Zymeworks Inc. (ZYME) Earnings Call Transcript & Summary

Welcome to Zymeworks HERIZON-GEA-01 Launch Conference Call and Webcast. [Operator Instructions] 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 afternoon, and welcome, everyone. My name is Ryan Dercho, Senior Director of Corporate Affairs at Zymeworks. Today, we will discuss the launch of Zymeworks’ second pivotal clinical trial for zanidatamab HERIZON-GEA-01. The call will begin with an introduction from Dr. Ali Tehrani, Zymeworks President and CEO, followed by an outline of the trial by our Chief Medical Officer, Dr. Neil Josephson; and then an overview of our commercial strategy for zanidatamab in gastrointestinal cancers by our Chief Commercial Officer, James Priour. This will be followed by brief closing remarks from Dr. Tehrani. All 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 this call. Forward-looking statements can be identified by words such as will, continue, may, potential, 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 our latest SEC filings as found on our website and as filed with the SEC. As a reminder, the audio and slides from this afternoon's event will be available on the Zymeworks website later today. I will now turn the call over to Ali.

Thanks, Ryan, and good afternoon, everyone. Thank you for joining us. My name is Ali Tehrani, President and CEO of Zymeworks. Today, we're thrilled to officially announce the launch of our second pivotal trial for zanidatamab called HERIZON-GEA-01. Before we get started, I would like to say a few words about our overall strategy and what this opportunity means to our company, shareholders and patients. As I sit here today, we are approximately 2 years away from becoming a radically different company. This transformation is already well underway and is expected to culminate in the global launch of zanidatamab in biliary tract cancer, followed by GEA starting in 2024. We see ourselves becoming a commercial stage company poised to be leaders in the treatment of HER2-expressing GI cancers. And today, our plan is to communicate how we intend to deliver on that vision. In just a few minutes, you will hear from Dr. Neil Josephson, who I'm proud to announce will officially transition from his role as interim to the role of permanent Chief Medical Officer. The timing of this is very fitting as it was under his leadership over the past 6 months that we designed and now launched our first global randomized multi-arm Phase III clinical trial for zanidatamab. Next, you will hear from James Priour, our Chief Commercial Officer, who will outline the assumptions underpinning our belief that zanidatamab will capture significant market share and become the new HER2-targeted standard of care in both biliary tract cancer and gastroesophageal adenocarcinomas. Our conviction in both our study design and commercial opportunity is based on the thesis validating data that we presented recently at the ESMO Annual Congress and the emerging data from our ongoing Phase II study of zanidatamab in combination with chemotherapy and trastuzumab, which we aim to share in the first half of next year. Taken together, our hope is that by sharing these insights, we align our expectations and have you share in our enthusiasm for the future of zanidatamab. With that, I will turn the call over to Neil Josephson to tell you more about zanidatamab and the Phase III HERIZON-GEA-01 trial.

