Hello, and welcome to Zai Lab Investors Webcast. At this time, all participants are on a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask the question during the session, you will need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. I would now like to hand the conference over to Dr. Rafael Amado. Sir, you may begin.
Hi, everyone, and thank you so much for joining us today. I am Rafael Amado, Zai Lab's President and Head of Global R&D. Before we begin, we will be making forward-looking statements today, and I ask you to review slide two for further details. Moving to slide three, during today's call, we will be discussing the monotherapy phase I dose-escalation clinical data of ZL-1310, our investigational DLL3-targeted ADC. These data were presented earlier today during a plenary session by Dr. Alex Spira at the EORTC-NCI-AACR Symposium (ENA) here in Barcelona. Dr. Spira is one of the lead researchers for this trial. He's here with us now to present the data. Dr. Spira is the Director of our Clinical Research and CEO at NEXT Virginia, Co-director of the Virginia Cancer Specialists Research Institute, and a Clinical Assistant Professor at Johns Hopkins.
He's widely recognized and awarded for his distinguished career treating patients and advancing innovative research. Following Dr. Spira's presentation, I will discuss next steps for the program, and then we'll take questions. I will now pass it on to Dr. Spira.
Hello, my name is Dr. Alex Spira, and I'm a medical oncologist in NEXT Oncology in Fairfax, Virginia. On behalf of my co-authors, I'm pleased to present the preliminary results from ZL-1310-001, an ongoing phase Ia/1b open-label, multicenter study evaluating ZL-1310, a DLL3-targeted ADC in patients with recurrent small cell lung cancer. Here are my disclosures. Lung cancer, as most of you know, is the number one cause of cancer deaths around the world. Small cell lung cancer represents approximately 15% of all lung cancer cases, affecting around 372,000 patients worldwide, including over 100,000 patients in the U.S. and Europe. Two-thirds of patients are diagnosed with extensive stage disease, and approximately 50% of patients will develop brain metastases.
The prognosis for patients with small cell lung cancer is particularly grim, with outcomes that are often devastating. The mortality rate is high, with a five-year survival rate of just 5%-10%, highlighting the critical need for treatments against this aggressive, fast-growing neoplasm. The typical patient journey begins with frontline treatment consisting of platinum etoposide therapy, plus an anti-PD-L1, followed by maintenance with PD-L1 inhibitors. While this treatment has shown a high response rate of approximately 60%-70%, there is considerable toxicity, with over 70% of patients experiencing grade three or higher treatment emergent adverse events. Moreover, the duration of response is relatively short, lasting only about 4-5 months, owing to the fast replicative potential of this tumor, leading to 12-13 months of survival. Treatment options are limited when patients progress.
Topotecan or other chemotherapies can be used but provide limited benefit with high morbidity. Recently, however, there has been progress in the recurrent setting with the accelerated approval of Imdelltra, also known as tarlatamab, earlier this year. With tarlatamab, we observed an increase in efficacy with a response rate of 40% and up to nine months duration of response. Although an important and promising treatment advance, serious adverse events occur at a rate of 58% with this bispecific drug. Other challenges with tarlatamab include need for dose titration and management of CRS and ICANS, which can further limit its usage. Thus, despite recent improvement versus the prior standard of care in the treatment of extensive-stage small cell lung cancer, there is substantial opportunity to improve outcomes across all treatment settings, whether that is on an efficacy, safety, and availability.
DLL3, or delta-like ligand three, is known to be a driver of neuroendocrine tumors. It is aberrantly expressed in over 85% of small cell lung cancers and is a validated target for these tumors. It is also minimally expressed in healthy tissue. As you can see in the left figure, ZL-1310 is a novel ADC developed using the proprietary TMALIN platform. It comprises a humanized anti-DLL3 antibody, a protease cleavable linker, and a camptothecin derivative payload termed C-24. This novel linker payload was designed to avoid common intracellular resistance mechanisms to other topoisomerase I inhibitors. With a high specificity for DLL3 and a drug antibody ratio of eight, ZL-1310 has shown significant anticancer activity in preclinical cellular assays and PDX models. Today, I'm happy to report the preliminary findings of ZL-1310 in patients with recurrent small cell lung cancer.
