Thank you for standing by. This is the conference operator. Welcome to Zymeworks' 2021 ESMO Conference Webcast and Conference Call. As a reminder, all participants are in listen only mode and the conference is being recorded. After the presentation, there will be an opportunity to ask questions.
I would now like to turn the conference over to Ryan Durko, Senior Director, Corporate Affairs at Zymeworks. Ryan, please go ahead.
Good morning and welcome everyone. My name is Ryan Durko, Senior Director of Corporate Affairs at Zymeworks. Today, we will review and discuss Results from our first line Phase 2 study of Zanadatumab in HER2 expressing gastroesophageal adenocarcinoma or GEA for short. The call will begin with an introduction from Doctor. Ali Turani, Zymeworks' President and CEO and a brief background on Zanadatimab and HER2 positive GEA of Doctor.
Neal Josephson, Zymeworks' Interim Chief Medical Officer and Senior Vice President, Clinical Research. Then we are pleased to have This will be followed by closing remarks from Doctors Josephson and Tarani. The speakers will be available for Q and A after the prepared remarks. And before we begin, I would like to remind you that we will be making forward looking statements during the call. Forward looking statements can be identified by words such as will, continue, may, potential of, initiate, look forward to, expect, believe, plan, anticipate, enable and similar words.
Forward looking statements are based upon our current expectations and various assumptions and are subject to the usual risks and uncertainties associated with companies in our industry and at our stage of development. For Call. For a discussion of these risks and uncertainties, we refer you to the latest SEC filings as found on our website and as filed with the SEC. As a reminder, the audio and slides from today's event will be available on Zymeworks' website later today. I will now turn the call over to Ali.
Thank you, Ryan, and good morning, everyone. Thank you for joining us at such an early hour. My name is Ali Tehrani, President and CEO of Zymeworks. Today, we will provide an overview of the data from our Phase 2 study of Zanadatimab plus chemotherapy in first line HER2 expressing GEA. While we are excited to get to the data, I would like to take a moment to review our strategic development objectives for zanadatimab and then Neel Josephson will provide Currently, Zanizatumab has multiple ongoing Phase 1, Phase 2 and registration enabling clinical trials across several indications, including biliary tract cancer, gastroesophageal adenocarcinoma, breast cancer and colorectal cancer.
These trials are underpinned by our development strategy for Zanadatumumab, which is focused on 3 specific strategies. First, we have our FAFSA market strategy. Here, our goal was to identify the fastest path to potential approval to get Zanadatimab into the hands of a broad group of physicians globally and expand access for patients in need. Based on the encouraging results as a monotherapy and a large unmet medical need in the setting, we selected advanced HER2 amplified biliary as the indication for our 1st pivotal trial called Horizon BTC01, which has been granted breakthrough designation by the FDA and is currently recruiting over 50 sites globally. 2nd, we have our display strategy, where our goal is to displace Herceptin as the standard of care in GEA and similarly Herceptin plus PERJETA in breast cancer.
We believe the data presented today represent key validation on route to accomplishing this goal. 3rd, We aim to expand the use of Zanadatumap into other HER2 expressing indications such as colorectal and endometrial cancer as well as expand potential combinations with other targeted and IO therapeutics such as BeiGene's anti PD-one, tazolizumab, ALX CD47 Blocker, evorcept, Seagen's HER2 TK1, tucatinib and Pfizer's anti CDK4six Ibrance. We will look to continue doing this moving forward as we execute on the development of Zanadatimab. With that, I would like to hand the call over to Doctor. Neal Josephson, our Interim Chief Medical Officer and Senior Vice President of Clinical Research to provide you with a brief overview of Zanadatimab's unique mechanism of action and the current HER2 positive GEA landscape.
Neil?
Thanks, Ali. Continuing on Slide 7. Zanadatumab is a bispecific antibody that targets 2 specific domains on the HER2 protein, the extracellular domain 2 and extracellular domain 4. Signaling through the HER2 receptor is a mechanism that promotes cell growth and proliferation in a variety of cancers, including a subset of GEA and breast cancer. Because of its configuration, Zanadatimab can simultaneously bind 2 distinct HER2 domains in a trans fashion, meaning that each arm of its enadatumab antibody Since each HER2 molecule can be bound by 2 different antibodies, this unique binding geometry enables cross linking of neighboring HER2 proteins creating large clusters of Zanadatinib on the surface of a tumor cell.
