Thank you for standing by. This is the conference operator. Welcome to Zymeworks HERIZON-GEA-01 launch conference call and webcast. 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. To join the question queue, press Star, then the number one on your telephone keypad. Should you need assistance during the conference call, you may signal an operator by pressing star and then zero. I would now like to turn the conference over to Ryan Durko, Senior Director, Corporate Affairs at Zymeworks. Ryan, please go ahead.
Good morning, good afternoon and welcome, everyone. My name is Ryan Durko, 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 two 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. 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 six 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 tislelizumab, 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 five. Zanidatamab is a bispecific antibody that targets two 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 a zanidatamab antibody targets a different domain on two separate HER2 molecules. Since each HER2 molecule can be bound by two different antibodies, 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 differentiate 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 six.
To date, over 400 patients have been treated with zanidatamab, and there's 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 antitumor 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 seven. 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 three 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 frontline 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 nine. 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 Gastrointestinal Cancers Symposium last January demonstrated that in very late-line patients, monotherapy treatment resulted in a confirmed objective response rate of 33% with a six-month duration of response. In patients who had received a median of two to three prior lines of therapy, zanidatamab plus single-agent chemotherapy resulted in a 54% confirmed objective response rate with an 8.9-month median duration of response and a 5.6-month median progression-free survival. These data compare favorably to data reported with other promising treatments in even less heavily pretreated patients, such as the recent presentation of second-line results within HER2 in DESTINY-Gastric02, 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 antitumor activity, with 75% of patients overall achieving a confirmed response, including 93% of the patients treated with CAPOX and FP. These are the two 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 deep and durable responses. As of this data cut, the median duration of 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 the study, we instituted mandatory diarrhea prophylaxis consisting of twice-daily loperamide during the first week of treatment. With that change to the protocol, the incidence of grade 3 diarrhea in cycle 1 decreased from 44%- 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 frontline chemotherapy, our partner BeiGene has been running a phase II in frontline 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 has 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 two experimental arms. Patients enrolled into arm two will receive zanidatamab plus physician's choice of CAPOX or FP chemotherapy. Those enrolled into arm 3 will receive zanidatamab plus tislelizumab and chemotherapy. Both experimental arms will be evaluated compared to arm one, 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 frontline studies. We estimate that esophageal cancer will comprise about 10%-15% of our study population. Stratification factors 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 for blinded independent central review and overall survival. This three-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 a 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 antitumor activity in HER2 expressing biliary tract 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 three-arm study will evaluate zanidatamab in combination with standard of care chemotherapy with and without tislelizumab for the treatment of frontline 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. 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 two gastrointestinal tumors that we have decided to prioritize strategically. Our goal at Zymeworks is to obtain three FDA approvals in the next five years in these two 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 GEA 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 four key reasons. Number one, globally, there are more than 60,000 new patients per year with HER2-positive BTC and GEA. Number two, zanidatamab's product profile is emerging across the two 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 ensure strong value and favorable access. Lastly, the familiarization with zanidatamab in second-line BTC will bolster its uptake in first-line GEA. Let's now review these four commercial value drivers, size of the addressable population, market map, and product profile and access for each of the two indications in more detail. Let me begin with BTC. Slide number 22 and 23.
BTC is comprised of cholangiocarcinoma, intrahepatic and extrahepatic, and gallbladder. Across these three 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 disproportionately 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 GEA, 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.
Currently, there is no approved therapy for HER2-positive patients. For these patients, current standard of care is chemotherapy and is suboptimal. 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 HERIZON-BTC-01 trial, single-arm trial that Neil Josephson briefly reviewed with you. Ultimately, we will expand 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 I 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 FGFR2 mutated cholangiocarcinoma. Other targeted therapies, Truseltiq from QED Therapeutics and TIBSOVO from Bayer and 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 it to see similar access and uptake. Next slide. Now, let me move on to our second and larger planned indication, first-line GEA or gastroesophageal adenocarcinoma. Next slide. GEA is the fifth most common cancer worldwide and is comprised of three 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 GEA 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%-15% of patients have no approved targeted therapy.
