Zymeworks Inc. (ZYME) Earnings Call Transcript & Summary

Thank you for standing by. This is the conference operator. Welcome to Zymeworks HERIZON-BTC-01 Webcasting Conference Call. [Operator Instructions] I would now like to turn the conference over to Kenneth Galbraith, Chair and CEO at Zymeworks. Ken, please go ahead.

Thank you. Hello, everyone, and thanks for joining. My name is Ken Galbraith. I'm the Chair and CEO at Zymeworks. I want to take the time with you today to discuss the positive top-line results for our HERIZON-BTC-01 study. In short order, I'll hand the call over to Dr. Neil Josephson, our Chief Medical Officer as well as Dr. Shubham Pant, who has experience treating patients with zanidatamab in our Phase I and pivotal trials and is also Chairman of the Steering Committee for the HERIZON-BTC-01 study. All 3 of us will be available for Q&A after the call. Before we begin, I'd like to remind you we'll 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, intend, encouraging and similar words in such statements include, without limitation, those forward-looking statements identified in our presentation slides and the accompanying oral commentary. Forward-looking statements are based upon our current expectations and various assumptions and are subject to usual risks and uncertainties associated with companies in our industry and our [ restage ] development. For a discussion of these risks and uncertainties, we refer you to our latest filings as found on our website, and as filed with the SEC and SEDAR website. As a reminder, slides in this event are already available on our website, and audio from today as well as an updated corporate presentation will be available on the Zymeworks website later today. I'd like to take a few minutes to thank the patients and teams involved in this pivotal clinical study, including study-set investigators and staff, our internal clinical development staff and our colleagues of BeiGene, all of whom have worked diligently on this development program. The results from our first pivotal study with zanidatamab are the culmination of years of work developing a novel therapy for patients with a rare and difficult-to-treat cancer. While we're only able to share top-line results today, we plan to present a full clinical data set from this study at a major medical conference in the first half of 2023. We're also planning a meeting to discuss the complete study data with the FDA as soon as possible in 2023 as the results represent a potential new treatment option for patients with advanced HER2 amplified biliary drug cancer, a difficult-to-treat cancer with a poor prognosis. This is an important study for BTC patients and for Zymeworks. But it's just a start, as we strongly believe in the potential for zanidatamab to treat a variety of HER2-amplified in expressing cancers, which we continue to evaluate in multiple clinical studies. With that, I'd like to hand the call over to Dr. Neil Josephson, our Chief Medical Officer, to present an overview on zanidatamab and its global clinical development plan.

Thanks, Ken, and good morning, everyone. Thank you for joining us today. My name is Dr. Neil Josephson, and I am the Chief Medical Officer at Zymeworks. I would like to provide some background on the development plan with zanidatamab, or HER2-targeted bispecific antibody. I will then hand the call over to Dr. Pant. This slide highlights the range of cancers where HER2 overexpression and our amplification has been demonstrated. The green checks designate the indications where we have early clinical data demonstrating antitumor activity with zanidatamab as monotherapy. On the right, we show our ongoing development plan in breast, stomach, biliary tract and colorectal cancers. Biliary tract cancer, or BTC, is the indication for this along in development, with Phase I data recently published a Phase II study in frontline patients that is currently enrolling and our first pivotal trial in previously treated patients now complete. We are also actively enrolling our second pivotal study, HERIZON-GEA-01, which evaluates zanidatamab with and without the PD-1 inhibitor, tislelizumab, in combination with standard of care chemotherapy in frontline HER2-positive gastroesophageal adenocarcinoma, or GEA. Of note, at the upcoming ASCO GI cancer symposium in January, we will be presenting mature data from our Phase II study of zanidatamab in combination with chemotherapy in frontline HER2-positive GEA, and this data will include an overall survival analysis. As highlighted in purple, we have multiple ongoing studies with zanidatamab in HER2-positive breast cancer. Most recently at the San Antonio Breast Cancer Symposium, we presented Phase II data for zanidatamab combined with palbociclib and fulvestrant in patients with later-line HER2-positive, hormone receptor positive breast cancer. Results from this study add to a growing body of clinical data in breast cancer and will help inform potential future development plans for zanidatamab. And finally, noted in green, we are actively enrolling colorectal cancer patients in the first line in a Phase II trial to explore zanidatamab in combination with standard of care frontline chemotherapy. I'd like to turn the call over to Dr. Shubham Pant now. Dr. Pant is a professor in the Department of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center. He specializes in the treatment of biliary tract cancer, and has kindly agreed to join us today to discuss the significant unmet need for patients with BTC and to share his experience in treating patients with advanced disease, including treating patients with zanidatamab in our Phase I and pivotal HERIZON-BTC-01 study. Shubham?