This clustering results in multiple mechanisms of action, which differentiates vanadatumab from monospecific antibodies like trastuzumab and pertuzumab, which combined to only one site, which each combined to only one site on HER2. When danevadab binds to HER2, It prevents the formation of HER2 homodimers as well as heterodimers of HER2 with other HER family members such as HER3. Preventing dimerization leads to a reduction in HER2 signaling and cell growth. Clustering also induces HER2 receptor internalization, leading to a decrease in the number of HER2 molecules present on the cell surface and further decreases HER2 signaling. In addition, the Zanadatinib PAR2 clusters promote immune cell recruitment to tumors, ozanodetimab in the clusters allows for binding of complement proteins, which can promote killing of heart 2 expressing cells via complement dependent cytotoxicity or CDC.
Ganadab's multiple mechanisms of action has been elucidated by our own preclinical research and now there is a growing body of clinical data demonstrating zanodetimab's potential for improving outcomes for patients with Heart2 Expressing Cancers, Slide 8. The data that Doctor. Ku will described shortly was generated in the first line treatment of patients with advanced unresectable or metastatic HER2 expressing GEA. As shown on this slide, GEA or gastroesophageal adenocarcinoma is a disease that has worldwide impact with the highest incidence being noted in Asia. Globally, gastric cancer is the 2nd leading cause of cancer deaths and about 20% GEA cases are Harteau positive.
Given the high morbidity and mortality and limited treatment options for patients with GEA, There is a significant unmet need. Slide 9. Trastuzumab in combination with chemotherapy is the accepted global standard of care for the first line treatment of HER2 positive gastric cancer based on results from the TOGA trial that was reported out in 2010. However, the Jacob trial that was subsequently performed failed to show a statistically significant benefit by adding pertuzumab to trastuzumab and chemotherapy. Slide 10.
While this has been the approved standard of care that is trastuzumab and chemotherapy. For over a decade, in May, the FDA granted conditional approval to pembolizumab in combination with chemotherapy and trastuzumab based on interim data from the KEYNOTE-eight eleven study. The approval is relatively new. We understand, however, that this has the possibility to change the standard of care landscape. And for those reasons, we ensured our upcoming pivotal study included a comparator arm using BeiGene's anti PD-one inhibitor, tislelizumab.
In summary, we see zanodanumab's Phase II results, which Doctor. Ku will speak to momentarily, as important to patient outcomes, providing not only another treatment option for physicians and patients, but one that is well tolerated with high rates of durable antitumor activity relative to the benchmarks set by current standard of care for first line GEA patients. Slide 11. Now I will be turning the call over to Doctor. Jeffrey Ku.
Doctor. Ku is an Assistant attending physician and Head of the esophogastric section in the gastrointestinal oncology service at Memorial Sloan Kettering Cancer Center in New York. He is a renowned physician scientist with expertise in the development of novel therapies for the treatment of gastric in Esophageal Cancers. And we are pleased to have him here today to present this newly released data with Zanadatumumab for the frontline treatment of HER2 positive GEA.
Thanks, Neil, for the very kind introduction. On behalf of my co investigators, it's my pleasure to present these data. Let Let me start with a summary of the current study on Slide 12. It is an ongoing global Phase 2 study of Zanadamab with chemotherapy in the first line setting for HER2 positive gastroesophageal adenocarcinoma or GEA. Fedadamab was initially administered on a weight based regimen.
Subsequently, this was changed to a 2 tiered flat dosing schedule. On the slide, you will see the 3 chemotherapy regimens that are evaluated are kPOXX 45 Fusysplatin every 3 weeks, along with an every 3 week administration of Zanizatinib as well as fofox and Zanizatinib every 2 weeks. There are 2 parts to this study. The primary endpoint in Part 1 was to establish safety, while the primary endpoint in Part 2 is the objective response rate of each combination. Next slide.
The current data analysis is from a data cutoff on July 28 and includes 36 patients. This table shows the demographics and baseline characteristics. Consistent with a global study, about 1 third of patients are Asian. You will note that 11% of patients are not considered HER2 positive. In Part 1, patients with tumors that are not considered HER2 positive by standard criteria could enroll.
There was also some discrepancy between local versus central testing. Next slide, please. This table shows treatment related adverse events. Overall treatment related serious adverse events occurred in 19 patients, All Grade 3 or more. 11% of patients discontinued treatment because of an adverse event.