Currently, as highlighted by Neil Josephson in his 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 compared very well with the current standard of care and with KEYNOTE-811. Without checkpoint inhibition in the combination, our doublet data showed a strong 75% overall response rate and 16.1 months median duration of response. Given the strengths of this data, we look forward to adding tislelizumab to zanidatamab and chemotherapy, CAPOX or FP, in our registrational trial, HERIZON-GEA-01, and establish 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 peak sales potential with the three indications we are pursuing in the next five 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, a 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 will 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 tract cancers and the launch of the phase III in the first line, HER2 positive GEA, we believe we are approximately two 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 sending patients home to their 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 GEA 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.
Thank you. We will now begin the question and answer session. To join the question queue, you may press star then one 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 two. We will pause for a moment as callers join the queue. Our first question comes from Jessica Fye of JP Morgan. Please go ahead.
This is Daniel for Jessica Fye. Thank you for taking our question. First, 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?
Yeah. This is Neil Josephson. You're right that the first readout is gonna be the first final readout, I should say, is gonna be based on PFS, but there will be an interim readout for OS at the time of the first readout for PFS. The final readout for OS does not occur until sometime afterwards.
Okay, great. In terms of the geographic and ethnic mix, should we expect something similar to that of the phase II study?
Can you repeat that?
In terms of enrollment, should we expect the geographic or ethnic mix of the phase III to be similar to that of the phase II study, or other studies like RATIONALE-305 and KEYNOTE-811?
Yeah. I mean, as I showed, this is a global study, so we're gonna be expecting, you know, a mix similar to other global studies. You're right, our phase II was a global study. It was performed in North America and South Korea. I can't say that it's gonna be exactly like it, but we have had a mix in the phase II and we're expecting based on the geography of the study for it to be a similar, you know, mix of ethnic groups. Just to go back to your first question real quickly, I just wanna clarify that, you know, PFS is an approvable endpoint for this indication.
It's something that we have discussed with the regulatory agencies. 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.
Okay. Regarding the median PFS of 12 months from the phase II that you reported today, is it based on all the chemo combos or just the CAPOX and FP?
It's based on all of them, all the patients enrolled in the study.
Okay, great. Thank you very much.
All the valuable patients. Yeah.
Our next question comes from Stephen Willey of Stifel. Please go ahead.
Hi, this is Ellen on for Steve. Thank you for taking our question. For the first one, is there anything that you can say about the powering assumptions in HERIZON-GEA-01? Then I have a few follow-ups. Thank you.
You know, we're not discussing the specifics of the statistics at this point. I can just say in general it's, you know, it's powered based on, you know, data that we have accrued in the phase II study that we've reported out data on, before. I'm not gonna get into the specifics of the statistics at this point.
Makes sense. Does the phase III trial protocol include any prophylaxis measures to mitigate severe GI tox like was implemented in the phase II?
Yeah. As was pointed out, in the phase II study, the institution of a short one-week period of mandatory prophylaxis was very effective and we're carrying that forward into the phase III study.
Okay, great. Last one for me. Can you remind us why a physician would choose CAPOX versus FP or vice versa in frontline GEA? Do you have any inclination as to which chemotherapy option will be the more common choice? I know that in the phase II, I think, more patients received CAPOX versus FP, so just wondering if you kind of are expecting that to be the case in the phase III. Thank you.
I mean, there are definitely differences based on physician preference. There are some regional differences in terms of physician preference. You know, one thing that's different between the two regimens is that the FP regimen is an IV regimen. All the medicines are given intravenously. 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. 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.
I think we would anticipate, you know, that the vast majority, I would say, you know, certainly more than three-quarters or more of the patients will likely get CAPOX. Again, it's physician's choice.
Okay, great. Thank you for taking the questions.
Our next question comes from Gena Wang of Barclays. Please go ahead.
Thank you for taking my questions. I have two questions regarding the trial design. The first one is, do you have any target number or percentage of patients that will have IHC 3? The second question is that for the trial design, how success is defined regarding the arms and also the endpoint?