Thank you, Neil, and thank you, Ken, for the kind introduction. Hi, everyone. I'm Shubham Pant, I'm a professor of GI Medical Oncology and Investigational Cancer Therapeutics, which is our Phase I department at MD Anderson in Houston, Texas. Next slide, please. So first of all, I just wanted to talk about the epidemiology of biliary tract cancers. So biliary tract cancers are actually can be in 3 different parts of our liver. So these are the bile ducts or little high bays, which run through our liver. So they are different from what we normally call as hepatocellular cancer. So there can be 3 kinds of biliary tract cancers. One is gallbladder cancer, and that we all know -- patients go to get the gallbladder removed for some reason. The second is called intrahepatic cholangiocarcinoma. Big words, but what it means is that it's the ability to track cancer, which emerges in the liver. And the third one is extrahepatic biliary tract cancers means these develop outside the liver when the bile duct is going -- when bile duct is kind of coming outside the liver. So the 3 kinds and sometimes they do defer genomically. That means what kind of targets do they express. Now gallbladder cancer, which is about 20% of the gallbladder cancers can express HER2-new, the protein we are talking about. It's incidence varies globally. So it's about 0.6% of all adult cancer worldwide, mostly found in Asia, Chile, northern part of India, and we do see it in the United States and Europe. Most cases of biliary tract cancers, gallbladder cancers are at late diagnosis. That means they are not resectable at diagnosis. So as you know, most cancers caught early can be resectable kind of going towards a cure, most cancers, which are advanced, they are stage 3 or 4 are the ones which are diagnosed at an advanced stage, need these therapeutics, a chemotherapy or target therapies to control that disease. Now after first-line therapy in the second line, we have chemotherapy that we currently give and I'm sure we're going to show on the other next slide about some targeted therapies we give. But again, the response rate for chemotherapy is about 10%. The interesting thing about biliary tract cancers in the previous half a decade, it's really made a jump towards lot of targeted therapies, absolute approvals and other for a number of target therapies in this indication. So it's really an exciting place of development in biliary tract cancer, exciting time in biliary tract cancers and development. Next slide. So then this is -- these are the targeted options which are, again, they're rapidly evolving in biliary tract cancers. Now the first-line option when the patient comes with advanced or stage IV biliary tract cancers, first-line treatment now is gemcitabine, cisplatin, durvalumab, and this recently was approved from the TOPAZ-1 Results in which the median overall survival was improved and the median progression-free survival. That means when the patients progress was improved also. Second-line options really don't have a lot. We have chemotherapy. There's a chemotherapy called FOLFOX that we used or we have targeted therapies. Like I said, majority of patients have genomic testing, just like we have different fingerprints, every tumor has different fingerprints. So it's very unique in every patient. And we can find out these mutations that we can target. So the target therapies are FGFR inhibitors, which have an overall response rate that meets a chance of shrinking the tumor more than 30% of 20% to 40% and something called IDH1 inhibitors or an IDH1 mutation. The overall response rate was about 2.4%. And really, in third line, we really do not have a lot of options for these patients. So it really -- it is a place where we are looking for newer agents. Now the HER2-new amplification rates in biliary tract cancer, again, they differ. Like I said, those 3 areas that I talked about, gallbladder cancer, intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma but the HER2-new rate can differ. Gallbladder is about 7% to 16%, extrahepatic cholangiocarcinoma is 8% to 11% and about 2.5% to 3% of intrahepatic cholangiocarcinomas. Next slide. So right now, what I'm going to talk about is zanidatamab and advanced HER2-expressing cancers, the BTC cohort. This is the Phase I trial, which we also had open at our slide, and I treated a few patients on this trial in the Phase I study. I'm going to specifically talk about the Part 2 monotherapy expansion cohorts in which one of the cohorts was the HER2-new expressing, which were quite a few cancers, but I'm going to talk specifically about the biliary tract cancers, which were treated at the standard dose of 20 milligram per kilogram every 2 weeks. Next slide. And this is a busy slide, but essentially, this is the Phase I study of zanidatamab in advanced HER2-new expressing cancers. On the right, you can see a slide called the waterfall plot. So the easy way to think about it is that every bar which is going down means that patients had some kind of tumor reduction. The thin dotted line that you see below, that means they had a response rate more than 30%, that in chance of shrinking the tumor more than 30%, and that's what that bar is. And if the bars are above the line -- the main line, then that means the tumors had slight increase in size. So in -- when we develop drugs, a response rate is greater than 30% decrease in size of the target lesions and stable disease is between a 30% decrease and a 20% increase of the size of the target lesion, that's called the RECIST measurement. And those are the 2 dotted lines that you see. But essentially, this is the way to look at a waterfall plot, anything going down, there's some reduction in the size of the target lesions, anything going up, there's some increase in the -- some of target lesions. So to kind of look at this data a little bit of granulary, we had about 22 patients with HER2-expressing biliary tract cancers, 13 had gallbladder cancer, 5 had intrahepatic cholangiocarcinoma and 4 had extrahepatic cholangiocarcinoma. Now these patients are heavily pretreated as is normal for a Phase I trial. They had a median of 2 prior lines of therapy, including 23% of another HER2-new targeted agents called trastuzumab, and they were all treated with the 20 milligram per kilogram every 2 weeks dosing. So again, it was well tolerated. It did demonstrate promising antitumor activity, as you can see on the waterfall plot. All treatment-related AEs were grade 1 to 2. The confirmed objective response rate was about 38.1%, and that's the confirmed one in which it's more than 30% reduction in some of target lesions. And the median duration of response, that means if a patient had a response, how long did they stay median duration was about 8.5 months. So again, this supported the FDA breakthrough designation and then development of the pivotal second-line HER2-amplified BTC trials. So some of the conclusions from my Phase I Discussion Board that this was well tolerated and demonstrated promising antitumor activity. The treatment-related AEs -- treatment-related adverse events for the patients were mostly mild to moderate, they were grade 1 and 2. And the disease control rate, and that means the response rate and the patients who had stable disease when I talked about the 30% reduction between a 30% reduction and a 20% increase, that's stable disease. So that's -- we club this together is called disease control rate was about 61.9% with an objective response rate of 38.1% and a median duration response of 8.5 months. Next slide. So this was the HERIZON-BTC-01 trial, which is a global pivotal second-line HER2-new amplified BTC. Again, 100 patients were going to be enrolled, 75 with IHC 2 or 3 plus. That's how we look at the expression of HER2-new and the tumor tissues and the cohort 2 were lower IHC 0 or 1. And again, it was 28-day cycles, zanidatamab, 20-milligram per kilogram IV day 1 and 15 every 8 weeks with primary endpoint of overall response rate and key secondary endpoints to ratio response greater than 16 weeks and some other secondary end points that we normally look at a clinical trials. And the full data, as I think Neil and Ken alluded to, will be presented on medical conference in 2023. So I'm going to pause there, give it back to Neil, and thank you everyone for joining after the World Cup. So it was hard for me to get up this morning. I hope it was the same for everyone. Neil?

