledge the fact that we have a small and here, we have a small data set. But certainly, and looking at our data, we are headed in the right direction. And 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. But 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. And 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 state of the others. And we're very excited about showcasing that and having that discussion. But 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 Herceptin plus PERJETA across all HER2-positive tumor types.

Our next question comes from Andrew Berens of SBV Leerink.

Congrats on the update. Very nice data. A lot of my questions have been answered. But I guess just a little more color on that first-line breast trial that you just mentioned, Ali. It looks like it's expecting data in '22 now, I think, is what it looks like on the pipeline graph. And then what do you think, and I think you probably talked about this a little bit in the prepared comments, but what does the regulatory pathway look like in GEA in regards to accelerated approval? And then the last one is you previously said that you plan to partner [ Suzanne ] and I was wondering if you could give us some updated thoughts here. 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. And 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 studies, the registrational study is 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. And then just to clarify, in terms of the accelerated pathway in GEA. I believe Keytruda did have an accelerated approval? And so is that something 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. So 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.

Our next question is a follow-up from Nick Abbott of Wells Fargo.

So for the PD-1 inhibitor, how convinced are you that tislelizumab is equivalent to pembro and why not allow U.S. physicians to choose between trastuzumab is equivalent to pembro, and why not allow U.S. physicians to choose between trastuzumab and pembro getting a pembros approved?

So 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. So 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 is -- has been shown to be a very effective therapy to pembrolizumab. In addition, there are actually -- leads us to think that it actually may be a better PD-1 inhibitor in terms of it's affinity to PD-1 in terms of the way that it engages certainly immune cells and that it actually maybe have mechanistically a better outcome. But in terms of trial design, I think that, as Ali said, we'll get into the specifics of that at -- when the first patient is in. But 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, but 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 what is being -- what is better than -- what is the best regimen to take forward.

Yes. No, I understand that. I guess it just seems like it's a risk going with an unknown quantity as far as the PD-1 element goes. And maybe just a follow-up on that. One of your competitors has said there is no evaluating anti-HER2 plus the PD-1 in GEA? Is this a strategy you're considering?

Say that again. I'm sorry, just mean that PD-1 and alone without chemotherapy?

Right. With the 2 [indiscernible]

Yes. So that's not currently part of our Phase III development plan. But 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. Nick, this is Ali. I'll jump in. We are -- we're constantly in dialogue with physicians and investigators such as Dr. Ku. And we will certainly consult with them in terms of what they believe they need to treat their patients best. And as necessary, we will consider other studies to meet their needs of treating their patients. So certainly, the potential of additional Phase IIs is within the books. But 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. And 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 assets and zanidatamab. With what we've been saying all along that it can be a foundational therapy in the treatment of HER2-expressing cancers. And I want to thank you 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.