Thank you for standing by. This is the conference operator. Welcome to the Zymeworks conference call to discuss initial results from the phase I trial of ZW191. As a reminder, all participants are on a listen-only mode, and the conference is being recorded. After the presentation, there will be an opportunity to ask questions. To ask a question, please press star one one on your telephone keypad. I would now like to turn the conference over to Dr. Sabeen Mekan, Senior Vice President of Clinical Development from Zymeworks. Dr. Mekan, please go ahead.
Good afternoon. Thank you for joining our call discussing the highlights from our presentation on preliminary phase I trial results for ZW191 at the AACR-NCI-EORTC Conference on Molecular Targets and Cancer Therapeutics today in Boston. Before we begin, I would like to remind you that this presentation contains forward-looking statements, and we encourage you to review our latest SEC filings for a full breakdown of risks and uncertainties related to any forward-looking statements we make during today's presentation. On today's call, Stuart Blanchard, Senior Director of ADC Development at Zymeworks, will begin by providing a review of the design rationale and scientific principles that guided the development of ZW191. Following this, Dr. Patricia LoRusso, Professor of Medicine at Yale Cancer Center, will then summarize highlights from the initial phase I clinical data as presented at the conference. Lastly, I will outline next steps for ZW191, including our development path forward.
At the end of the call, Dr. LoRusso and I will be available for Q&A. As a reminder, the audio and slides from this call will also be available on the Zymeworks website later today. I will now turn the call over to Stuart.
Thank you, Dr. Mekan, and thank you all for joining us today. Before we get to the exciting clinical data, I'd like to quickly review the design of ZW191. At Zymeworks, we think deeply about how we design our antibody-drug conjugates, and over the past few years, we've shared many of our insights through publications, all of which can be found on our publications page of our website. Those learnings directly shaped the design of ZW191, including both the antibody features and the linker payload properties. ZW191 is built on a novel IgG monoclonal antibody that specifically binds to folate receptor alpha and is conjugated through a peptide-cleavable linker to our proprietary topoisomerase I inhibitor, ZD-06519, to a drug-to-antibody ratio of eight.
The antibody binds a distinct epitope on folate receptor alpha and was selected for its ability to internalize efficiently, deliver high levels of payload, and penetrate tumors more effectively, allowing ZW191 to target tumors with low folate receptor alpha expression and achieve strong anti-tumor activity. The ZD-06519 payload was selected for its moderate potency in the one to 10 nanomolar range, along with strong bystander activity and proven antibody linker stability, all of which are intended to support better tolerability, enable higher protein dosing, and maintain activity even in tumors with low or heterogeneous folate receptor alpha expression. Taken together, the antibody and linker payload features create a differentiated profile for ZW191 that we believe will translate into a compelling clinical performance, and that's exactly what we're beginning to see in the data presented today. With that, it is now my pleasure to hand over to Dr.
LoRusso, the lead author of the poster presented at the AACR-NCI-EORTC Conference today. Dr. LoRusso brings more than 25 years of expertise in medical oncology, drug development, and early phase clinical trials. Dr. LoRusso, over to you.
Thank you so very much, and I thank everybody on the link for watching this presentation today, as I'm very excited about this drug. I've actually been doing clinical drug development for over 35 years, and to have a drug as exciting as this one is a true treasure, not only as an investigator and a physician treating patients, but as I think you will see and hopefully appreciate and understand as well, a true pleasure and very exciting data for our patients. If you could advance to the next slide, please. First, I'm going to just show you briefly, this is the study schema of the phase I trial that we've been that is currently ongoing pursuant to ZW191.
As you can see, the key eligibility included obviously patients greater than or equal to 18 years of age and focused in escalation on three primary tumor types: platinum-resistant epithelial ovarian cancer, serous or endometrial cancer, and finally, adenocarcinoma non-small cell lung cancer. These patients, as you will see, had exhausted available systemic treatment options, and we did not require a prerequisite of folate receptor alpha expression. That was done looking at that retrospectively, and our patients were allowed to have a performance status of either zero or one. I'm going to be presenting to you today the dose escalation cohort as it exists prior to the data cutoff date. This trial is currently ongoing, and as Sabeen will talk to you later, is going into or currently enrolling in dose optimization.
As you can see, the many cohorts that we evaluated all the way from 1.6- 11.2 mg/kg in this dose escalation cohort. Next, this drug, by the way, is given once every three weeks intravenously. This is a very busy slide, I know, but it looks at the baseline characteristics of the 41 patients that were treated up to the time of data cutoff, which was September 10th, 2025. As you can see, there was a mix of Asians and Caucasians. Roughly 70%- 75% of them were Asians, the remainder Caucasians. Next slide. As you can see, there was about a 50/50 split between patients who had an ECOG of zero versus those that had an ECOG of one. Next slide.