Thank you, Dr. Pant for that clear overview and for highlighting the unmet need and potential opportunities to improve outcomes for patients with advanced unresectable biliary tract cancer. I will now discuss the encouraging topline data from our press release that we issued earlier this morning. First, I'd like to highlight a couple of points from Dr. Pant's presentation. The findings that Dr. Pant reviewed are from our Phase I study. And that data was generated from a patient population that is similar to the patients who are enrolled in cohort 1 of the HERIZON-BTC-01 study. These patients have advanced gallbladder cancer, intrahepatic cholangiocarcinoma or extrahepatic cholangiocarcinoma that is HER2-amplifies determined by insight to hybridization and also express a moderate-to-high level of HER2 protein as determined by immunohistochemistry staining with scores of 2 plus or 3 plus. All patients enrolled in the HERIZON-BTC-01 study had received at least one prior gemcitabine containing systemic chemotherapy regimens for advanced disease and have progressed or intolerant to their most recent treatment regimen. Cohort 1 of the study is the primary efficacy population and data from this cohort is intended to support potential regulatory submissions in the U.S., China and other relevant jurisdictions on behalf of the [Technical Difficulty] plan and consultations with regulatory agencies in 2023. Safety data to support these submissions will come from all the patients treated in both Cohorts 1 and 2. The confirmed objective response rate in Cohort 1 is 41.3% as determined by independent central review. This represents a potential significant improvement over current treatment options for these patients, which, as Dr. Pant had mentioned, is typically single agent or multi-agent chemotherapy regimens [Technical Difficulty] response rates ranging from 5% to 15%. Other options for relapsed patients with HER2-amplified and expressing BTC include a clinical trial or active symptom control without anticancer therapy. Zanidatamab monotherapy was not only active in cohort 1 patients, but the responses seen were durable, with a median duration of response of 12.9 months. And importantly, for all the patients treated on this study, zanidatamab monotherapy was well tolerated with a manageable and acceptable safety profile that was consistent with the previously reported monotherapy experience. I'm delighted to be able to share these top-line results with you today, and we look forward to presenting a full data set at a medical meeting in 2023. Finally, I want to sincerely thank all patients and their families who took part in this clinical trial. I also want to thank the investigators and study staff who cared for the study patients and made invaluable contributions to this trial. With that, I'd like to turn the call back over to Kenneth Galbraith, our CEO, for some closing remarks.