This is an ongoing phase I, first-in-human dose escalation and expansion study of ZL-1310 in patients with extensive-stage small cell lung cancer, following a platinum-containing regimen initiated in January in the United States and China. Patients with asymptomatic brain metastases, both treated and untreated, as well as patients with prior DLL3-targeted therapy, were allowed. The primary endpoints are safety-related, and secondary endpoints will assess clinical activity as well as pharmacokinetics. This study has progressed through four dose levels, from 0.8 mg/kg to 2.4 mg/kg, and is currently enrolling at a dose of 2.8 mg/kg. As of the data cutoff date of October 10, 2024, 25 patients have been dosed who are evaluable for safety. Nineteen of these patients have had at least one post-treatment tumor evaluation and are evaluable for efficacy.
After the dose escalation is completed, we will optimize the dose by evaluating the totality of safety and efficacy data from two doses in a randomized fashion. The baseline demographic data on the slide highlight that all patients had progressed following standard platinum-based chemotherapy regimens, and 56% of patients have failed at least two prior lines of therapy. 92% of patients progressed after immune checkpoint inhibitors, and one patient progressed after Imdelltra. 28% of patients had brain metastases listed as either target or non-target lesions at study entry, including two patients who entered the study with asymptomatic, untreated CNS disease. Pharmacokinetic analysis of ZL-1310 demonstrates that the systemic exposure of the ADC and the total antibody were approximately equal and dose proportional, as shown in the top part of the graph, while demonstrating relatively low levels of circulating naked payload seen in green below.
The observed half-life of six to seven days supports the current every three-week dosing regimen. Overall, ZL-1310 is very well tolerated, with only 40% of patients experiencing a grade three or higher treatment-emergent adverse event, regardless of causality, and only 20% of patients have a treatment-emergent adverse event being related to ZL-1310 by the investigator. One transient DLT of neutropenia and thrombocytopenia occurred in a patient treated at the 2.4 mg per kilogram dose level. Dose interruptions were uncommon at 20%, with dose reductions required for only 12%. The adverse events associated with dose reductions were mostly hematologic or gastrointestinal in nature, as might be expected. Furthermore, there have been no adverse events leading to study drug discontinuations. The most common treatment-emergent adverse events, regardless of causality, included nausea, hematological toxicity, and decreased appetite.
Hematologic toxicities were responsible for the majority of grade 3 or greater toxicities, appeared to be dose-dependent, and the majority were still grade 1 or 2. It is important to note that no grade 3 hematologic toxicity was observed at the 1.6 milligram per kilogram dose, and only 30% neutropenia was observed at 2.4 milligrams per kilogram, suggesting that ZL-1310 may have a therapeutic window amenable to combining with other agents. This waterfall plot shows the change in the sum of target lesions for the 19 patients who had at least one post-treatment tumor assessment. Objective response rate per RECIST 1.1 is 74%, with 5 confirmed and 9 unconfirmed responders, with responses observed at all dose levels tested, including 0.8 milligrams per kilogram.
Importantly, responses were rapid, typically observed by the first tumor assessment, which is between six to nine weeks. One patient showed significant tumor reduction as early as three weeks after a single dose of ZL-1310. As small cell lung cancer usually progresses quickly, the rapid responses to ZL-1310 may be beneficial for patients with aggressive disease, especially those patients with intracranial lesions. In addition, the six response evaluable patients enrolled with brain metastases achieved an objective response, including the two with previously untreated asymptomatic CNS disease. Although the data are still early, with a median follow-up of only 2.4 months, 13 of 14 responders remain on study, with one patient on at 6.5 months. I would like to draw your attention to the one patient who does not seem to have any benefit.