The most notable toxicity was diarrhea. 94% of patients experienced diarrhea, 42% with Grade 3 or more toxicity. Other toxicities are in line with standard chemotherapy combination. Pre medication was mandated on the study for Zanadatinib and 15% of patients experienced a Grade onetwo Infusion Related Reaction. 9% of patients experienced a cardiac event, but only one patient had a decreased ejection fraction.
Next slide. In terms of dose limiting toxicities identified during Part 1, there was no DLT in the kPOXX group and dosing was confirmed for Part 2. DLT occurred in 1 of the 2 patients receiving FP and accrual to this arm in Part 1 continues. In the FOLFOX arm, 2 DLTs were noted at 62% of patients developed Grade 3 diarrhea. As such, The Safety Monitoring Committee recommended modification of a FOLFOX regimen with a mission of the bolus Pfizer FU.
Around this time, a prophylactic anti diarrhea regimen was also introduced. With these measures, one DLP was noted in 7 patients and the modified TOLFOX dosing was confirmed for Part 2. Next slide, please. Turning to efficacy analyses, 28 patients were evaluable for efficacy. This efficacy evaluable population was defined as all HER2 positive subjects with at least one evaluable post baseline disease assessment All who discontinued study treatment due to death or clinical progression.
Of the 8 patients who were not efficacy evaluable, 4 were HER2 negative, 3 get all the measurable disease and one withdrew before having their first scan. Of the 28 patients, 17 remain on treatment. The confirmed objective response rate is 75% with confirmed complete response in one patient. Disease control rate is 89% and the median duration of response is 16.4 months. Next slide please.
This is the waterfall plot. As you can see, 27 of 28 patients had some tumor shrinkage. Next slide. This is the SIRENS plot and it highlights the durability of the responses. Approximately 25% of patients have been on treatment longer than 12 months with responses ongoing And 2 patients continue on treatment more than 20 months later.
Next slide. This slide of plot is another way to visualize these data. In addition to again seeing the durability of some of the responses, we also note that several patients with durable responses continue to experience a deepening response over time. Next slide. And finally, here we have the Kaplan Meier curve, which shows the median progression free survival, which is 12.0 months.
Next slide. In conclusion, zanadetimab for chemotherapy as refined therapy for HER2 plus GEA is encouraging antitumor activity. Specifically the confirmed objective response rate in the kPOXX and FP arms at 92% and 100%, respectively. Most frequent toxicity is diarrhea, which is manageable with a prophylactic anti diarrhea regimen. Final slide.
Lastly, I would like to express our gratitude to the patients and the family members who have participated in the study. I also thank the team at Zymeworks for preparing these slides. Thank you very much for your kind attention. And with that, I would like to turn the call back over to Doctor. Neal Josephson.
Continuing on Slide 23. Thank you, Doctor. Ku for reviewing the data. All of this data builds on work that we've done previously. Go to Slide 24 now.
Previously in late line GEA, evaluating Zanadatimab first as monotherapy in late line GEA, followed by a study or data with Zanadatumab plus chemotherapy in late line GEA. The data presented by Doctor. Fu today key validation of zavendatumab in early line of therapy as we continue to observe the high rates of durable activity of our molecule. Next slide. In parallel to this study that we presented today, We have been running a Phase 2 study with our partner BeiGene of Zanadatinib in combination with tislelizumab in chemotherapy.
And we'll be starting a global Phase 3 study that will begin enrollment in 2021, Q4 of 2021, so by the end of this year. Slide 26. This study plans to evaluate Zanadatumumab and chemotherapy with or without the PD-one inhibitor tislelizumab for the first line treatment of locally advanced unresectable or metastatic Heart 2 Positive GEA. With that, I would like to turn the call back over to Ali.
Thank you, Neil. As we think about the future of Zanadatumab, I want to make sure that everyone that is listening understands that we see zanadetimab as a treatment option not only for patients suffering from biliary tract cancer or gastric cancers, But that we believe that zanzetimab's differentiated mechanism of action that Neil described earlier may enable it to displace Herceptin and Herceptin plus PERJETA across the entire HER2 targeted therapeutic space. This has the potential to change the standard of care in first line metastatic GEA as as well as metastatic, neoadjuvant and even adjuvant breast cancer. We see these data as thesis defining and look forward to continuing along this trajectory as we march towards our ultimate goal of sending patients home disease free. With that, I would like to open the line for questions.
Thank you. We will begin the question and answer session. We will pause for a moment as callers join the queue. Our first question comes from David Novak of Raymond James. Please go ahead.