Thanks, Neil. Certainly, a special responsibility for us as Zymeworks to be involved with bringing a therapeutic candidate like zanidatamab through different phases of clinical development that support its potential to address the needs of patients that truly are in need of additional, effective and tolerable treatment options. For Zymeworks, our next steps have already started as we prepare for upcoming regulatory consultations in both the U.S.A. and other relevant foreign markets. As Neil mentioned, we also intend to submit a full set of clinical results for presentation at a major medical meeting in 2023. Further, we're continuing to enroll patients with advanced HER2-expressing biliary tract cancer in our Phase II trial evaluating zanidatamab in combination with gemcitabine and cisplatin in a first-line setting. We're pleased to see the activity in durable responses in later lines of therapy and believe this may have potential applicability in the earlier lines of therapy and in combination with other approved agents. Compared to prior clinical data presented with other HER2-targeted therapies in BTC, we believe these results are unprecedented in this patient population, and we look forward to discussing next steps with appropriate regulatory agencies as rapidly as possible. Further, with the results from a subgroup analysis and first-line BTC patients, recently presented at ESMO Asia from the TOPAZ-1 study, we believe these data support that there continues to be a significant unmet need for those patients with actionable biomarkers, particularly ErbB2 genomic alterations like HER2 amplifications. As we continue enrollment for patients with BTC in our frontline study and continue to offer our expanded access program for qualifying patients, we will work towards finalizing and completing our global commercial supply arrangements for zanidatamab in preparation for ultimate commercialization by our partners upon regulatory approval. We're extremely excited about the results presented today and the meaningful difference zanidatamab could make as another treatment option for BTC patients upon approval. We look forward to reporting further progress during 2023 as we consult regulatory agencies around the world. Additionally, the next clinical data presentation for zanidatamab is rapidly approaching. As we're scheduled to present additional and more mature data from our ongoing Phase II study evaluating zanidatamab and chemotherapy in first-line GEA patients on January 19 at the ASCO GI Symposium in San Francisco. Thank you all very much for listening to the prepared remarks today. I'll now pass the call on to the operator for Q&A, where Dr. Pant, Dr. Josephson and myself will be available on the line to answer questions.

[Operator Instructions] Our first question comes from the line of Charles Zhu with Guggenheim Securities.

Congrats on this impressive top-line readout. My first question, well, Jazz will do whatever they do. But on the FDA regulatory front, I guess, given you have breakthrough therapy designation, I assume you've had several touch points with them. Any color around what you -- this has probably been -- but any color around if this is truly or definitely good enough to meet that accelerated approval benchmark especially just given what we have seen with the single on accelerated approval studies recently?