This patient, interestingly, had no detectable DLL3 by IHC, with an H-score of zero. Only one patient with a confirmed response has progressed, presenting with a new lesion. The other patients who have stopped treatment also progressed with new lesions. We look forward to the continuing maturity of these data. Here's the swimmer plot. 20 of 25, or 80% of patients, continue on study. One patient continues after a dose escalation from 0.8 to 1.6 mgs per kilogram. Three other patients have required dose reductions, as previously noted. Overall, 13 or 14 responders continue on treatment, with the longest at 6.5 months. Preliminary evaluation of DLL3 expression is available from 16 adequate pre-treatment biopsies stained by IHC for DLL3.
These biopsies demonstrate a range of H-scores from zero in one patient up to 260, with a median of 92.5. It is impressive that objective responses were observed with an H-score as low as five and clinical tumor reduction as low as two. Clinical activity has been seen with other next-generation antibody drug conjugates in tumors, in patients whose tumors express low levels of target. The mechanism of action may reflect the avidity of the ADC or the putative bystander effect of the linker payload. Interestingly, the only patient who did not have a clinical benefit had an H-score of zero. Further analysis on the correlation between expression and response will continue as the study matures. We would like to highlight two patients in the trial.
The first is a patient of mine who developed progressive disease in 2023 after focal consolidation, lung irradiation, and a standard triple therapy who presented with a new brain lesion seen here. He is one of the two patients included in the data cut who had asymptomatic, untreated CNS disease at baseline. Thus, the brain lesion was included as target lesion and measured over time. After two doses of ZL-1310, the patient achieved a PR, partial response, at the first scan, with a 45% target lesion reduction, including almost complete resolution of the intracranial lesion without any CNS-directed therapy. As previously mentioned, while most CNS lesions were entered as non-target lesions and not measured due to prior radiation, all six response evaluable patients with brain metastases at study entry achieved partial response.
This activity is clinically significant, given that over 50% of small cell lung cancer patients develop intracranial lesions, which is a source of significant morbidity. This slide highlights a patient with prior Imdelltra failure. This patient is a 66-year-old woman with a recurrent, extensive stage small cell lung cancer, with lesions in the lung, liver, and peritoneum. She responded initially to frontline therapy, but required consolidation and radiation to the lung. Upon recurrence, she received tarlatamab, to which only one liver lesion decreased in size, but she unfortunately progressed in all other lesions. She then received an Aurora kinase inhibitor on a clinical study, but also progressed after two months. A tumor biopsy obtained after the tarlatamab failure was tested for DLL3 and showed an H-score of 170, as seen here on the left.
She was subsequently enrolled and received ZL-1310 at 2.4 milligrams per kilogram. Her first tumor assessment showed a decrease in all of her target lesions, resulting in a 67% overall reduction, and she continues on study. In conclusion, we are very excited by the preliminary clinical activity of ZL-1310 in patients with recurrent small cell lung cancer. ZL-1310 has a good safety profile at all therapeutic dose levels. ZL-1310 shows a robust 74% objective response rate across all dose levels treated to date, including dose level 1 and 0.8 milligrams per kilogram in patients with brain metastases, and anecdotally, in a patient with previous tarlatamab therapy, suggesting that DLL3 target loss may not be a mechanism of resistance across modalities. These data support continued development in both recurrent and earlier lines of small cell lung cancer as monotherapy and combination with other agents.
Thank you very much, and with that, I will pass the call back to Rafael.
Thank you, Dr. Spira. We have a great opportunity to significantly improve outcomes of patients with small cell lung cancer, and we will work to rapidly accelerate ZL-1310 in relapsed refractory small cell lung cancer. We are in the latter part of dose escalation and currently enrolling at 2.8 milligrams per kilogram dose level. We will then be in a position to bring forward two doses into dose optimization to find a dose level ready for a pivotal study evaluating ZL-1310 as a monotherapy treatment in second-line plus small cell lung cancer. While it is premature to assess the durability of response, the response rate is the highest observed to date in second line and beyond in small cell lung cancer, and among the highest with an ADC in any disease.