Thanks, Ali. Slide 5. Zanidatamab is a bispecific antibody that targets 2 distinct domains on the HER2 protein, ECD2 and ECD4. Signaling through the HER2 receptor is a mechanism that promotes cell growth and proliferation in a variety of cancers, including a subset of gastroesophageal cancer and breast cancer. Because of its configuration, zanidatamab can simultaneously bind to HER2 in a trans fashion. And that means that each arm of zanidatamab antibody targets a different domain on 2 separate HER2 molecules. Since each HER2 molecule can be bound by 2 different antibodies, this unique antibody -- this unique binding geometry enables cross-linking of the neighboring HER2 proteins, creating large clusters of HER2 bound by 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 can each bind 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, which decreases the number of HER2 molecules present on the cell surface and further diminishes 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 cancer cells via complement dependent cytotoxicity or CDC. Slide 6. To date over 400 patients have been treated with zanidatamab and there is a growing body of clinical data demonstrating zanidatamab's potential for improving outcomes for patients with HER2-expressing cancers. As a monotherapy and in combination with chemotherapy, zanidatamab has shown promising anti-tumor activity across multiple different types of HER2-expressing cancers with a manageable adverse event profile. As shown here, the majority of HER2-expressing biliary tract cancer and gastroesophageal cancer patients treated on study with zanidatamab demonstrated a reduction in the size of their target lesions. Slide 7. In biliary tract cancers, which includes cancers of the gallbladder and intra and extrahepatic cholangiocarcinoma, zanidatamab monotherapy in our Phase I study demonstrated a 40% confirmed objective response rate with a 7.4 month median duration of response. The treatment was well tolerated with no patients experiencing a Grade 3 or higher zanidatamab-related adverse event. This led the FDA to grant breakthrough therapy designation in this indication and prompted the initiation of Zymeworks first pivotal trial, HERIZON-BTC-01. Slide 8. HERIZON-BTC-01 is a study of zanidatamab monotherapy in patients with advanced or metastatic HER2 amplified biliary tract cancer who have progressed after standard of care front line chemotherapy. The study will enroll about 100 patients and has a primary endpoint of objective response rate as determined by independent central review. I am happy to report this study is over halfway enrolled, and we are on track to submit our first biologics license application in 2023. Slide 9. In addition to biliary tract cancer, zanidatamab has performed very well in late-line advanced unresectable and metastatic HER2-expressing gastroesophageal adenocarcinoma or GEA. As shown here, data reported at the ASCO GI Cancer Symposium last January demonstrated that in very late-line patients, monotherapy treatment resulted in a confirmed objective response rate of 33% with a 6-month duration of response. And in patients who had received a median of 2 to 3 prior lines of therapies, zanidatamab plus single agent chemotherapy resulted in a 54% confirmed objective response rate with an 8.9 months median duration of response and a 5.6 month median progression-free survival. These data compare favorably to data reported with other promising treatments and even less heavily pretreated patients, such as the recent presentation of second-line results within HER2 in DESTINY-GASTRIC-02 presented at the annual ESMO meeting in September. Slide 10. The promising data in late-line HER2-expressing gastroesophageal adenocarcinoma prompted us to evaluate zanidatamab in the front line setting where the HER2-targeted antibody trastuzumab and chemotherapy together are currently the global standard of care. Data recently presented at ESMO demonstrated that zanidatamab in combination with standard front line chemotherapy for GEA has potent anti-tumor activity with 75% of patients overall achieving a confirmed response, including 93% of the patients treated with CAPOX and FP. These are the 2 regimens that we plan to study in the Phase III HERIZON-GEA-01 study that I will describe shortly. Slide 11. As shown in this maturing data set, a high percentage of first-line patients treated with zanidatamab plus chemotherapy have experienced a deep and durable responses. As of this data cut, the median duration response was 16.4 months and median progression-free survival was 12 months. Slide 12. Zanidatamab plus chemotherapy in front line gastroesophageal adenocarcinoma demonstrated a manageable safety profile. The majority of treatment-related adverse events were Grade 1 or 2. The most common Grade 3 treatment adverse event was diarrhea. However, this was manageable in the outpatient setting. During this study, we instituted