You know, for the first question, I mean, 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. This is a, you know, 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's no there it is. Whoever is eligible will be enrolled based on the standard ASCO CAP criteria. Then can you repeat your second question?
Yeah. The second question is, you know, regarding how the trial will be defined as success and mainly, you know, 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. Also regarding the primary endpoint, you have PFS and OS. How is the, you know, is it splitting alpha or will it be the statistical hierarchy? Then if it's a statistical hierarchy like, you know, the PFS, when you show the interim data, do you have to show positive trend of OS?
Yeah. You know, again, I wasn't gonna get into the details of the statistics of the trial design. I can, you know, 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 designed it in a way in which we can show the contribution of components. The design does allow and support an approval that would be based on both arms. It's not just arm C. It is arm 2, not just arm 3. It is arm 2.
You know, there was a question about the endpoints. This is, you know, PFS and OS are standard endpoints. It is powered overall to show a difference in both PFS and OS. I think that the overall design, as I said, is really to allow approval of zanidatamab with or without tislelizumab in combination with chemotherapy. I hope that answers your question.
Thank you. Just want to make sure I understand. 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 gonna be compared to arm 1. There's 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. For arm 2, we need to show, to get approval, that zanidatamab is better than the standard of care when added to chemotherapy. For arm 3, we have to show that tislelizumab also contributes to the improvement. They're, you know, again, both independently being compared to arm 1.
I see. Either one is superior that will define as success.
You know, it's the, you know, with the studies, you know, you can't really predict exactly how the study is gonna 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 will evaluate whether the addition of tislelizumab to that combination adds additional benefit. That's the overall design of the study, is to show the contribution of components and show superiority above the standard of care agent.
Okay. Thank you.
Once again, if you have a question, please press star then one. Our next question comes from Nick Abbott of Wells Fargo. Please go ahead.
Hello. Thanks for taking our questions. First question is on, are there any geographic differences in the expected duration of treatment for the biologics? Are you providing any guidance on maintenance use of biologics in the trial?
In the trial, all the antibodies are continued after the completion of chemotherapy until the point of progression. 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.
Currently, Neil, what is the practice in different parts of the world? I mean, I could imagine parts of the world where, you know, there's a focus on costs that there isn't a lot of maintenance use as, say, in the U.S.
Yeah. I think, honestly, I think the 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. The standard of care for, you know, trastuzumab would be to continue until the point of disease progression or intolerability.
Okay.
You know, for a complication. I think that maintenance is, you know, after completion of chemotherapy is pretty standard. Like I said, you know, that's based on the standard of care with trastuzumab.
Okay. You sort of mentioned the fact that patients who are unable to swallow will need an IV option. Now our understanding is that, you know, that the majority of patients who are getting diagnosed in the U.S. are getting diagnosed with advanced disease. The oral option-
Are getting diagnosed with, m ay not be ideal.
They're getting diagnosed in the advanced setting. So you know, oral chemotherapy may not be a good option. So are you getting any pushback 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?
In answer to your first question, FOLFOX is another regimen, but FP and CAPOX are standard regimens. I think that actually the vast majority of patients can swallow. It's the rare patient that can't. If you look through you know the ToGA and JACOB studies, those use slightly different regimens, but the capecitabine-based regimens were the majority regimens that were used. Again, I'm anticipating that the majority of patients will be getting CAPOX. In terms of FOLFOX is on a different schedule.
For a comparison of you know the two different regimens that we are using, our Q3 week regimen, which allows us to give both the PD-1 inhibitor and you know tislelizumab and trastuzumab in arm 1 and zanidatamab in arm 2 and arm 3 on a Q3 week schedule. There are design reasons to maintain the regimens that we have. Again, they are standard regimens. They are the regimens that are used globally.
Okay. Fair enough. Just last question from 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?
Yeah. 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. Right now our focus is on patients who have metastatic or unresectable disease.
Okay. Great. Thank you very much.
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 as ever about the launch of our HERIZON-GEA-01 pivotal trial in first-line GEA, the commercial opportunity presented in GI cancers and the potential for zanidatamab to become the new foundational therapy in treatment of HER2 expressing cancers. With that, I wanna 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.