Owing to the length of follow-up, we are unable to estimate the median duration of response, but two individual patients continue to respond past six months. We plan to share further updates over the course of next year. In addition, we will move quickly into the frontline setting as well. We're evaluating ZL-1310 added to atezolizumab, and we will continue with combination of atezo plus chemotherapy in the same phase I study. We're hopeful that ADCs like ZL-1310 will play an important role prolonging survival in frontline small cell lung cancer, replacing one or both chemotherapeutic agents in the current IO plus chemo triplet standard of care, just like Nectin-4 targeted ADC plus pembrolizumab in frontline bladder cancer, and we're excited about the possibility of combining ZL-1310 with other treatment modalities.
Good tolerability and combinability of such new treatments in frontline patients will be very important, especially if added on to IO maintenance. While our data is still preliminary, the safety profile of ZL-1310 appears to afford prolonged therapy. DLL3 is also highly expressed in other neuroendocrine tumors, and we will explore other potential indications for ZL-1310. Lastly, I would like to end with a snapshot of our global pipeline that is in development. This year, we have added four new programs to our global portfolio. In oncology, this includes our ROR1 ADC in solid tumors, which we're licensing preclinical stage. We also have two new preclinical assets yet to be disclosed. One is an ADC in solid tumors, and the other is a next-generation technology in DNA damage repair pathway.
In autoimmune disease, we disclosed some presented preclinical data for our internally discovered IL-13/IL-31 bispecific earlier this year, which we are aiming to develop in atopic dermatitis and other inflammatory and pruritic conditions. We also have several other undisclosed IND-enabling assets in development, with the goal of generating at least one IND per year, and we are well on our way to achieving that goal. I look forward to providing you with more updates on our global pipeline over the next year.
With that, we will now be entering the Q&A portion of the call. As a reminder to ask the question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster. Our first question comes from the line of Yigal Nochomovitz, Citi. Your line is open.
Hi, guys, this is Ashiq Mubarack on Yigal. Thanks for taking my question, and congrats on this interesting looking data. I'm just curious how you would characterize the dose response at this point, and I'm curious how you're thinking about, you know, the go-forward doses you'll take into expansion. Also, I'm also wondering if you're thinking about introducing a biomarker approach, although that seems that might be a little unnecessary, but curious how you're thinking about next steps and expansion at this stage?
I guess I can take that as Alex. So a couple of things. So, I mean, the N is still relatively low, as you all can see, so with, you know, small numbers per patients per cohort. So,
... You know, in terms of dose response and the go-forward dose, I think we still have a lot of learning to do. You know, getting through that last cohort where we are and then expanding it cohorts to see which one is the optimal dose. I mean, given the fact that you've seen the responses at the lowest dose level, I think tells us that we wanna see what the durability of some of these responses are before a dose is finalized. Obviously, going forward to obviously abrogate any toxicity. Did I get your question in? You asked me something else as well, and I apologize, I don't remember.
Yeah, yeah, it was related to the biomarker. It seems like it's may not be necessarily giving the same responses at low expression levels, but-
So if you look right now, there's, you know, we're seeing responses across the board, number one. If you look at the history of DLL3 as a biomarker as well, there hasn't been a really any clear biomarker that works. I'm sorry. DLL3 has not been a biomarker in the previous iterations of ADCs or even in tarlatamab, as far as we can tell. So I don't think it'll be helpful to do that. Obviously, we're gonna get more biopsies and more data there, but it seems to me that right now there's a good agnostic approach regardless of the biomarker, which is actually helpful for small cell lung cancer patients. Clinically, they're often very hard to get biopsies on, number one, and getting repeat biopsies would be inordinately challenging because of the rapidity of the growth of their disease.
Got it. And if I could just sneak in one more on safety. I think we've seen hematologic talks and neutropenia and related AEs with other topoisomerase ADC payloads. I'm just curious how you might compare and contrast the safety profile with other similar ADCs. And to the neutropenia point, I'm just wondering if Pegfilgrastim was part of any prophylactic regimen, or if it was all treated as it happened? Thanks.