mandatory diarrhea prophylaxis consisting of twice daily loperamide during the first week of treatment. And with that change to the protocol, the incidence of Grade 3 diarrhea in Cycle 1 decreased from 44% to 18%. Slide 13. You can see that the results with zanidatamab and chemotherapy, including overall response rate, duration of response and progression-free survival compare favorably to benchmarks that come from the completed pivotal studies, ToGA and JACOB, that have established trastuzumab in combination with a fluoropyrimidine and platinum agent as a standard of care treatment for first-line HER2-positive gastric cancer as well as interim data from the KEYNOTE-811 study, evaluating the addition of pembrolizumab to the standard of care. In parallel to our Phase II study with zanidatamab plus standard of care front line chemotherapy, our partner, BeiGene, has been running a Phase II in front line HER2-positive gastric cancer, evaluating the combination of zanidatamab and chemotherapy plus BeiGene's anti-PD-1 antibody, tislelizumab. We anticipate that data from this study will be reported out in the first half of 2022. Slide 14. It is now my pleasure to present to you the HERIZON-GEA-01 trial, which was recently opened for enrollment. The start of this trial is particularly timely as November is National Stomach Cancer Awareness Month, and we are hopeful that this study will lead to improved outcomes and a new standard of care treatment for patients with HER2-positive gastroesophageal adenocarcinoma. Slide 15. HERIZON-GEA-01 is a 3-arm study, evaluating zanidatamab in combination with standard of care chemotherapy with and without the anti-PD-1 antibody, tislelizumab, for the treatment of first-line HER2-positive gastroesophageal adenocarcinoma. There are 2 experimental arms. Patients enrolled into ARM 2 will receive zanidatamab plus physician's choice of CAPOX or FP chemotherapy and those enrolled into ARM 3 will receive zanidatamab plus tislelizumab and chemotherapy. Both experimental arms will be evaluated compared to ARM 1, the current global standard of care, trastuzumab plus chemotherapy. The patient population is previously untreated patients with advanced unresectable or metastatic HER2-positive gastric, gastroesophageal junction and esophageal adenocarcinoma. 714 patients will be randomized equally into the 3 arms and the primary study endpoints are progression-free survival and overall survival. Slide 16. HERIZON-GEA-01 is an open-label study with disease assessments determined by Blinded Independent Central Review. In addition to gastric and GE junction cancer, the study population also includes esophageal adenocarcinoma. The metastatic HER2-positive esophageal adenocarcinoma is typically treated with the same approach as gastric and GEJ cancer. This pathology has not been included in other pivotal front line studies. We estimate that esophageal cancer will comprise about 10% to 15% of our study population. Stratification practice for the study include geographic region, HER2 IHC score and ECOG performance status. Patients will be enrolled regardless of PD-L1 status, and the study has dual primary endpoints of progression-free survival per Blinded Independent Central Review and overall survival. This 3-arm study is designed to support an indication for zanidatamab and chemotherapy with or without tislelizumab for previously untreated advanced or metastatic HER2-positive gastroesophageal adenocarcinoma. Slide 17. The study has recently opened to enrollment. We are projecting a 24 enrollment period, which leads to an estimated primary study completion date of June 2024 and the supplemental BLA submission in the second half of 2024. Slide 18. We are targeting enrollment at about 300 sites in 38 countries across North and South America, Europe, the Middle East and Africa and the Asia Pacific region. Currently, we have sites open in Spain and South Korea. Slide 19. To sum up, zanidatamab is a novel HER2-targeted bispecific antibody with a binding geometry that drives multiple mechanisms of action. Clinical data demonstrates that zanidatamab monotherapy has potent anti-tumor activity in HER2-expressing delay track cancer and gastroesophageal adenocarcinoma. In GEA, zanidatamab in combination with chemotherapy produces high overall response rates with durable tumor control. HERIZON-BTC-01 is Zymeworks’ first pivotal study. It is enrolling well and will support submission of a biologics license application for previously treated advanced unresectable or metastatic HER2-expressing BTC with a projected submission in 2023. HERIZON-GEA-01 is now open for enrollment. This 3-arm study will evaluate zanidatamab in combination with standard of care chemotherapy with and without tislelizumab for the treatment of front line HER2-positive gastroesophageal adenocarcinoma. With that, I would like to turn the call over to James Priour, our Chief Medical Officer. James?