Also, as you can see, 70% of the patients that were recruited in the escalation had metastatic platinum-resistant ovarian cancer, 20% endometrial cancer, and the remaining 10% non-small cell lung cancer. Next slide. The median number of prior treatments was three, but as you can see, the range of prior treatments in this population was anywhere between one to nine. Looking specifically at the number of prior treatments, what you see is that roughly a little over a third had three to four prior treatments, and about a third also had five or more prior treatments. I would consider this a heavily pretreated patient population. Next slide. As you can see, based on the prior treatments that these patients had, because the ovarian cancers were the predominant patient population and because of the tumor types involved, all patients had seen prior platinum as well as prior taxane.
The majority had also seen prior bevacizumab. There were only two patients recruited because of that. There were only two patients that were treated on the study that had had prior mirvetuximab, in large part because of the geography of where the patients had been treated, as well as not requiring prior mirvetuximab for protocol entry. Next slide. Overall, based on the summary of baseline characteristics, enrollment continued at a dose of 11.2 mg/kg, and that was currently ongoing at the time of data cutoff. Only six participants had discontinued ZW191 treatment, and all of them had discontinued because of disease progression. Of the 41 patients enrolled, 35 were continuing on ZW191 treatment at the time of data cutoff. Next slide. This is just a slide looking at the summary of safety of this patient population.
As you can see, in those 41 patients, the grade 3 or greater treatment-related adverse events was very minimal, very minimal compared to what I see with many of the other antibody-drug conjugates of similar payload. Only seven patients had greater than or equal to grade 3 treatment-related adverse events. Importantly, there were no serious treatment-related adverse events. There were no discontinuations due to adverse events, and there were no deaths from drug. Next slide. This again is a busy slide, but basically, it shows treatment-related adverse events of any grade that occurred in at least 15% of patients. It looks quite busy, but the data is actually very similar, especially if we look at the last two columns, which are the total number of treatment-related adverse events of greater than or equal to 15% in the cohort of 41 patients that were recruited to this trial.
As you can see, any treatment-related adverse event of greater than or equal to grade 3 occurring in at least 15% or more of patients only occurred in seven patients for a total of 17%. Of those seven patients that reported greater than or equal to grade 3 adverse events, treatment-related adverse events, the most common was anemia, which was identified, as you can see, in four patients, as well as neutropenia, which occurred in two patients, and thrombocytopenia that occurred in two patients as well. Next slide. This is the waterfall plot, as well as a preliminary efficacy table demonstrating the anti-tumor activity in this patient population. As you can see on the left, the waterfall plot shows significant reduction in tumor size across various doses of drug administered, and responses as seen in as low as the 3.2 mg/kg dose.
What is also very interesting on this graphic on the left is that looking at the bar graph on the top, or the bar on the top, what we see is, albeit there were responses in folate receptor alpha high patients, we see quite amazingly significant anti-tumor activity in patients that were either folate receptor low or negative, which with other folate receptor alpha inhibitor targeted ADCs currently FDA approved, the requirement for efficacy based on significant data in those drugs, in mirvetuximab as an example, those patients had to have folate receptor alpha high based on the data that had come out of the randomized phase III trial. The initial data showing very little activity or no therapeutic advantage of that ADC in folate receptor low to medium patients.
This is, to me, quite astounding data to be able to not have to necessarily preselect for folate receptor alpha expression and yet get significant anti-tumor activity in this patient population. The chart on the right is looking at preliminary efficacy for response evaluable participants that had gynecologic cancers. There were 24 patients for which we could look at response in this patient population. Of those, 50% of the patients had a partial response, and at the time of data cutoff, 29% had confirmed partial response. If we look specifically at the 6.4 to 9.6 milligram per kilogram dose, 64% of patients with gynecological malignancies had a partial response at the time of data cutoff, with, as you can see, over 25% having confirmed partial response. Next slide.
This is on the left, the swimmer's plot, and as you can see, again, across the board, patients had response at low doses, and there were several patients that actually had dose escalation. What is very impressive in this swimmer's plot is that the majority of patients that were treated, in fact, there were very, very few patients at the time of data cutoff that had discontinued treatment. The majority of patients remained on study for a prolonged period of time while they were being followed on this trial up to the time of data cutoff. The graph on the right shows the percent change from baseline in CA-125 over a week's duration, which again is quite impressive in this patient population. Next slide.