Good morning, folks. Thanks for taking my questions this morning and congratulations on these class leading results. And I guess to kick things off for me, Looking at the safety profile, things look pretty good considering you're outperforming KEYNOTE-eight eleven on both activity and durability without any neutropenia or thrombocytopenia. However, you do call out an increased rate of GIAE, specifically diarrhea across all chemo arms. This does seem to be well managed by prophylaxis loperamide.
I guess my question is, does diarrhea persist past cycle 1. And further, could you provide us some insight into how you're thinking about a prophylaxis regimen in the pivotal trial? And maybe some insight into How you're thinking about this in the context of other indications such as breast cancer? Is this a regimen specific or indication specific effect?
Thank you. This is Neil Josephson. Manageable adverse event that's associated with Zanadatumab. And it's also described in general with HER2 targeted therapies when given in combination with chloropyrimidine and platinum agents in frontline treatment of HER2 plus of GEA. For us, the key in developing an effective regimen of Zanadatumumab in frontline HER2 plus GEA is to come up with a management plan for diarrhea that controls the diarrhea that allows patients to stay on therapy.
And
through the course of
the Phase 2 study, That's what we've done. So if you look at what we did with the FOLFOX regimen, that meant making small adjustments It was not necessary for us to make any changes to the backbone chemotherapy kPOXX and that's the chemotherapy regimen that's going to be the primary chemo regimen used in our pivotal Phase 3 study. But more importantly, as we discussed, the management across all treatment arms is improved by So we've instituted a 1 week mandatory diarrhea prophylaxis with twice daily dosing of oral loperamide on cycle 1 and that's very effective in preventing the onset of diarrhea. So In this study, prior to the institution of prophylaxis, the rate of Grade 3 diarrhea was 44% in cycle 1 And after the institution, it was 18%. And no patients discontinued treatment due to diarrhea after we instituted prophylaxis.
So It has been an effective management tool and will be employed in our Phase 3 study. Thank you.
Great. That's helpful. Thanks so much. And I guess just moving on to durability. You're showing here a median duration of response of 16.4 months with a number of patients still on therapy.
That significantly outperforms TOGA at 6.9 months, Jacob at 10.2 months and even KEYNOTE-eight eleven at 10.6 months. Can you talk a little bit about the durability advantage you're seeing here, specifically versus Keynote 811? And maybe some insight into how you're thinking about the
Yes. So I mean, you're right. The durability of this regimen looks very good. This is ongoing data. As we've mentioned, we still have many patients that are on treatment.
So the data is evolving and
but what
we're seeing looks quite promising. And as Doctor. Ku showed in the Spire plot. Many of the patients that respond have prolonged responses that deepen over time. With the PD-one inhibitor, we're hoping that not only would that contribute to an increase in response rate, but would also contribute to durability.
We know that that's what has been seen with PD-one inhibitors in other studies. So the data here is from a global study that we believe is representative of the type of study that we're going to do in as our Phase 3 study. We're very pleased with the data that we have obtained so far. It is evolving. So we can't say exactly What the durability will be, but it looks quite promising right now.
And again, as you mentioned, and adding the PD-one inhibitor In the Phase 3 study, we have we're theorizing that that's actually going to improve the results, not only from the standpoint of increasing response rate perhaps, but also increasing the durability.
Great. And just finally, lastly for me on activity. Could you talk a bit about the response variability between the kPOXX and the flupox arm? Is this simply a sample size effect?
It is true that if you look
at the study, in the kPOXX and FP, which are the 2 regimens that we are Taking forward in the Phase 2 study, we saw of the 14 patients, 13 of the 14 patients Had a partial response. So, 93% of the patients treated with the regimen that we're taking forward into the Phase 3 study Had a response. But we're also seeing good responses in FOLFOX as well. So I think that in total, the data looks very promising, but I don't think that we have enough data To be able to say that necessarily one regimen works better with Zanadatinib than another. But again, what we have here from this entire body of data is an overall excellent response rate.
And In particular, when you look at the regimens that we're taking forward, a response rate that we're really excited about.
Great. Thanks, Neil, and congratulations again.
Thank
you. Hi, everyone.
This is Ali Tironi. Before we take the next question, I just Wanted to turn the mic over to Doctor. Koo to see if he had also any additional thoughts on the response and the duration of response.
Thanks, Ali. I think one thing I did want to add is that I think what's particularly impressive to me about the Durability of the response is that many patients on the study, so many patients that were treated at Memorial Actually had maintenance at adenumab alone. Frequently with oxaliplatin based regimens, We stopped the oxaliplatin by continuing the floropyrimidine. But the protocol allowed for the possibility of stopping all And I think it was something that we did with trepidation early on. But again, many of these responses are occurring with So really as kind of a chemotherapy free maintenance option, the toxicity profile is very favorable And the durability really speaks for itself.