So PEG was not used prophylactically in any of these patients. You know, getting back to your other question right now, you know, the, we had the one DLT at the 2.4 dose level, but other patients were able to be treated. Obviously, we're going on and gonna see where we get with the doses there. I think the, you know, the real question is, is there gonna be more neutropenia in new doses or not? You know, you asked, and again, I'm, you know, without having without implementing too much bias, I will say this is less neutropenia than I think than we've seen with some of the other ADCs out there. So I think it's certainly on the more benign side of all the other ADCs.
Got it. Thanks very much, and congrats again.
Thank you. Please stand by for our next question. As a reminder, ladies and gentlemen, please limit yourself to two questions. Our next question comes from the line of Anupam Rama with J.P. Morgan. Your line is open.
Hi, guys. This is Priyanka on for Anupam. Congrats on the data. Just have a question for the KOL, Dr. Spira, on the line. How do you think about the safety profile and the dose escalation relative to the competitive landscape? And for the company, how do you think about moving in combinations given the safety profile observed thus far?
Yeah. So, you know, the competitive landscape, and I think there's two different landscapes. One is compared to tarlatamab, and certainly this is easier than tarlatamab. I mean, if you look, you know, tarlatamab is a good drug, we cannot deny that, but it has the inpatient requirements, which are still mandated, and that's really limited because of the CRS and the ICANS in terms of how well it can be administered in real world situations. Remember, the patients that ended up on the earlier study were all selected because they could travel to these places, so they could do it. But real world small cell lung cancer patients are older, sicker, extensive tobacco use, commonly making it a little bit more challenging. In terms of combinability, I think we certainly have an opportunity to combine given the toxicity profile.
The phase I combo with the checkpoint inhibitor is ongoing, so I think there's certainly a window there to combine it, or even with chemotherapy, as well in the future. I think I got your questions. If I... I know we're limiting it to two, but if I missed one, just let me know.
No, those are both my questions. Thank you so much for taking them.
Thank you. Please stand by for our next question. Our next question comes from the line of Michael Yee with Jefferies. Your line is open.
Hey, guys. Thanks for taking our questions. Congrats on the data. This is Kyle Yang for Michael Yee. So really quick on the dose expansion studies, I guess how many patients are you planning to enroll? And looking further beyond, what does the regulatory pathway look like? Have you sat down with the FDA? Do you think you're gonna be able to file with the accelerated approval pathway? Thanks.
I'll defer to my colleague. Rafael? Rafael?
Rafael, check to see if you're on mute.
So I'll come, and Rafael, if you wanna come in my room, I'm actually have good audio here, but it looks like we're planning on 50 patients. Oh, there you are, Rafael. Okay.
Oh, okay. Thank you. I apologize for that. I was having difficulties with the audio.
... So, as you've seen, we are in the dose escalation period now. We have moved to 2.8 milligrams per kilogram, and we actually filled that cohort already. We will analyze the data both in terms of safety and efficacy, and allow enough durability to see whether there's a, you know, dose proportional effect with regards to durability. Very quickly after that, we will do a dose optimization, which, as you know, is often asked by FDA and their Project Optimus, and select a dose, and continue expanding the selected dose in conjunction with FDA discussions.
Once we have enough durability and we think that we know what doses we're going to test, we will try to apply for designations for breakthrough and orphan drug status, and then come up with an agreement with FDA with regards to whether there's a pathway for accelerated approval. As you know, Imdelltra has accelerated approval only, even though they, they're obviously are doing their confirmatory trial. So there's still a window in two plus line, which would be our first indication. And you know, FDA has also, you know, shown some leeway to products that are well differentiated, that have different mechanism of action, that are relatively non-toxic, that are, you know, highly active, and especially if there's durability.
And in this case, you know, we've seen or you know factors like activity in low expression tumors, as well as rapid responses, as Dr. Spira said before, potential for combinability, et cetera. So our plan is to move as quickly as possible next year to do dose expansion and engage with FDA on a regulatory pathway that we hope could be through accelerated approval in second-line therapy.