In conclusion, I believe that ZW191 has been safely administered during dose escalation up to the 11.2 mg/kg dose, with the majority of participants still on treatment. I personally enjoy treating patients on this drug because of the lack of side effects and the prolongation of response. There have been low rates of dose modifications, dose delays, and greater than or equal to grade 3 adverse events, and there were no discontinuations due to adverse events. Again, quite impressive. Preliminary activity, I believe, is promising, starting at 3.2 mg/kg every three weeks. The overall response rates, especially at the doses between 6.4 to 9.6 mg/kg, were overall 53%, but if you looked at gynecological malignancies, 64% of patients up to the data cutoff that had gynecological cancers had, at minimum, a partial response. The anti-tumor activity was observed, as I said previously, across all folate receptor alpha expression levels.
Finally, these data represent a broad therapeutic window for ZW191 and support further investigation in advanced solid tumors. As a practicing Medical Oncologist that does early phase clinical trials exclusively in my practice, this type of a trial, this very trial which I am participating in, is extremely exciting for us, and we welcome recruiting patients to this clinical trial. Thank you so very much for your time today.
Thank you, Dr. LaRusso. The data that you've shared today will provide important clinical validation for our ADC design philosophy. We're encouraged by these initial results and look forward to continue following the data as it matures further over the coming months. Beyond the data presented here, we have determined 11.2 mg/kg as the maximum tolerated dose and are proceeding with part 2A of the study focused on dose optimization in patients with platinum-resistant ovarian cancer. Based on the integrated assessment of safety, efficacy, and pharmacokinetic data, we have selected two doses: 6.4 mg/kg and 9.6 mg/kg for randomized dose optimization, with approximately 30 patients planned in each cohort. We are planning to begin enrollment this quarter. This will allow us to further refine the balance between efficacy and safety and justify the optimal dose for registrational studies.
We expect to share additional data at a future medical conference with a larger and more mature data set. Overall, early results continue to support ZW191 as a potential best-in-class asset with promising early activity and a manageable safety profile. As previously, we would continue to be data-driven in planning our further development plans for registration and expand into earlier lines of monotherapy and combinations. As we move forward, our focus remains on disciplined clinical execution while exploring strategic partnerships that could accelerate development and expand global reach. That said, ZW191 is also giving us important translational insights that could help accelerate and de-risk the future development of ZW251 and other pipeline ADCs using our ZD-06519 payload. Based on our data thus far, informing our growing understanding of tolerability and efficacy for our novel payload, we're confident in moving ZW251 into phase I clinical development this year.
As you can see on this slide, we also have other preclinical candidates beyond ZW251 targeting more novel antigens, such as LYSIGHT-E and PTK7. Our NAPI2b-targeting candidates program remains IND ready, and we continue to explore next-generation ADCs. With that, I'd like to thank everyone for listening, and I'll turn the call over to the operator to begin the question- and- answer session. Operator?
Thank you. We'll now begin the question- and- answer session. To join the question queue, you may press star, then 11 on your telephone keypad. You will then hear an automated message advising your hand is raised. If you are using a speakerphone, please pick up your headset before pressing any keys. To withdraw your question, simply press star one again. We will pause for a moment as callers join the queue. Our first question coming from the line of Mayank Mamtani with B. Riley Securities. Your line is now open.
Yes. Good afternoon, Dean. Thanks for taking our questions, and great to see some exciting data here. On the two patients who had prior mirvetuximab, could you maybe talk about what the experience there was? I was curious, as you think about those expansions and optimization, do you expect to enroll more with prior mirvetuximab exposure? I was also obviously curious to hear the data that you presented on folate receptor alpha positive versus negative. I guess a derivative question there is, are you thinking of the development plan being different for positive versus negative patients?
I can go with Sabeen's start. Sabeen?
Sure. Thank you for this question. I think from our clinical trial eligibility, we allow patients with prior mirvetuximab treatment. However, this is a global trial, and we enrolled a large number of patients from Asia where mirvetuximab is not approved and available. That is one of the reasons we had a few patients with mirvetuximab. The other reason also is we're enrolling all levels of folate receptor alpha expression levels. As you know, about two-thirds of patients, even in the U.S., where mirvetuximab is available, are not candidates for this treatment. That's, I think, part of the reason, a main reason why we have fewer patients. I think as mirvetuximab gets approved globally and gets more use, as we go into expansion part of our studies, we probably would get more patients.
Over to efficacy with regards to folate receptor expression levels, we're pretty pleased with efficacy across folate receptor expression. I'll turn over to Dr. Patricia LoRusso. She talked a fair amount about it in terms of the fact that we're seeing efficacy in patients both folate receptor high as well as medium low. Dr. LoRusso?