Yes. Thanks, Charles. I guess this data are also, as you can see, very impressive and unprecedented. So we look forward to getting the earliest consultation we can with FDA. And I think those types of discussions we'll have with them and present the full data set. And I think any updates we have about that with respect to filing times, et cetera, we'll communicate after we have the opportunity to discuss that with FDA.

Got it. Great. And maybe 1 more -- 1 question for Dr. Pant. I think you mentioned that the majority of these BTC patients are tested. Just wanted to clarify and confirm that, that includes HER2 mutational testing and maybe also -- or how does that look like in terms of how frequently patients are tested for HER2? And as a follow-up question, I guess, how are you currently testing or treating these patients potentially with some off-label trastuzumab, pertuzumab from My Pathway study? And how do you think you may use the zanidatamab in relation to that?

Yes. So I can answer -- I'll -- there are a number of questions there. So to answer [ parts by parts ]. The first thing is the next-generation sequencing, which is the tumor tissue-based assays or ctDNA-based assays. They are very frequently used now, and part of that is because of, again, we have FGFR inhibitors in the second line and we have the IDH1 inhibitors in the second line. So after -- so we've really seen an uptick, I'll tell you, being in this for some time, I've really seen an uptick in patients getting sequenced for sequencing. And yes, that does include HER2-new amplification, what we are looking for. So to answer your question, it has done -- it is done in a majority of the patients. Again, academic versus community, but it is done in quite a few patients now. And we're seeing the uptick that its increasing graph that is being done in these patients. That's one. So normally for second-line patients, and beyond their different options, one is FOLFOX, which is part of the ADC trial that I talked about. And there is the My Pathway results were published recently. And there is uptick of that. We do use that either if you can get it covered trastuzumab single agent or maybe combination in some of these patients. So we use them on that. As far as zani data once the whole data is out then Ken can comment further on that. I really can't comment on the Phase II part. I can comment on the Phase I part where we solve those responses. But that's what I can say on that.

Yes. Thanks, Shubham. Let me just add one thing. So Charles, as Shubham pointed out, many patients today are being tested by NGS. And with that, you can find a number of actionable mutations to treat. The patients that were enrolled in this study specifically were enrolled using a companion diagnostic that was developed specifically for HER2 amplification and expression in biliary tract cancer. So I just want to clarify that we are using an specific assay for this indication with this drug.

Our next question comes from the line of Stephen Willey with Stifel.

Congratulations on the results. Can you remind us what is known about the variability of HER2 expression within biliary? And I guess I asked the question because I know when you look across other solid tumor types, there seems to be some kind of differential between tumors like breast and gastric, where the latter is just more difficult to access. You get a little bit of loss of expression between lines of therapy. What do we know about biliary at this point?

I think that was towards me, this is Dr. Pant.

Yes, sorry about that.

Okay, okay. All right. So yes, so in biliary tract cancers, again, we are getting more and more data as we go along. It seems to be pretty but really in biliary tract cancer is like I said in the beginning, there are 3 different kind of types when you look at it. There's gallbladder cancer. There is intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma. And their expression of HER2-new seems to be different with each of those cancer types. So 20% maybe -- 16% gallbladder maybe as high as some reports at 20%. Extrahepatic, a little bit lower in the 7% to 11% and then intrahepatic is the lowest about 2% to 3%. But as far as when we look at the published data on this and with other targeted agents and with -- as than in the first line -- in the -- sorry, Phase I setting and everything, that -- those responses seem to -- these next-gen sequencing, which are being done, there seem to correlate maybe Neil can comment on the testing that was done specifically for this trial. It really do seem to correlate at least in the real-world data that we see of which the data has been bubbling for -- HER2-new targeting biliary tract cancers has been bubbling for about 5, 6 years, the case reports first then a few like single-arm studies and then there's obviously zani study, which is coming out. And maybe, Neil,you could comment on the HER2 new, what was done for this trial.

Sure. So as Dr. Pant was saying, the testing that has been used in the community has not been a test that is validated and for biliary tract cancer for use with the drug. So we've developed a companion diagnostic for this disease, and it's using a sort of a standard technology of insight through hybridization to look for the amplification status of patients and then also using immunohistochemistry to look for expression. There is a variable amount of literature on what people have seen in terms of expression and amplification in biliary tract cancer. But I think that the range is quite variable. When our data come out, we'll be able to see [Technical Difficulty].