Thanks. If I may, just a quick follow-up. What's sort of the breakdown between China and U.S. patients, and have you seen a difference between the two populations in terms of responses? Thanks.
Yeah, that's we've looked at that. There's, I think just a couple of differences in the number of patients, so it's very close. And the response rates are also very close, in the high sixties in the U.S. and, you know, in the higher seventies. But, you know, one patient up or down in either one of the regions would just change that. So just the numbers are too low to see to really you know make a conclusion that there's any difference in terms of outcomes with regards to China versus the U.S.
Got it. Thanks so much.
Thank you. Please stand by for our next question. Our next question comes from the line of Louise Chen with Cantor. Your line is open.
Hi, thanks for taking my questions, and congratulations on the great data. So I have two questions. First one I wanted to ask you is, what do you think about the regulatory path for ZL-1310, and can you get accelerated approval? Second question was, I wanted to ask you that there are a lot of different treatments under development for SCLC, and how do you think about ZL-1310 in comparison to those others in development? What are your thoughts on how the landscape is gonna evolve for both first line and second line? Thank you.
Thanks for the question. I'll make some comments and then pass it on to Dr. Spira, particularly for the second part of your question. So as I said before, we think we're approaching the doses that we're going to select for randomization, and hopefully, we will be able to get a randomized phase II dose within the same study that we can expand to, you know, a sizable number of patients. And, you know, the development path, for instance, of Imdelltra, which is approved under accelerated approval based on response and durability in a single arm trial. So, again, as you know, regulatory-wise, that doesn't constitute an impediment for another drug to receive accelerated approval.
So we plan to move fast in this space. We have also the advantage that at least anecdotally, it appears that DLL3 remains expressed. So we could enroll patients that have received DLL3 directed therapy, and we don't have any reason to think that B7-H3 should be cross-resistant. So we're not putting any restrictions there, and we've seen every patient that we've treated with brain metastases respond as well. So we think that the patient population is actually quite broad, and if we continue to see very high levels of response rate with enough durability, you know, around six months or thereabout, then I think we could potentially get designation and accelerated approval.
So, we are opening the study in Europe very soon. That's where we will, together with China and the US, conduct, you know, what I just mentioned to you. In terms of how the field will evolve, I mean, all I will say is that this is a disease with dismal prognosis, and I'm glad that there are more and more agents that are active. It appears that many of these agents may not be across the system, so it may afford patients the opportunity to receive sequential therapies or combination therapies.
In our case, we are very hopeful that we can combine it, given the, that the toxicity, the tolerability has been good and the toxicity, you know, has, even though it's preliminary, looks, favorable, compared with, the agents that are out there. But how eventually the treatment of small cell lung cancer, will look like, I think remains to be seen. The last thing I would just say is that, you know, FDA has encouraged sponsors to move products to earlier line of therapy early, in the development. And, we're doing just that, with, the combination with PD-1 and, and, potentially being able to at least pair one of the chemotherapeutic agents, that is, just, you know, the, the normal, regimen that is, currently given, to patients in frontline.
You know, in terms of how this will shape up, perhaps Dr. Spira, you can make some comments in terms of, you know, what you see in the future.
Yeah. Thanks, Rafael. I wish I could tell you exactly what's gonna be in the future. That being said, you know, there's clearly still an opportunity with none of the drugs that have been shown to be efficacious, I-DXd as an example, or some of the other B7-H3 compounds, still ways away from where we're from approval. None of them have clearly moved into the frontline setting either, which is a huge opportunity. You know, talking about Tarlatamab, but Tarla's, as I mentioned before, is an interesting drug. Clearly, it's got everybody reinvigorated about small cell, but the logistical administration of it is still very challenging with real toxicity. And it has still not made it out to the broad community with access issues.