Yes. First, I'd like to answer or have you, Sabeen, help me answer the one question that he had. Do you know what the responses were in the two patients that had had prior mirvetuximab?
We are seeing activity regardless of prior mirvetuximab.
Yeah. They both responded. Just to let you know, that is the one huge advantage of this drug over mirvetuximab as an example. Because mirvetuximab, if you know the randomized phase III data, the first phase III that they did, they didn't get therapeutic advantage in the medium, low, or negatives. They were only in the high folate receptor alpha. This has a huge advantage there. I don't even believe yet in the data in the patients that we're treating that the degree of expression has anything to do with the efficacy. This is pretty amazing for me as a clinician and clinical investigator. I've done a lot with antibody-drug conjugates, especially with topoisomerase I payloads. To see this lack of toxicity as early as in the phase I trial, this little toxicity with this degree of efficacy, I'm very impressed. I'm very impressed.
I don't have the fortune of having that opportunity often, even after working with some of the ADCs that have since been FDA approved for this patient population, mirvetuximab as well as others. I hope that answers your question.
Yes. Thank you. Dr. LaRusso, maybe just a quick follow-up for you. We saw at ESMO a lot of data also from the folate receptor alpha ADCs, some of them next generation. If I had to ask you, I know the data is very early in this case, but we're just curious, as we think about a lot of these therapies moving to earlier lines, and they will be all topoisomerase I inhibitor based, if you're thinking about the next generation, how would you maybe think about the different data sets that you've seen?
Yeah. I'm familiar with about three of them that were presented: the RYNE, the AZ, I know of the AZ one, and a few of the other ones. In fact, I believe one of them may have been presented in one of the sessions that I also presented a different drug on. One of the unique characteristics, and remember, that data was phase I, primarily phase I. Some of it included some expansion, but for the most part, what we saw was the phase I data. If you dissect out just toxicity initially, let's just look at toxicity and look at the toxicity profiles of at least three of them that we saw versus what we see with this drug. This drug is much safer. Some of the phase I's required folate receptor alpha expression.
We don't require folate receptor alpha expression within the context of our phase I trial to demonstrate efficacy. You know, when we're treating patients, efficacy is very important. For quality of life, toxicity is extremely important as well. You know, I don't work for Zymeworks. I have no stake in Zymeworks. I have no reason other than benefit for my patients to talk about this drug. The toxicity profile that I'm seeing at this stage is extremely encouraging relative to what some of the toxicity profiles of some of the other drugs that were presented demonstrated. Does that help?
Super helpful. Thank you. Yes, very helpful. Thanks so much.
Thank you. Our next question.
Some of them had like grade 2, 3 nausea of like 80%. One of them, anyway, I don't have to go on. I think I've brought my point home. I apologize.
Our next question coming from the line of Adigalna Lukowitz with Citigroup. Your line is now open.
Yeah. Hi. I had a question. In the folate receptor alpha low negative, for the two, there are two ones in blue there that are low negative at the very right side of the waterfall. I guess, how did you, how do you get responses in the negatives? Meaning, I guess it's just negative on the biopsy, but it was a false negative. There must be some folate receptor alpha present, obviously, right? Can you just explain how you get such strong responses in the negatives, not the lows, but the negatives?
Yeah, I can walk you a little bit through that.
Stuart, could you? I'm sorry.
Yes.
Come on, if you guys could start.
I think that relates to our construct of our ADCs and our ADC design, as Stuart had pointed out earlier during our presentation. For our ADCs, particularly for this one as well, we utilize a very highly internalizing antibody and go in tumors that have high levels of expression for the target. Ovarian cancer, endometrial cancer, and non-small cell lung cancer that we're evaluating have all very high levels of expression of folate receptor alpha. We are moving in with high expressing antibody, internalizing antibodies, and our linker payload system. It's a moderately tight linker, moderately toxic payload that allows us to deliver a lot more payload to the tumor compared to some of our competitors. That, we believe, brings us the edge in terms of having patients respond in very little levels of expression for the target.
I think one of the examples that I can provide with ADC construct in this design is the fact that certain gynecological malignancies, for example, are pretty sensitive to topoisomerase I inhibitor. If you have very, very little, they require very, very little expression of folate receptor alpha with this highly internalizing antibody and payload construct to work.
Thank you. My second question for the Principal Investigator, please. You mentioned that 11.2 is the maximum tolerated dose, but you also mentioned that you're going to take forward two of the lower doses in a dose optimization. Doctor, given that you said that it's so well tolerated, I'm just wondering if you would be curious or are you curious to see how this drug could perform in more patients at that higher 11.2? Are you sort of happy with the way the company is going with these two other doses?