Okay. And so these were patients that also all had fresh biopsies prior to study entry. Is that correct?

Correct. So all the patients who are enrolled in this study has potentially reviewed pathology and that was reviewed based on the companion diagnostic that I've discussed.

Okay. And then I know you're not providing any more details at this point, but is there just anything broadly that you can say about maybe the exploratory cohort, the 1 plus, the non-expressing patients? And then maybe just any impact you may have seen as a function of subtype, whether intrahepatic, extrahepatic or geography?

Yes. So I can start with a little bit about geography. In terms of this study, this study was an international study. And so it enrolled patients in -- on 4 continents. So North America, Europe, Latin America or South America and Asia. And so we have patients represented from the globe. And we also have a good representation of patients in each of the biliary tract subtypes that you mentioned. I can't give any specific information about subgroup analyses or specific cohorts. As was pointed out, we designed a study in a way that cohort 1 was meant to be the primary efficacy cohort because it includes the patients that are expressing at moderate-to-high levels. And that's the cohort that we are reporting our top-line data out on. That's the cohort that we believe will be the one that is -- so that population in patients, we believe is the one that would be emphasized in the efficacy analysis, but I can't give specific breakdown of anything on -- in terms of cohort outcomes from an efficacy standpoint. The other thing I would add is that safety, we are going to report out or file based on all of the information that we have, every patient that was treated on this study, the safety data from that is important for the FDA and other regulatory agencies to see as well. But when we present this data, we'll obviously have a chance to look at all of these kinds of questions that you have.

Our next question comes from the line of Yigal Nochomovitz with Citi.

This is Ashiq Mubarack on for Yigal. Congrats on the data. I just wanted to ask one on Jazz, I know you probably aren't sharing too much more in terms of additional detail. But are you sticking with your previously provided time lines, I know you've guided to the upfront $50 million payment and the often $225 million payment is before year-end. So just wondering if you have any color there?

Yes. So I think we said all we can about the agreement between ourselves and Jazz. Obviously, the $50 million payment for the HSR clearance was some time ago. So that payment has already been received. We've provided the data -- the full data set that was acquired in the agreement to Jazz on Friday. And we expect the timing to be exactly the same as the previous guidance we've given. And I think the data clearly speaks for itself, and I think we'll let Jazz speak for themselves when they choose to do so.

Very awesome. Thanks for confirming all that. I wanted to ask another one on duration. It seems like you're spending well above standard of care on ORR, but I'm wondering about how you're thinking about the approvability of your duration? I was also just wondering if you can comment on differences between the Phase I and pivotal cohorts duration? It seems like it went from 8.5 months to 12.5 months -- 12.9 months. I mean -- and I'm wondering if that has something to do with HER2 expression or maybe something else?

Sure. I'm happy to take that question. I think that a median duration response of 12.9 months is very, very good in this line of therapy. So when you think about a drug, you're also looking at response rate and you're also looking at the duration of response in terms of how effective that drug is. So I think that on both benchmarks, we're pleased with the results that we saw. In terms of the Phase I versus the Phase II patient population, they are similar. In the Phase I study, we did allow patients to have prior HER2-targeted therapies that was a part -- patients were ineligible for enrollment in the pivotal study if they have had prior HER2-targeted therapies. I've talked a little bit about the companion diagnostic, the companion diagnostic that was developed was specifically used in the Phase II study and not in the Phase I. So there are some differences between the patient populations. The Phase I was enrolled in North America and South of Korea. This one includes Europe and South America as well. So there are some differences. The biggest difference is the number of patients and the fact that these are -- that the review of this data is all through a central independent review. And so I wouldn't make too much about differences in terms of the duration of response that we saw in the Phase I versus the Phase II study. We're pleased that the median duration is longer, obviously, in the Phase II, but it was a larger patient population was independently reviewed the data set. And I think that it is very encouraging to see the results that we're seeing in this data set.

Got it. And then last one for me. What are your expectations maybe for the HER2 low cohort in this trial?