Thank you, Neil. Slide 21, please. And good afternoon, everyone. My name is James Priour, Chief Commercial Officer at Zymeworks. Today, I plan to provide you an overview of zanidatamab's commercial strategy in both HER2-positive biliary tract cancer, BTC, and gastroesophageal adenocarcinoma GEA, which are the first 2 gastrointestinal tumors that we have decided to prioritize strategically. Our goal at Zymeworks is to obtain 3 FDA approvals in the next 5 years in these 2 tumor types. I will start my presentation by speaking more about BTC, a rare cancer with high unmet need and no approved positive -- HER2-positive targeted therapies. Although a rare tumor, BTC represents a very important strategic choice as it will drive clinicians initial familiarization with zanidatamab and ensure rapid uptake when we launch the larger first line GA indication. It will also importantly serve to anchor the high-value of zanidatamab with payers globally. At Zymeworks, we believe zanidatamab has blockbuster peak sales potential in biliary tract cancer and gastroesophageal adenocarcinoma for 4 key reasons. Number one, globally, there are more than 50,000 new patients per year with HER2-positive BTC and GA. Number two, zanidatamab's product profile is emerging across the 2 tumor types as potential new standard of care. Number three, there is a favorable pricing and reimbursement context as shown by the new targeted medicines in cholangiocarcinoma, Pemazyre, Truseltiq, Tibsovo to incur strong value and favorable access. And lastly, the familiarization with zanidatamab in second-line BTC will bolster its uptake in first-line GEA. Let's now review these 4 commercial value drivers, size of the addressable population, market map and product profile and access for each 2 indications in more details. Let me begin with BTC, Slide #22 and 23. BTC is comprised of cholangiocarcinoma, intrahepatic and extrahepatic and gallbladder. Across these 3 tumor types, approximately 10% of patients are HER2-positive with an estimated 9,000 new HER2-positive patients across first-line and second-line BTC per year that would be addressable by zanidatamab globally at peak. Noticeably, the incidence of BTC is growing and disproportionate is greater in Europe and Japan. The second-line and first-line BTC indications represent approximately 18% of the total addressable population for zanidatamab, but its value will expand beyond this as it will drive the anchoring of our initial launch, value and access expectations and form the springboard to the rapid adoption of our second larger indication first-line GA, as you heard it from my colleague, Neil Josephson. Next slide, BTC is a very heterogeneous disease with little to no overlap between HER2 amplifications and other mutations or alterations. And currently, there is no approved therapy for HER2-positive patients. For these patients, current standard of care is chemotherapy and is sub-optimal. Zanidatamab has the opportunity to be the first HER2-targeted therapy to open a new lane for second-line HER2-positive patients based on potential approval from the ongoing horizon BTC-01 trial, single-arm trial that Neil Josephson briefly reviewed with you. Ultimately, we will extend this lane to first-line upon completion of a confirmatory trial. Next slide, our reasons to believe in zanidatamab is based on proven clinical results. On the left-hand side of the slide, you can see our 40% single agent overall response rate data from our Phase 1 trial. This drives our confidence in delivering superior efficacy versus the current standard of care chemotherapy in second line, FOLFOX, with potential to translate it into more durable response. As shown by the data, zanidatamab has the potential to become the first approved chemo-free HER2-targeted therapy for second-line BTC, the new standard of care and the segment leader. Next slide, from a pricing and reimbursement standpoint, we are encouraged by the U.S., European and Japanese payers who have recently shown willingness to pay a premium price for new targeted therapy, Pemazyre from Incyte for FGFR-2 mutated cholangiocarcinoma. Other targeted therapies, Truseltiq from QED Therapeutics and Tibsovo from Servier for other mutated or altered cholangiocarcinoma are also approved and receiving reimbursement in the U.S. While not competitors to zanidatamab, they provide a relevant and recent pricing analog in this indication. And given the strong commercial uptake of Pemazyre in the U.S. as per Incyte's third quarter 2021 earnings report, we remain encouraged by zanidatamab and the potential for -- to see similar access and uptake. Next slide. Now let me move on to our second and larger plant indication, first-line GEA or gastroesophageal adenocarcinoma. Next slide, GEA is the fifth month common cancer worldwide and is comprised of 3 types, gastric, gastroesophageal junction or GEJ and esophageal adenocarcinoma, EA. With an average HER2 positivity rate of more than 20%, first-line GEA represents a sizable peak opportunity of an estimated 42,000 addressable new patients per year globally. Like BTC, the incidence is growing and is disproportionately greater in Europe and Japan. Next slide, in HER2-positive first-line GEA, zanidatamab has a clear lane, which is to become the backbone HER2-targeted antibody to combine with other mechanisms of action. Trastuzumab plus chemo has been the standard of care and trastuzumab, the antibody backbone of choice in GA for more than 10 years. Recently, the accelerated approval by the FDA in June for the combination of pembrolizumab with trastuzumab and chemotherapy, as shown in KEYNOTE-811, established the triplet combination of HER2-targeted antibody plus checkpoint inhibition plus chemotherapy as the new potential standard of care. Thanks to its unique and innovative bispecific mechanism of action, zanidatamab has the potential to displace trastuzumab as the new antibody backbone. In addition, zanidatamab would be the first approved therapy in esophageal cancer, EA, where an estimated 10% to 15% of patients have no approved targeted therapy. Currently, as highlighted by led by Neil in its section, esophageal adenocarcinoma patients will be eligible to enroll in our HERIZON-GEA-01 registrational trial. Next slide, in terms of combination profile, our Phase II zanidatamab plus chemotherapy data presented at ESMO Congress in September compare very well with the current standard of care and with KEYNOTE-811. Without checkpoint inhibition in the combination, our government data showed a strong 75% overall response rate and 16.1 months median duration of response. Given the strength of this data, we look forward to adding tislelizumab to zanidatamab and chemotherapy, CAPOX or FP in our registrational trial, HERIZON-GEA-01 and established this triplet combination as the new standard of care for HER2-positive GEA patients in first line. To be perfectly clear, leadership share is our goal in this line of treatment. Next slide, in summary and conclusion, zanidatamab's development and commercial strategy in BTC and GEA support our confidence in achieving global blockbuster pixels potential with the 3 indications we are pursuing in the next 5 years, second-line BTC, first-line GEA, followed by first-line BTC. The commercial revenue drivers are compelling. We have a sizable addressable HER2 patient population -- HER2-positive patient population, a clear lane to compete and establish leadership share, the favorable pricing and access context, as shown by the recently launched but non-competing cholangiocarcinoma targeted therapy. I thank you very much for your attention today, and we'll turn now the call back over to Ali for some closing remarks.