Yeah. I can first comment on that, Sabeen, if you want me to, and then you can add to my comments. I'm a big proponent, first of all, of dose optimization. There was one DLT that was identified at the maximum tolerated dose of 11.2. We saw what makes you, what makes one help identify what doses one is going to advance forward in Project Optimus dose optimization that would lend you some level of comfort to advance that dose into a randomized phase III trial. We think that I believe that at 6.4, 9.2, we've really achieved many of the pillars that we would look at to assist us with a significant level of confidence that we have the right dose to advance forward. Number one, patients are extremely tolerable. There's very little toxicity, and I'm talking specifically at 6.4 and 9.2. There's very little toxicity.
We've achieved with pharmacokinetics, we've overachieved with pharmacokinetics the exposure levels that we were hoping to obtain in order to elicit significant efficacy based on preclinical models. The duration is significant, virtually minimal toxicity. Why would I want to potentially enhance both what I have now in my portfolio, which I'm looking as a clinician who's guiding in identification of the optimal dose, the main five pillars that would help me determine what dose I feel comfortable with in moving forward? I've achieved all of those pillars with both 6.4 and 9.2. I've got, and it's very tolerable. Let me just tell you something. I see a lot of patients that are treated with ADCs either on our investigational studies, but more importantly, have come to me and had progressed on ADCs. This drug is so tolerable at those doses that I really feel we're there.
I don't know if that helps, but I can go on, and Sabeen, maybe you can add to that.
Thank you, Dr. LoRusso. I think you've been pretty comprehensive, so I don't have much to add beyond that.
Thank you.
Thank you. Our next question coming from the line of Yaron Werber with TD Cowen. Your line is now open.
Hi. This is Diana on for Yaron. Congrats on the data, and thanks for taking our question. A couple of quick ones from us. Your unconfirmed overall response rate was really impressive at 6.4% and 9.6% mixed for takeout 64%. Obviously, the confirmed response rate was a little lower. I think the five pending response or unconfirmed responses have been confirmed since your September data cut. To dig a little deeper into the mechanism, obviously, your safety is very, very clean, much cleaner than a lot of the other ADCs in the field. What aspect specifically of your ADC design do you think accounts for this very low rate of kind of grade 3 toxins, especially neutropenia versus other ADCs? Thanks so much.
Sabeen, you want to start with both of those questions?
Sure. I think from our safety profile, this is, again, coming back to the ADC. Also, given the fact that we have very little free payload in the circulation because that's often what's associated with toxicity, and given the fact that our payload is a linker payload system where we have a moderately tight linker with a moderately toxic payload, we're different from a number of our direct competitors who have much more toxic payloads compared to us. I think that's what is driving the safety profile that we're seeing.
They wanted to know about the efficacy of those five patients that had unconfirmed PRs at the time of data cutoff. Can you expound on any of the efficacy that we've been seeing since then?
The efficacy part of the reason that the unconfirmed responses was is those patients did not have enough follow-up at the time of the data cut for confirmation of the responses. All of those patients are ongoing on study treatment. They were all awaiting confirmation when we reported them. Since then, some of those responses have been confirmed. Others are still awaiting confirmation, and all of those patients remain on treatment.
Thank you so much.
I just want to add one thing. I got cut off because I think Zoom froze, so I apologize if Sabeen has said this. Working with ADCs for as long as I have, the linker chemistry is pivotal for efficacy and toxicity. Their linker chemistry is different.
Thank you. One moment for our next question. Our next question is coming from the line of Jonathan Miller with Evercore ISI. Your line is now open.
Hi, guys. Thanks for the great results and congrats on the progress. I would love to ask about time to response. I ask that partially because of the questions we just had about confirmatory scans on patients who have unconfirmed responses. Among the patients who have had responses, how late have you seen patients go before they tripped over into response? Is it possible we could see some of those stable disease patients still on therapy transition over? Is it reasonable to expect that ORR might even go up from here? I have a follow-up after that.
I can speak to that. Yes, it depends. This is a dose escalation. We have started escalating from a pretty low dose of 1.6mg/kg . As we mentioned, we started seeing confirmed responses at 3.2 mg/kg . That's a relatively low dose. In seeing those responses, that did take a little while, more than the first couple of scans to see the confirmed responses. As we've gone up higher on the doses, we've started to see responses much faster, particularly at the higher doses going from 6.4- 9.6. Many of the responses that we've observed have occurred on the first imaging scan.
The other thing you have to keep in mind is not only is it a, do you mind if I add to this, Sabeen?
Sure.