So I think that's something that's also worth noting. And then I think the then also I guess on a related note, I think I would also agree with Neil's point that this is a small sample size and I don't know that we should over read into activity between FOLFOX and kPOXX. The one thing I would add also is that patients who receive kPOXX were much And I think there continues to be a debate about gastric cancer in Asia versus rest of world even in the HER2 positive subset. I think the big picture top line results are certainly what are extremely impressive to me.
Thank you, Doctor. Ku. Why don't we go to the next question, operator?
Our next question comes from Stephen Willey of Stifel. Please go ahead.
Couple from me. So the first, I guess I'm just trying to rationalize The difference here in the incidence rate of grade 3 diarrhea that was observed in this study relative to what was seen Previously in the 2nd line plus trial when combined with chemo whereby I believe there was a 0% incidence rate of grade 3. So I guess just given the high rates that you're seeing after cycle 1, it doesn't appear to be a function of duration of therapy. So maybe you can just Help me understand if there's anything specific to this study with respect to just how drugs being administered or whatnot
So I'll take that. We've covered the issue of diarrhea, but I'll just say That diarrhea is more of an issue in frontline regimens with heart 2 targeting therapy with gastric cancer in combination with the 2 agents, the floraparmedine and the platinum agent. So there is a difference in the backbone chemotherapy. And as we pointed out in this presentation. This proper management, this diarrhea can be managed.
Thank you.
Okay. And then maybe you can also just explain, I guess, what the intention was
Yes. So flat or fixed dosing is a more convenient a way of dosing Zanadatinib. It also leads to less wastage of the product. And we've chosen a dosing scheme, a 2 tiered flat dosing scheme that gives the same coverage in terms of dose density or dose coverage over on a variety of weights that we would see in patients. So there's really over the population of patients, There's really no difference in terms of weight based and flat dosing in terms of the population coverage of the drug.
It's a more convenient, less wasteful way of giving it. And so we will be going with The flat dosing, the 2 tier flat dosing regimen in the Phase 3 study.
Okay. And then just lastly, and forgive me if I missed it, but I know that you have the pilot study that's being conducted with BeiGene with the addition of tislelizumab here. Curious as to when we might expect to see that data. Thanks.
That study is underway and we're working with our partner BeiGene to bring that data out. We're currently looking at maturing the data set. We believe right now that data set will come in the first half of twenty twenty two, which would proceed the start of the Phase 3 in Q4 as we noted.
Great. Thanks for taking the question, guys.
Our next question
comes from Nick Abbott of Wells Fargo. Please go ahead.
Good morning. It's I won't even say it's bright and early here, Ali, on the West Coast, but it's early, early. Congratulations on a terrific set of data. And a question for Doctor. Koo.
Doctor. Koo, you're One of the authors listed on the 2020 Lancet Oncology paper describing it Memorial's experience with KEYTRUDA plus kPOX. And so you've had obviously direct experience of both these regimens. Can you compare your observations from the two trials, how Easy these regimens are, how tolerated they are. And then I have a follow-up.
Sure. I mean, I would say that, I think pembrolizumab with trastuzumab and chemotherapy is well tolerated. I think the results of the 811 study, the KEYNOTE-eight eleven study really kind of bear that out. Again, I would say that the major difference that we're seeing with zenadinemab and chemotherapy without a PD-one or PD L1 inhibitor Is the diarrhea? So I think that as investigators on the study, there certainly was a learning curve.
I think we're simply recognizing the fact that the diarrhea exists. But I think the prophylactic Imodium regimen in combination with patient awareness and physician awareness has ultimately made it manageable. So again, I mean, the 2 regiments are slightly different because one has PD-one inhibitors and one does not. But I think that would be the major difference that emerges. I know there have been questions about the diarrhea toxicity.
I would say that patients who are on Zanadatinib monotherapy Have very minimal diarrhea and certainly don't require any anti diarrhea medications. Similarly, FOLFOX I think there clearly is an additive or even synergistic component When we bring that and that amount together with a 4 Permian base regimen. And but I think with a I mean, I think it's certainly manageable with a prophylactic regimen moving forward. Beyond that, I think Other toxicities are certainly very comparable between both of these combinations. And I think in general, all other toxicities are actually Very manageable as first line regimens go.