So the HER2 low cohort was always an exploratory cohort and the data from that will be part of our presentation at a major medical meeting in the first half of '23. It was not designed to be the cohort that was the basis for approval. But it was something that we did want to look at, and we will report out the data when we can in terms of that subset.

Our next question comes from the line of James Shin with Wells Fargo.

I just had a question sort of related to BTC and then the readthrough to GEA. I think you previously mentioned a lot of the BTC physicians and GEA position overlap. So now that you kind of have a good picture of ORR, DOR and safety for BTC, 2 different diseases, but given physicians are familiar with both, can Dr. Pant kind of sort of give us expectations for GEA? That's my first question. And then secondly, it sounds like the ball is in Jazz' court regarding the BTC data.

I think we lost you. But maybe we'll -- I'll try to answer the second question first, then I'll let Dr. Pant and Neil talk about any relationship between the BTC study and GEA. And I think as I already said in the call, I think we've said all we can about the agreement between Jazz and ourselves is pretty clear. We've delivered to them the data set that was acquired under the agreement, and we did on a Friday. And so I think, again, the data speaks for itself, it's very clear, unequivocal and unprecedented in this patient population. And we'll let Jazz speak to themselves when they choose to do so under our agreement. And I don't -- Neil, do you want to say anything about BTC and GEA?

Yes. Yes, I'd be happy to. I think that an important point I make about BTC is that there are no approved HER2-targeted therapies in BTC. And so it's an area where I think that this is potentially the first HER2-targeted therapy. So there's not the same usage of our 2 targeted agents historically. But I think that what we're showing here and through the work that we did in our Phase I and continue to work -- continue to do is that even in indications that don't have an approved therapy that zanidatamab has activity. I'll let each of the studies speak for themselves in terms of the data. And I think that they are different in terms of how we're pursuing regulatory pathways in both BTC, which is as a monotherapy now in later-line patients and in GEA, which is in combination with chemotherapy as a first-line agent against a standard of care that includes HER2-targeted therapy. So -- and I think that physicians are going to make their own decisions about the data based on the readout and not based on speculation in terms of what this study means for the pivotal HERIZON-GEA-01 study. So I'm excited about both development paths, but they are different, and we have different studies to show the benefit of zanidatamab in each of the indications. And again, I'll let the data speak for itself when it's available.

And just to conclude on that specifically on that again, we -- as I mentioned earlier, we probably disclosed, we will have an opportunity in a few weeks on January 19 to provide an update on our Phase II study in treating first-line GEA patients. And that will be a great opportunity in a peer review setting to upgrade -- update our colleagues. And so we're looking forward very much to the ability to do that. And I think that will really inform a lot more about the potential path for zanidatamab in GEA patients.

Our next question comes from the line of Akash Tewari with Jefferies.

This is Amy on for Akash. We have 2 questions, one for BTC and one for GEA. So for BTC, just how impactful do you think the first-line indication was for the Jazz deal given that you've indicated before that first line and second line BTC represents around us, I think, 18% of zani opportunities and only 15% to 40% of Aduvant BTC patients may have received subsequent line cell therapy? And also, what's your expectation on first-line given the cycle that you've shown today? And also for GEA, is for the updated data to be present next year at ASCO for zani and chemo in first line? Should you expect the combo to maintain the ORR of around 75% with no new [indiscernible]? And also, is it fair for us to assume that you will need to show at least [ in line ] data as KEYNOTE-811 to show best-in-class profile in GEA? And also what's your bar for OS there?

Yes. Yes, many of the things we probably can't address. But Neil J, do you want to say anything about the first-line study in BTC and then maybe whatever you'd like to about GEA.

Sure. So we have a Phase II that's ongoing in first-line BTC. When we have data that is mature, we will present that. And the development path in first-line -- potential development path is something that we're not -- until we have that data and can speak to it. We won't really be able to speak to a development path. But I -- and then the other question was about GEA. And I don't think that we can speak to a lot of the questions that you had. I do think that the data at GI ASCO, which is upcoming in January, we'll answer the questions that you had about response rate, about overall survival. So you'll get to see all of that data presented there. And I think that we don't know what KEYNOTE-811 is going to read out or -- so it's hard to speculate on any of these things. And again, I think we just need to let the data speak for themselves. And as we did in this study, we will talk to a data when it's available and can present it.