The other thing to keep in mind is not only are we starting low and going high, these are heavily pretreated patients. Many of the ADCs that are currently in development in phase I are limiting the number of prior treatments in the metastatic setting. That is something else to take into consideration where you're seeing patients that have had five priors, six priors, up to nine prior treatments responding. It's, first of all, amazing that they're responding. Secondly, it's not uncommon, at least with other drugs that we see, that if we're going to get a response, it may be later. These responses are actually happening earlier than what we would have anticipated given the heavy pretreatment of this patient population.
Doctor, I did hear you earlier say that patients who had prior Elahere did respond. Can you confirm that both of those patients with prior Elahere did respond? Can you talk a little bit about mechanisms of resistance for folate receptor alpha-based ADCs? Would you expect that antigen loss is a major driver there, or should we expect it to be reasonable to see similar response rates across previously treated patients and patients who haven't been previously exposed?
I'll let Sabeen start. Specifically, Sabeen, with the mirvetuximab patients and what type of a response they had.
Like I said, we had a small population of patients with mirvetuximab, and they have responded in the study population. From what I can see, there's been a fair amount of data that has been public on the expression of folate and how stable it is. From what we reviewed across the literature, folate receptor expression remains stable because a lot of these samples, not just from us, but also from our competitors, they are archival samples which were evaluated at the time their patients were diagnosed. Over time, these folate expression levels have remained stable with other therapies and with the use of folate receptor therapies as well. We expect that the responses in patients who have received the prior mirvetuximab should be similar. I mean, mirvetuximab has a different payload. It's not a topoisomerase I inhibitor payload, it's DM4. We should be expecting a similar level of efficacy.
Overall, our population in this study, as Dr. LaRusso pointed out, is quite heavily pretreated, and we would consider mirvetuximab as one of those previous treatments.
Can I add to that?
Please do.
The other thing you need to take into consideration, first of all, you asked a million-dollar question, mechanism of resistance with ADCs. You know, is it the payload? Is it the target? Some of the quote-unquote "potential resistance" mechanisms could be export of the payload from the cell after it gets internalized. I believe that this payload does not do that nearly as much as some of the other payloads, specifically with things like BCRP and other transporters. I think that is a potential another advantage, not only the chemistry of the linker on both ends, but also the chemistry of the payload.
Makes sense. Maybe one final one for me, if I may. Sorry if I missed you talking about this earlier, but given the safety profile looking very clean, even all the way up to the higher doses, I'm curious, what were the events that drove 11.2 mg to be defined as the maximum tolerated dose?
I'll let Sabeen, yes.
That makes sense. Thank you.
There has been no ILD either, which is really exciting for me as a clinician.
Yes, very important. Yes. Thank you.
Thank you. Our next question coming from the line of Ryan Dercho with JP Morgan. Your line is now open.
Hey, guys. Thanks for taking our questions today. Maybe just first, can you elaborate a little bit more on the one DLT event that you saw, the 6.4 mg/kg? The 11.2 mg/kg, you said that is defined as the maximum tolerated dose. Can you just give us a little bit more color on how or what drove that definition of maximum tolerated dose there? Thank you.
I can start with the 6.4 mg/kg. Do you want to, Sabeen? Sabeen, why don't you take it away?
Okay. The 6.4 mg/kg patient, we had one patient with anemia, and this patient had grade 3 anemia occurring at cycle one, day eight, recovered spontaneously by the time the next dose was due, did not require transfusions. At the earlier version of a lot of the protocols, we do not have grade 3 anemia that does not require intervention as a DLT, but ours did. We wanted to be transparent and call it as a DLT. Following on with your next question on what qualified 11.2 as a maximum tolerated dose, as Dr. LoRusso alluded to earlier in this call, after this data cut that we presented today, we had one dose-limiting toxicity at the 11.2 mg/kg dose, which was a cytopenia.
We could have expanded that cohort further, but given the fact that we are all aware that there's a lot of competition in this area, we're seeing a lot of good efficacy and a safety profile, we wanted to move forward into dose optimization given the balance of safety and efficacy we're seeing. That's why we're moving forward at this dose.
Great. Maybe just a second for Sabeen, following up on your comments related to a combo strategy here. You know, you're seeing Lilly moving forward with a combo with Elahere. Does it make sense to combine ZW191 with Elahere, or do you think that it makes more sense to pick another component in a combo approach?
What I would say is that a number of combination approaches can be tried given the safety and efficacy that we're seeing. Bevacizumab is an easier combination because there are very little overlapping toxicities with bevacizumab. That's certainly one of the options, particularly as we go to earlier lines of treatment in ovarian cancer. The majority of patients do get treated with Bev. However, we're looking at other combinations as well. For example, in earlier lines, patients are treated with platinum combination. That would be another combination that we may be willing to experiment with given our clean safety profile that we're observing at this time. There are a number of options that we're considering in terms of combinations and also going into earlier lines of therapy.