Okay. Thank you. And then from your Prior comments that you had banning maintenance. Presumably, when you have pembro, you're using So as you think of the Phase III, do you consider that patients will be receiving PD-one and Zannie Maintenance.
Yes. I mean, I'll definitely have Neil Yes, exactly. I mean the one thing I would clarify is that even with even based on the KEYNOTE-eight eleven paradigm, I think few of us actually are completely omitting the Teneo a small permitting chemotherapy as a maintenance strategy and that's really kind of historical and something that's commonly done in upper GI as well as colon cancer. But the Neil certainly can address the Phase 3 study.
Yes. Thank you. So in the Phase 3 study, patients who are randomized to the arm with the PD-one We'll continue
with tislelizumab
and Zanadatimab. But details of the Phase 3 study will be reviewed and at the time of first patient in.
Thanks. I'll hop back in the queue.
Our next comes from Gena Wang of Barclays. Please go ahead.
Thank you for taking my questions and also congrats on the great data. So I have two questions for Doctor. Ku. First, my question is regarding the Fofox arm. Just wondering what is the percentage of IHC III plus And then the second question is, and you comment It could be a small number of patients, but on the other hand, we did see XANI dosing regimen are different between Fofox and kPOXX.
So do you think the response rate differences beyond the small number of patients also partially due to Zani dosing or the chemo itself?
Yes. I mean, those are both great questions. I guess, I don't I would say, I don't have the breakdown of for 2 whether it's 3 plus or 2 plus FISH positive based on the regimen. Neil may have that information. So I'll address Your second question.
And again, I think it's absolutely a hypothesis that potentially The schedule and the dosing of the flurofenin plus the dosing of Zanadatinib could certainly I mean, one concerning hypothesize that, that has an effect Both on toxicity and efficacy. I think ultimately, we don't know. Again, I would also throw in that there is also the confounder of ethnicity with most patients receiving kpox being Asian, and it's also pretty well established that toxicities of capecitabine Clearly vary based on ethnicity and based on geographic location. So I think to answer your question, essentially, I think we don't know. But I think certainly, I think it's fortuitous and it's encouraging that the regimens that are moving forward in Phase 3 include kPOXX, where I think the seemingly the most favorable toxicity profile and the highest response rates we're seeing.
Yes. And in terms of IHC status between the KPOXX and the FDA, I don't have it tallied or broken down, but there's not any significant difference in terms of The IHC status and what we're seeing in the different arms. And I would Just echo what Doctor. Kree said previously that this is a small data set. It's hard to parse out differences between the arms.
And I would also point out that there are some patients here, One patient that I think Doctor. Hu can talk about that technically is a progressive disease based on an early diagnosis of a brain metast, but is now 2 years into therapy with fantastic management of his systemic disease and doing well. So while that patient may count as a PD in the FOLFOX arm, I think by all measures that patient has had Tremendous benefit from PolFox plus anadatumumab.
Yes. I mean, I think I could just briefly add to that. So this is a patient who was having symptoms prior to start of treatment. So clinically, certainly it was not progression. The trial based initiation of therapy was found to have a brain metastasis.
So by resist that was considered progression. I mean that patient is getting close to the 2 year mark of being on treatment. And to Neil's point, I mean that patient is treated on the full FOX arm. So So I think there's always the temptation to kind of read into the tea leaves. I think sometimes there's a risk of
Our next question comes from Jessica Fye of JPMorgan. Please go ahead.
Hey, guys. Good morning. Thanks for taking my question. There's been a little discussion about geographic and ethnic differences as it relates to response. I'm curious whether the geographic mix in this trial is comparable to what you would anticipate in Phase 3 and also how it compares to the geographic mix in other large HER2 gastric trials.
Sure. And I'm happy to take that question. So this is a global study. So it was performed in Canada, U. S.
And South Korea. And about a third of the patients are Asian. And this is probably Pretty similar to what we'd expect in the Phase 3 study. It's similar to what's been seen in other Phase 3 studies. There was some difference.
I think that we saw more FOLFOX given in North America. The KPOXX was Where treated patients were pretty much split between North America and South Korea. But overall, the mix of patients that we're seeing here is similar to what we expect to see in the Phase 3.
Okay, great. And any comparison to other trials?
Again, I think that if you look at other large Phase III trials that have been done in gastric cancer. You see somewhere between 30% to 50% The patients are typically Asian and so I'd say that this is similar as well.
Okay, great. And then Doctor.
Ku, do you have anything
to add to that?