Thank you, James. Today, we heard a thorough review of the large global need in HER2-expressing GI cancers and how zanidatamab is well positioned to be a leader in this space. With the ongoing pivotal study in HER2-expressing biliary try cancers and the launch of the Phase 3 in the first-line HER2-positive GEA, we believe we are approximately 2 years away from both first sales for zanidatamab and becoming a commercial stage company. Both things, I couldn't be more excited to have shared with you. I'm also thrilled to be part of an organization that is truly dedicated to living its values, namely funding patients' homes that are loved ones disease free. As CEO, this is what keeps me coming into work every day, and we will continue to focus on this goal as we move towards being a leader in the treatment of HER2-targeted cancers. While today's focus was on GI cancers, our next zanidatamab clinical update is planned for the San Antonio Breast Cancer Symposium in December, where we are excited to share data from our trial of zanidatamab plus chemotherapy in late-line metastatic breast cancer. We also plan to share clinical data at multiple medical conferences in 2022 across breast cancer and gastric indications, including our first-line and late-line combo breast cancer data, first-line triplet in GEA and data for ZW49. We look forward to talking to you then. Thank you again for listening. With that, I would like to open up the line for questions.

[Operator Instructions] Our first question comes from Jessica Fye of JPMorgan.

This is Daniel for Jessica Fye. With PFS and OS as dual primary endpoints, how will you be able to file in 2024 with just the PFS data that's expected in 2024 or are you also expecting overall survival data?

Yes. So this is Neil Josephson. So you're right that the first readout is going to be -- the first final readout, I should say, is going to be based on PFS. But there will be an interim readout for OS at the time of the first readout for PFS. But the final readout for OS does not occur until sometime afterwards.

And then in terms of the geographic or ethnic mix, should we expect something similar to that of the Phase 2 study?

Can you repeat that?

In terms of enrollment, should we expect the geographic or ethnic mix of the Phase III is to be similar to that of the Phase 2 study or other studies like JACOB and KEYNOTE-811?

I mean, as I showed, this is a global study. So we're going to be expecting a mix similar to other global studies. You're right. Our Phase 2 was a global study. It was performed in North America and South Korea. So I can't say that it's going to be exactly like it, but we have had a mix of -- in the Phase 2, and we're expecting based on the geography of the study for it to be a similar mix of ethnic groups. And just to go back to your first question real quickly, I just want to clarify that PFS is an approvable endpoint for this indication. It's something that we have discussed with the regulatory agencies. And also just to confirm that, yes, at the same point, to reiterate what I said that we had PFS readout, we will have an interim OS readout, but the final OS readout is not until later.