I certainly think that it, you know, there's still plenty of room for other drugs, including DLL drugs, despite that as well. I will tell you, in my practice, which is largely community-based, we have no tarlatamab site within a hundred miles, and that's right outside of Washington, D.C. While it's available on other sites, I think everybody will be very excited about moving to a drug that does not have all the CRS, ICANS, as I mentioned before, but more importantly, doesn't require an inpatient admission, which is incredibly challenging and incredibly expensive. Thank you.
Thank you. Please stand by for our next question. Our next question comes from the line of Zhiyi Qin with Goldman Sachs. Your line is open.
Great. Thank you. Thank you for taking my question. I just got one question. I'm kind of curious about the technology itself applied to the ADC you have. Because the TMALIN technology, for, you know, based on what we understand, is that can enable very strong bystander effect through the linker cleavage and a payload release in the, in the tumor microenvironment. So is that the reason, you see the stronger response, of the DLL3, your DLL3 ADC, versus other treatment, other DLL3, peers? And also, based on your understanding, any synergy of this technology with DLL3 targets? And also, we try to understand a bit more on DLL3 expression, you know, heterogeneity among the, small cell lung cancer patients. Thank you.
Yeah, I'll make some comments on your first point, because it's very critical, and perhaps Dr. Spira can comment on what has been seen with other ADCs, like Enhertu, for instance, with regards to, you know, how many- you know, how much expression is required. You know, we were very gratified to see that, even with an H-score of five, we have seen a partial response. This has to do probably with two points. One is the ability of the antibody and its penetration into the tumor. But also, as you mentioned, this is designed for the payload to be able to efflux the cell and have a strong bystander effect in cells that do not express the target. And that may be sufficient to actually resulting in a partial response.
This is, I think, a critical difference between the older generations of ADCs and the newer generations, in addition to, you know, modifications that have been made to try to minimize, toxicity and circulation of the payload. But, I would say that, you know, with other ADCs, you know, similar phenomena have been seen. And, you know, whether this is really the real mechanism of action, we believe it is, because patients that don't express, at least one patient have not responded, and a patient that expresses, you know, with an H-score of 2, and remember, that goes from 0 to 300, you know, had stable disease.
It's actually really gratifying to see that, you know, low levels of expression can result in clinical benefit. So, but, perhaps, Dr. Spira, you can comment on, you know, the similarities that perhaps that same thing with, with, in the breast cancer field with ADC.
Yeah, I mean, I have very little to add to what you said, but I agree completely with that sentiment. So I think there are some similarities there, obviously, as well. I'll defer to you on the TMALIN technology, but I do think it's exactly as you said, and similar in that aspect.
Great. Thank you.
Thank you. Please stand by for our next question. Our next question comes from the line of Jonathan Chang with Leerink Partners. Your line is open.
Hi, guys. Thanks for taking the questions. First question, can you discuss the reasons for confidence in confirming the unconfirmed responses and in achieving a durable responses with longer follow-up? And then second question, can you provide some thoughts on the activity that you're seeing in patients with brain mets? Thank you.
Yeah, I mean, obviously, we're waiting to get those confirmed scans. We don't have it until we get those. But obviously, the first five have had confirmed PR scans, and we hope that all of them do. Obviously, we're still headed in the right direction there. You know, the brain met thing is interesting. I think we just underestimate the fact that, you know, this so-called, quote, "blood-brain barrier" doesn't really exist as much as we thought, number one, and we've had multiple episodes lately of other ADCs with CNS penetration. If you follow the non-small cell lung cancer world, pertuzumab penetrates, nipotumab penetrates. There's even data that amivantamab has penetration as well.
And I think in small cell, and if you look at the slide, that's my patient with small cell and the brain metastases, you know. You imagine the blood-brain barrier doesn't exist anymore with a lesion that big. So I think there's a couple of factors there, and I think it just causes us to rethink how we think about CNS penetration of drugs, most importantly.
Understood. Thank you.
Thank you. Please stand by for our next question. Our last question comes from the line of Jack Lin with Morgan Stanley. Your line is open.