No. And I think part of that is that I think many studies deliberately limit the number of Asian patients just to make sure that there's equal representation. Again, I mean, it's one of these things that GI medical oncologists like to talk about as to whether there really is truly a difference between Gastric cancer in the East and West. I mean, I think that really remains also kind of an unresolved issue. So I think it's part of Good trial design to ensure that no one geographic location is overrepresented.
Okay, great. And then lastly, can you maybe walk us through the 3 patients who couldn't be kind of captured in the ORR due to lack of measurable disease. Maybe talk about how they did clinically and if there were other assessments that you used to determine if they were benefiting?
Yes. So I think that as was pointed out, patients who do not have Resist target lesions are not responsive valuable, But those patients can be enrolled to some studies and can be The progression free survival of those patients is certainly something that can be assessed. I know, Doctor. Ku, you had one of those patients on this study, so maybe you can speak to that patient specifically.
Yes. Is that the patient with a lymph nodes who had surgery?
Yes. Yes, exactly.
Yes. Okay. Yes. So I mean, again, I mean, It's actually very helpful to have studies that allow patients who have evaluable but not measurable disease by RECIST criteria. I It's a little bit of a technical distinction, particularly the lymph nodes are a little bit smaller.
They're less than 1.5 centimeters in the short axis. But still for all intents and purposes, there is disease that we can follow. So like Neel said, I think in terms of estimating progression free survival. That's still absolutely something that can be done. And so in fact, this is exactly the situation with this There were lymph nodes that we could clearly see.
We could see them getting smaller, but certainly we would have seen them getting bigger. Just that the largest was not big enough to be considered measurable. So this patient actually had a very significant response 2 treatment and actually radiographically all of the lymph nodes period. And ultimately, his treating physician decided to take him to surgery where he actually had, I believe it was an esophageectomy as well as resection of the original lymph nodes that were involved. There was residual disease at the time of the surgery and then subsequently his physician elected to continue him on maintenance trastuzumab as he had come off the study to have surgery.
And I think it's been at this point about 8 months since the surgery and the patient remains disease free on imaging.
Thank you.
Our next question comes from Yigal Nochomovitz of Citi. Please go ahead.
Hi, this is Carly on for Yigal. Thanks so much for taking our questions and congratulations on the data. We have two questions. First, We were just hoping you could expand a bit on the point you made during your prepared remarks about sort of the broader strategy to displace Herceptin and PERJETA and why you believe there should potentially be read through from this gastric trial to other tumor types, specifically breast cancer when you think about sort of the Jacob trial as a proxy. And then the second question is on the Phase 2 study for the triplet being led by Beijing.
Can you just talk about what you see as the bar on ORR for that regimen in light of the data that was presented today? Thank you.
Thank you. I'll take that. This is Ali Tehrani. I think you asked a really good question and I'm glad you brought up the Jacob trial. The key pieces of therapeutics in the Jacob trial are Herceptin, Perjeta in chemo.
And in the same setting, in the frontline gas I believe the data that was generated there had a 57% ORR. And we Acknowledge the fact that we have a small and here we have a small data set, but certainly and looking at our data, we are headed in And we believe we are absolutely showcasing the fact that, as I mentioned, we have a thesis defining piece of data here. Naturally, we have to expand the data set. Naturally, we are excited to see how this data matures over time and as we begin to showcase the data for our triplet combination in the first half of the year. But I would say that we're also on track to showcase the breast cancer data over the course of the next few months this year and certainly in the first half New Year to directly corroborate our thesis that there is a read through to breast cancer.
I want to remind everyone that we have an ongoing first line metastatic breast cancer study with our partner where we're looking at the combination of zedadatimab plus chemo. And also we have an ongoing late line breast cancer study in combination with chemo, which will be presented at a near term medical conference. I think when that data comes out, there can be a direct sort of a discussion between the read through of this data and the others. And we're very excited about showcasing that and having that discussion. Well, from the very beginning, as I mentioned in my prepared remarks, we've always gone into the development of Zanadatumab with a viewpoint that This asset has the potential of displacing Herceptin and Herceptin plus PERJETA across all HER2 positive tumor types.
Our next question comes from Andrew Berens of SVB Leerink. Please go ahead.
Hi, thanks. Congrats on the update, very nice data. A lot of my questions have been answered. But I guess just a little more color on that first line breast trial that you just mentioned, Ali. It looks like it's expecting data in 'twenty 2 now, I think is what it looks like on the pipeline graph.