And then regarding the median PFS about 12 months from the Phase II that you reported today, is it based on all the chemo combos or is it just the CAPOX and FP?

It's based on all of them, all the patients enrolled in the study, all the valuable patients, yes.

Our next question comes from Stephen Willey of Stifel.

This is Ellen on for Steve. For the first one, is there anything that you can say about the powering assumptions in HERIZON-GEA-01? And then I have a few follow-ups.

So we're not discussing the specifics of the statistics at this point. I can just say, in general, it's powered based on data that we have accrued in the Phase 2 study that we've reported out data on before. But I'm not going to get into the specifics of the statistics at this point.

And then does the Phase III trial protocol include any prophylaxis measures to mitigate potential GI talks like those implemented in the Phase 2?

Yes. So, as was pointed out, in the Phase 2 study, the institution of a short 1 week period of mandatory prophylaxis did -- was very effective, and we're carrying that forward into the Phase 3 study.

And then last one for me. Can you remind us why a physician would choose CAPOX versus FP or vice versa in front line GEA? And then do you have any inclination as to which chemotherapy option will be the more common choice? I know that in the Phase 2, I think, more patients received CAPOX versus FP. So just wondering if you're kind of expecting that to be the case in the Phase 3.

So I mean, there are definitely differences based on physician preference on -- there are some regional differences in terms of physician preference. One thing that's different between the 2 regimens is that the FP regimen is an IV regimen. So all the medicines are given intravenously. So that has the advantage in some patients who can't swallow well that they can get therapy, whereas in the CAPOX regimen the capecitabine has to be given orally. So some patients who have gastroesophageal adenocarcinoma are not swallowing well. And so that would be a challenge for them. However, in general, CAPOX is used more than FP. And I think we would anticipate that the vast majority, I would say, certainly more than -- 3 quarters or more of the patients will likely get CAPOX. But again it's physician's choice.

Our next question comes from Gena Wang of Barclays.

I have 2 questions regarding the trial design. The first one is, do you have any target number of percentage of patients that will have IHC 3? And the second question is for the trial design. How is defined as success regarding the arms and also the endpoint?

For the first question, I mean, the enrollment criteria in terms of what is positivity for HER2 is based on the standard ASCO CAP criteria, so that being IHC 2+ and amplified or IHC 3+. We don't have a target. There is a -- this is a -- we will accept any of the patients that meet the criteria. We are stratifying based on IHC 2+ and 3+, but we don't have a target for it. There's no capping. There is no -- there -- it is -- whoever is eligible will be enrolled based on the standard ASCO CAP criteria. And then can you repeat your second question?

Yes. The second question is regarding how the trial will be defined as success? And mainly, you have ARM 2 and ARM 3 against ARM 1. And how is defined as a success? Is either one of the arms or has to be both arms better than ARM 1? And also regarding the primary endpoint, you have a PFS and the OS, how's the -- was splitting alpha or will be the statistical hierarchy? And then if it's a statistic hierarchy, like the PFS, when you show the interim data, do you have to show positive trend of OS?

Again, I'm not -- I wasn't going to get into the details of the statistics of the trial design. I can -- to reiterate my point before which is that both of the arms, ARM B and -- or ARM 2 and ARM 3 will be compared against the standard of care. We've designed it in a way in which we can show the contribution of components. But the design does allow and support an approval that would be based on both arms. So it's not just ARM C. It is arm -- not just ARM 3, it is ARM 2. There was a question about the endpoints. This is -- PFS and OS are standard endpoints. It is powered overall to show a difference in both PFS and OS. So, I think that the overall design, as I said, is really to allow approval of zanidatamab with or without trastuzumab in combination with chemotherapy. I hope that answers your question.

Just want to make sure I understand. So basically, both ARM 2 and ARM 3 has to show superiority over ARM 1.