Hi, thank you for taking my question, and congratulations on the data. I have two questions and one kind of basically following up with the previous question asked. One is, I think you've made it fairly clear in terms of the monotherapy regulatory path. Just curious on your expectations on the combination, as well as other label indications. You know, what is. Because I think given the expression patterns with DLL3s, I mean, is there any other opportunities for accelerated paths or other label expansion studies? So that's the first one. The second one is, I think also alluding to the earlier questions and answer, that in terms of combination therapy, right, I understand we're looking for first line in combination with PD-L1 agent and the chemotherapy.
And I think there are other players in the field that are also doing the combination with the DLL3 bispecific, with B7-H3 ADC. Just curious on your thought in terms of the two different kind of combination and the potential roles, or what the success rates and where the roles might be in terms of the overall small cell lung cancer treatment. Thank you.
Yeah, thanks for the question. Maybe I'll take the first question, and Dr. Spira can take perhaps the next one. You're correct. I mean, the DLL3 is expressed in other tumor types, and we are actually planning to explore those indications as well, and they are neuroendocrine tumors, neuroendocrine carcinoma, you know, both well- and poorly-differentiated NETs, which happen in the GI tract, but also in the prostate, bladder, you know, there's an entity called Merkel cell as well, and so overall, if one you know takes all these tumors, it's actually quite a sizable number. You know, over 170,000 every year.
Obviously, you know, not all of them are going to be metastatic or perhaps require systemic therapy, but many of them do, and there isn't really a lot of effective therapy there. And other agents have failed in this space, so this is something that we're very keen to really explore and see whether there is activity. We're gonna do this in the form of a basket trial to really try to understand whether there are differences among the different pathologies and pursue those that you know really have the potential to derive benefit from this treatment. So you know, our plan is actually quite comprehensive for this product.
Obviously, we want, you know, the approval to be as quickly as possible in second plus line. We have plans for front line, but we're also looking at these other underserved entities that could potentially benefit from DLL3-directed therapy.
And I'm just gonna ask you to repeat the second question. Sorry.
Yeah, of course. The second question kind of follows, I think, one of the question asked earlier, just basically in terms of comparing with what's being explored out there, right? And I see that our plan for a combination is going to first line in combination with PD-L1 and a chemotherapy agent. And I understand that I think there's a couple collaboration going on between DLL3 bispecific and B7-H3 ADC, I mean, I think between MediLink and Amgen and Merck and Daiichi Sankyo. So just curious in terms of your thoughts, in terms of how likelihood of success for those combination, given I think you mentioned safety profiles and success rate. And i-
Sure.
Given if those combination can succeed, like, where do you think that positions against, like, the combination that we're going for?
So a couple thoughts. One is, and obviously it's early on, but I think these response rates are certainly superior to what we've seen with the other drugs, B7-H3 in particular. So we are clearly at a much higher level. Whether or not, obviously, we hope that continues to be the case, but there's still a lot of room, number one. Number two is, you know, given where we are right now, I still think there's a huge opportunity. One is there's still, you know, none of those are so far down the path that it will affect regulatory approval, which is obviously different if you have to do a definitive study there.
So you know, there's still clearly an opportunity there for multiple paths if both you know, if both options are good for patients, as I said right now. So I'm not concerned about a regulatory path to approval, assuming we get that far in either situation. I will say, you know, just getting back to, and again, I am an investigator, obviously, I gave the talk today, so you could easily accuse me of bias. But the toxicity profile for this drug is really benign so far. And if you compare it to, you know, Daiichi's B7-H3, you know, that does have real toxicity, as well. So I think there's an advantage of that here. Obviously, it needs to be borne out clearly with more patients over time, but I'm, you know, a very enthused with those caveats.
Thanks.
Operator, are there any more questions?
Thank you. There are no more questions in the queue. I would now like to pass the call back to Dr. Rafael Amado.
Thank you, operator, and thanks everyone for joining the call today. I would like to thank Dr. Spira for his presentation. I'm personally very excited about the advancements that we're making across our global portfolio, and I look forward to sharing more updates of this data set in the near future. So with that, thanks everyone, and have a great day.
Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.