I think a lot would depend upon further data that we see with longer follow-up, more patients, and the fact that as with our company strategy, we are planning to move along with a partnership model. Being in discussions with that would also help clarify the development path.
Great. Thank you.
Thank you. One moment for our next question. Our next question coming from the line of Akash Tewari with Jefferies. Your line is now open.
Hi, this is Sabeen for Akash. I just wanted to ask about the 8 mg/kg dose. Can you tell us what the grade 4 TRAE was? Is that why you didn't take forward this dose into the next step? Additionally, what gives you the strong confidence behind the selected 6.4 and 9.6 mg doses, given that the grade 3 TRAEs don't seem to have a dose response with the relatively small n? Thank you.
That's exactly right. Between 6.4 mg/kg and 9.6 mg/kg, we did not really see a dose response with regards to safety. That's why we believe that our drug has a pretty wide therapeutic index for both efficacy and a safety perspective. Taking that, we wanted to take a wider range in terms of selecting doses for optimization. We thought that 6.4 and 9.6 give us that range to evaluate for the most optimal dose to take to registration studies, both from a safety perspective as well as an efficacy perspective. The 8 mg/kg dose safety seemed as reasonable as the other two doses. It's just that from a clinical pharmacology perspective, there is a larger difference between 6.4 and 9.6. With our optimization, we think that it will give us better clarity of the optimal dose between those two.
Understood. Thank you. Actually, on the grade 4, was there any color on what that one was?
As I said, we did not, we are not sharing patient-level data. It was a cytopenia, and it was a grade 4. That's all I'm going to say.
Okay. Understood. Thank you.
Thank you. Our next question coming from the line of Jonsu with LifeStar Capital. Your line is now open.
Hello. Good afternoon. Congrats on the data. I had a quick one for you. Noticed this, but can you talk about why you're dose optimizing only in ovarian, but then when you continue onward with dose expansion, it looks like you listed endometrial and non-small cell lung cancer, but not ovarian cancer. Thank you.
The reason that's a very simple answer is because dose optimization in ovarian cancer will give us the expansion data in endometrial and non-small cell lung cancer. We thought that since ZW191 is our first antibody-drug conjugate in the clinic, we wanted to move forward in optimization in ovarian cancer because that's where we have the biggest benchmarks with other folate receptor alphas and other antibody-drug conjugates. That's why we wanted to move forward in optimization there. Once we have an optimized dose, we think we can easily apply that to other tumors, such as endometrial and non-small cell lung cancer for expansion.
Understood. Great. I also wanted to ask regarding your thoughts on potential partnerships. To what degree would you want to partner this asset? To what degree would you want to retain some sort of in-house rights rather than or versus fully out-licensing or somewhere in between? Thank you.
For Zymeworks, our recent model for further development, as outlined in our last earnings call, has been the partnership model. We have a number of assets in early clinical development that we would like to focus on. Ultimately, as we develop further, we would like to pass on the development of our assets to partners who can take these assets and advance them much faster and better than we can, particularly for folate ADC. We are very well aware of the competitive landscape in this area and the need to move forward very quickly. Therefore, we think the partnership model would be the best one that can help take us forward further, not only into registration studies, but also in going into earlier lines of treatment and in combination therapies where we can expand and develop much faster and quicker.
In terms of this model, I think we will be looking at the right partnerships with the right companies, and it's going to be fit for purpose for each asset in terms of how best and where we can develop it ourselves, whereas at what point a partnership can take on further from there on.
Thank you very much. Congrats again on the strong data.
Thank you. Our next question coming from the line of Steven Miller with Stifel. Your line is now open.
Hey. This is Josh on for Steve. Congrats on the data, and thank you for taking our question. I'll start with a question for Dr. LoRusso. What assets or mechanisms do you think would make for a good combination partner in these gynecological malignancies? What's the appetite for an ADC with this kind of safety and tolerability profile in the platinum sensitive and maintenance setting? I have a follow-up.
Yeah. Going all the way to the platinum sensitive. First and foremost, I want to be brutally transparent. I'm a Phase I investigator. I routinely do not treat patients with standard of care. I just see them after they failed standard of care. Given the heme profile, first of all, platinum sensitive patients, obviously, you've just pretty much, it would be interesting to see what the combination with platinum would look like. Given the role of PARP inhibition in ovarian cancer, especially in the metastatic setting, some of the PARP-1 selective agents are looking very good, especially in terms of less heme toxicity, some that were presented at ESMO this year. I think that especially in those patients that have DDR alterations, this may be an exciting combination to take forward, this ADC with one of the PARP-1 selective inhibitors, small molecules. I think that that's just looking at ovarian.