Our next question comes from the line of Gena Wang with Barclays.

Just want to follow 1 question regarding Jazz decision. Just wanted to make sure we used to announce the results before year-end, assuming the time line is still on track? And then my second question is for Dr. Pant. I wanted to know, you gave a very good introduction about the 3 different types of BTC, gallbladder, intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma. So just wondering, if all those 3 cancer types with the same IHC status, what will be [Technical Difficulty] differences in disease if they say 2 plus across all 3, will the response will be different? Anything the biology-wise, would there be any difference among the 3?

I'll answer the first part of your question, and then I'll turn it over to Dr. Pant. I think, as I said before, we've provided the full data set on the study to Jazz, which we did on Friday. And our guidance has not changed with respect to completion of the agreement. And the data is very clear and unequivocal and really unprecedented in this patient population. So I think it clearly speaks for itself, and we'll let Jazz speak for themselves when they choose to under the terms of our agreements. I don't think we can say more than that. And I'll turn that second question over to Dr. Pant for any comments he'd like to make.

Yes. Thank you for that question is a very relevant question. From the Phase I data that we saw for zanidatamab and for other kind of HER2-targeted agents, there really doesn't seem to be a really big difference. There just seems to be a difference in the percentage of positivity to gallbladder seems to lead the percentage of positivity. And -- but there really doesn't seem to be any difference between -- again, these are small data sets before this trial, but they're really at least in the ones which have been published, Phase I -- the Phase I study and other target agent, there really doesn't seem to be a difference between the response rates in like the different settings seems to be fairly consistent across them against small numbers till now.

Our next question comes from the line of Andrew Berens with SVB Securities.

Congrats on the data. Just a couple of more for me. I wanted to follow up on Charles' earlier question about the confirmatory trial. What would that look like to this indication and given the FDA's heightened focus on converting accelerated approval to full approval, where are you in the process? And then 2 questions for Dr. Pant. I was just wondering about other drugs being developed for HER2-positive biliary tract cancer. Are there any data for any of the ADCs like HER2? And then wondering if he's excited about any other novel agents in BTC? I know there's a VEGF/DLL4 that's being developed in a similar setting. And congrats on the data again.

Yes, I'll just take your first question, and I'll turn over to Dr. Pant. But obviously, with an accelerated approval pathway that confirmatory study will be one of the discussion points that we'll have with FDA. I think the guidance is very clear. I think our data, as you've seen, is pretty clear and unprecedented patient population where there is no approved targeted HER2 therapy anywhere in the world right now. So I think -- we look forward to having those discussions. And I think once we have some guidance from FDA, then we'll be able to give some more guidance about time lines to filing and nature of the confirmatory study requirements that we might have for that filing. And until then, I don't think we'll be able to have much discussion until we have that consultation with the regulatory agency. And maybe I'll turn your next question over to Dr. Pant.

Thank you for that question. So -- so the published -- the other things which have been published in case reports with trastuzumab before, the bigger one was obviously My Pathway against small numbers, which was for trastuzumab, pertuzumab, we have response rate data in that. And then the other one is basically trastuzumab, deruxtecan, which was a smaller study, which was IAT from Korea and ASCO this year. So there are certain other development going -- kind of going on or kind of published already, that's the extent of the kind of the published data. As far as BTC, it's a very genomically rich disease, lots of development in different spaces, obviously, HER2, this big data set, which is coming out with zani and their FGFR inhibitors, second, third generation FGFR inhibitors for that specific area. So there are a number of -- and obviously, you want a checkpoint-inhibiter durvalumab, which is approved in the frontline setting. So there's kind of different efforts, different targets, which are being developed, again, at different stages of development. But that's a 1-hour conversation. So that's kind of the high-level stuff.

There appears to be no further questions. I'd like to turn the conference back over to Zymeworks for closing remarks.

Thank you all for joining us today. Obviously, you can see based on the data that were presented today, we're very excited about the potential of our employees, partners and collaborators to make additional advancements for patients in HER2-targeted therapies and beyond in the years ahead. And we look forward to reporting our continued progress on that mission in the weeks, months and years ahead. I want to thank you all sincerely for your time and support for our vision at Zymeworks, and have a great day.

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