I didn't say that. I said that they're both going to be compared to ARM 1 and there is no requirement that they both show superiority. They will both be compared. The design allows us to determine the contribution of the components, meaning that we're going to show that both zanidatamab and tislelizumab add to it. So for ARM 2 we need to show that zanidatamab, to get approval that zanidatamab is better than the standard of care when added to chemotherapy. And for ARM 3, we have to show that tislelizumab also contributes to the improvement. But they're -- again, they're both independently being compared to ARM 1.

I see. So either one is superior, that will define as success?

It's -- there -- in general, with the studies, you can't really predict exactly how the study is going to go. I would say that it is designed to show that tislelizumab -- I'm sorry, that zanidatamab improves outcomes when added to standard of care chemotherapy. Again, that's ARM 2. And then ARM 3, we'll evaluate whether the addition of tislelizumab to that combination adds additional benefit. That's the overall design of the study which is to show the contribution of components and show superiority above the standard of care agent.

[Operator Instructions] Our next question comes from Nick Abbott of Wells Fargo.

First question is on, are there any geographic differences in the expected duration of treatment for the biologics and are you providing any guidance on maintenance use of biologics in the trial?

So in the trial, the -- all the antibodies are continued after the completion of chemotherapy until the point of progression. So, in essence, every one of the arms has a maintenance component to it, depending on what the antibody regimen is, if it's trastuzumab for ARM 1 or zanidatamab for ARM 2 or zanidatamab and tislelizumab for ARM 3, those will be continued as maintenance.

And currently, Neil, what is the practice in different parts of the world? I mean, I could imagine part of the world where there is focus on cost that there isn't a lot of maintenance use versus say in the U.S.

I think, honestly, I think the standard is, well, standard is we don't have PD-1 inhibitors approved globally for this indication. So I don't know that we can say what the standard of care would be in this indication for PD-1 inhibitors. But the standard of care for trastuzumab would be to continue until the point of disease progression in tolerability for complications. So, I think that maintenance is after completion of chemotherapy is pretty standard. But like I said, that's based on the standard of care with trastuzumab.

Okay. And you sort of mentioned the fact that patients who are unable to swallow will make an ideal option. Now our understanding is that, that the majority of patients who are getting diagnosed in the U.S. are getting diagnosed of advanced disease, so the oral option may not be ideal -- are getting diagnosed in the advanced setting, so oral chemotherapy may not be a good option. So are you getting any push back on the inability to use FOLFOX and then allied to that given the Keytruda is approved in the U.S. on the use of tislelizumab as the PD-1 inhibitor?

So in answer to your first question, FOLFOX is another regimen, but FP and CAPOX are standard regimens. And I think that actually the vast majority of patients can swell as the rare patient that can't. And if you look through the ToGA and JACOB studies, those use slightly different regimens, but the capecitabine-based regimens were the majority of regimens that were used. So, again, I'm anticipating that the majority of patients will be getting CAPOX. And then in terms of full FOLFOX, FOLFOX is on a different schedule. And for comparison of the 2 different regimens that we are using our Q3 week regimen, which allows us to give both the PD-1 inhibitor and tislelizumab and trastuzumab in ARM 1 and zanidatamab in ARM 2 and ARM 3 on a Q3 week schedule. So, there is -- there are design reasons to maintain the regimens that we have. And again, they are standard regimens. They are the regimens that are used globally.

And then just last question for me, and that is, can you talk about what you think the adjuvant opportunity might be in Japan given universal screening for gastric cancer in that country?

So I mean, adjuvant therapy in gastric cancer is definitely an area where there's been a lot of interest. It's something that is -- something that we could certainly take on at a future study. But right now our focus is on patients who have metastatic or unresectable disease.

There appear to be no further questions. I'd like to turn the conference back over to Dr. Ali Tehrani for any closing remarks.

Great. Thank you everyone for listening today. We are as excited about the launch of our HERIZON-GEA-01 pivotal trial in first-line GEA the commercial opportunity present in GI cancers and the potential for zanidatamab to become the new foundational therapy in treatment of HER2-expressing cancers. With that, I want to thank you all again for joining us. Have a wonderful rest of your day.

This concludes today's conference call. You may disconnect your lines. Thank you for participating, and have a pleasant day.