There may be opportunities for other tumor types as well. I don't know if that helps. When you're.
Yes, it does.
When you have less with this toxicity profile and some of the other agents that are coming through that treat these tumors in terms of toxicity profile, I'm pretty excited. I mean, like I had said previously, a lot of these other folate receptor alpha-targeted ADCs have significant myelosuppression, GI tox. Some of them have ILD, but also some of these folate receptor alpha inhibitor ADCs that have topoisomerase I inhibitor payloads are also seeing ophthalmologic tox, which I thought was very interesting when I'm looking at their phase I data. This has not manifested any ophthalmologic tox, has not manifested any ILD. The heme profile, I think, is quite acceptable. I think there is opportunity for combination strategies, at least from my perspective, as a result of the toxicity. One question that was posed previously is Bev. Let's just talk about that.
I see a lot of metastatic gynecological malignancy patients, and they've cycled Bev through multiple lines of treatment. That could potentially, although I know somebody asked about that. I do believe that especially if this drug was brought into a much earlier metastatic setting, which I think it has a lot of potential to do so, Bev would not be unrealistic at all as a combination. I think it would be a very, very welcomed combination.
Okay. Great. For Zymeworks, there was some pretty interesting NAPI2b data presented at ESMO for a DAR8 topoisomerase I inhibitor-equipped ADC. I'm just curious how that may impact your perception of ZW220 prioritization, if at all, especially now with your payload being a little more incrementally de-risked and how the overlapping indications with ZW191 might influence any decision to move this candidate into the clinic.
I can speak to that. I think ZW220 was deprioritized from IND earlier this year to make room for ZW251 to move forward because we thought that the antibody for ZW251, GPC3, was something we wanted to move forward more urgently. We still believe in NAPI2b. We've always done so. The other reason we wanted to hold off on ZW220 was the fact that we are already developing our folate receptor alpha ADC, ZW191, in the same tumor types, like in gynecological malignancies and non-small cell lung cancer. However, with this data, we still believe in our NAPI2b as a great target. It has pretty high expression in gynecological malignancies and non-small cell lung cancer. We're also looking at other tumors, such as gastroesophageal and other GI tumors, where we could see expression of NAPI2b and potentially can take forward in those tumors.
We would like to do that with the help of a partner. We're actually evaluating whether we should do it ourselves or, quite likely, with the help of a partner into the clinic. Our interest in NAPI2b remains intact, and we think that this is a great ADC to move forward.
Great. If I may just sneak in one more quick follow-up, I know you talked about the development of potential combination-based strategies. I'm just curious if you could expand a little bit more on your prioritization here and when you think any combination-based trial could potentially initiate.
We're going to take our development step by step. The first thing we want to do is get and justify a monotherapy dose for ZW191 through our dose optimization, and that's what we've unveiled today. We are looking through our combination strategy and strategy for further development overall for ZW191. We're developing it very closely, and we will be ready to share the detailed steps at a future date. However, combination strategy going into earlier lines, these are all opportunities we want to evaluate. We are very well aware of the competitive landscape. We know that we have the ability to differentiate based upon their safety and efficacy profile, and we would like to leverage that as much as possible. Combination will be part of our strategy in terms of differentiation.
Okay. Great. Thank you for taking our questions and congrats again on the data.
Thank you. Our next question coming from the line of Derek Archila with Wells Fargo. Your line is now open.
Hi. This is Yvonne for Derek. Congrats on the data, and thanks for taking our question. A quick one from us. Still early days, but it looks like there's not much response in lung compared to patients with ovarian and endometrial. Do you have any updated thoughts on how you're thinking about development and the opportunity in lung versus gynecological cancers based on this data? Thanks.
As you've mentioned, the majority of our data that we presented today is in gynecological tumors, and that's why the emphasis here is on gynecological tumors. We only enrolled a very small number of patients in non-small cell lung cancer in this trial. As you can see in the baseline characteristics, only four patients, and three out of those four patients are efficacy evaluable. All of these three patients had low negative levels of folate receptor expression.
It's very early to say how the efficacy for this ADC is going to be in non-small cell lung cancer. I think as we develop further, we would likely need to generate more data to determine the efficacy and antitumor activity in non-small cell lung cancer, which, as you can see from our trial design, is part of our development plan.
Thank you. I'm showing up for the questions. No canning here at this time. Ladies and gentlemen, this concludes today's conference call. Thank you all for participating, and you may now.