And then what do you think and I think you probably talked about this a little bit in But what does the regulatory pathway look like in GEA in regards to accelerated approval? And then the last one is you previously said that you plan to partner Tazani and was wondering if you could give us some updated thoughts here. Thanks and congrats again on the good data.
Thank you. Good to speak with you again. First on the first line metastatic breast cancer study, A good number of patients have been enrolled. We are currently maturing the data set. And as we've showcased here, when we highlight that data for everyone, we want to make sure that we have Followed these patients for a sufficient amount of time such that we can have a comprehensive discussion as it relates to comparable trials, especially the CLEOPATRA trial.
That's why we are going to bring that data set in the first half of the New Year. In terms of the second question and when it comes to the potential of an accelerated approval in GEA. We'll be happy to elaborate further on the trial design on the specifics of the Phase 3 at the initiation of the study later this year. And last but not least on the partnership. As I've always mentioned before, we view a partnership critical to accelerating The path to patients for Zanadatumab and of course broadening it.
Zymeworks is well positioned for the studies, the registrational studies currently underway. However, as we embark on additional registrational studies, especially in globally around the world and that priority remains well within our corporate objectives.
Okay. And then just to clarify in terms of the accelerated pathway in GEA, I believe KEYTRUDA did have an accelerated approval. And so is that something that you guys think is possible here too?
Absolutely. Obviously, when there is a precedent set by another therapeutic, it creates the opportunity for other assets to benefit from that. So we are aware of that. We have studied that. And as I mentioned, At the initiation of the study, we'll be in a much better position to completely discuss that with everyone.
Okay. Thanks and congrats again.
Thank you.
Our next question is a follow-up from Cabot of Wells Fargo. Please go ahead.
Great. Thanks for taking the follow-up. So for the PD-one inhibitor, how convinced are you that tislelizumab is equivalent to pembro? And why not allow U. S.
Physicians to choose between tislelizumab and pembrogitinopembroz approved.
So this is Neil Josephson, and I will answer that question. I'm not aware that there's been head to head studies looking at the efficacy of of different PD-one inhibitors. So it's hard to point to specific data to say Anything in direct comparison. I think what we can say is that from a mechanistic standpoint, BeiGene's PD-one inhibitor is, Agenem's PD-one inhibitor has been shown to be a very effective therapy to tislelizumab. In addition, there are actually Reasons to think that it actually may be a better PD-one inhibitor in terms of its affinity to PD-one in terms of the way that it engages certain immune cells and that it actually maybe have mechanistically a better But in terms of a trial design, I think that As Ali said, we'll get into the specifics of that when the first patient is in.
But we have to control the elements in the different arms to be able to make an assessment of the regimen and the regimen that we're looking at with the PD-one inhibitors specifically with tislelizumab and Not with other PD-one inhibitors. It does not prevent us from doing other studies with other PD-one inhibitors, but for this study that we're talking about the Phase 3. It is one where we have to control the regimen so that we can really tell What is being what is better than what is the best regimen to take forward?
Yes. I understand. I guess it just seems like it's a risk. You're going with an unknown Quantity
as far as
the PD-one element goes. And maybe just a follow-up on that. One of your competitors has said that it is now evaluating anti HER2 plus PD-one in GEA. Is this a strategy you're considering?
Say that again. I'm sorry. Just meaning that PD-one And alone without chemotherapy?
Right. With the 2 there's the 2 That was
Yes. So that's not currently part of our Phase 3 development plan. But again, we will talk about specifics of the Phase 3 study at first patient in.
I'm sorry, I guess I was just saying not as part of the Phase III, but as an additional trial concept.
I'll jump in with that. Nick, this is Ali. I'll jump in. We are constantly in dialogue with physicians and investigators such as Doctor. Koo.
And we will certainly consult with them in terms of what they believe they need to treat their patients best. And as necessary, we will consider other studies to meet their needs of treating their patients. So certainly, the potential of additional Phase IIs is within the books. But at this time, what I would like to bring everyone's attention
This concludes the question and answer session. I would like to turn the conference back over to Zymeworks for any closing remarks.
Great. And I think this is coming back to me. This is Ali again. I just wanted to conclude the discussion today by saying that We are very excited as ever about the potential of our lead assets, anadatumumab, with what we've been saying all along that And I want to thank you all of you again for joining us. And I know everyone is really busy with the ESMO conference.
So thank you and have a wonderful rest of the day.
This concludes today's conference call. You may disconnect your lines. Thank you for participating and have a pleasant day.