ADC Therapeutics SA (ADCT) Earnings Call Transcript & Summary

Good morning, ladies and gentlemen, and welcome to ADC Therapeutics December Corporate Update Conference Call. [Operator Instructions] I will now turn the call over to Marcy Graham, Investor Relations Officer for ADCT. Marcy, please go ahead.

Thank you, operator. This morning, we issued a press release announcing initial data from the LOTIS-7 Phase Ib clinical trial evaluating ZYNLONTA in combination with glofitamab in patients with relapsed/refractory diffuse large B-cell lymphoma. This release and the slides we will use in today's presentation are available on the Investors section of the ADC Therapeutics website. I'm joined on today's call by our Chief Executive Officer, Ameet Mallik, who will provide an overview of the ZYNLONTA strategy in LOTIS-7, followed by our Chief Medical Officer, Mohamed Zaki, who will review details of the initial LOTIS-7 Phase Ib safety and efficacy results. We will then open the call to questions. Before we begin, I would like to remind listeners that some of the statements made during this conference call will contain forward-looking statements within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These forward-looking statements are subject to certain known and unknown risks and uncertainties and actual results, performance and achievements could differ materially. They are identified and described in the accompanying slide presentation and in the company's filings with the SEC, including Form 10-K, 10-Q and 8-K. ADC Therapeutics is providing this information as of today's date and does not undertake any obligation to update any forward-looking statements contained in this conference call as a result of new information, future events or circumstances, except as required by law. The company cautions investors not to place undue reliance on these forward-looking statements. I will now turn the call over to our CEO, Ameet Mallik. Ameet?

Thank you, Marcy. Welcome, everyone, and thank you for joining us for today's update on LOTIS-7, our Phase Ib open-label trial evaluating the safety and efficacy of ZYNLONTA in combination with the bispecific antibody, glofitamab in patients with relapsed or refractory diffuse large B-cell lymphoma. We will begin our discussion today with an overview of the ZYNLONTA strategy as well as an overview of our LOTIS-7 trial. Mohamed will then take us through a more detailed review of these initial results. I will close with how this translates into the overall growth potential for ZYNLONTA. ZYNLONTA is currently approved in third-line plus DLBCL with multiple opportunities to expand usage in earlier lines of therapy for patients with DLBCL and indolent lymphomas, all of which are classified as B-cell non-Hodgkin lymphomas. In this trial, we are studying the combination of 2 potent FDA-approved single-agent drugs in DLBCL, ZYNLONTA and glofitamab. Promising initial efficacy data has shown best overall response rate of 94% and a complete response rate of 72%, combined with a manageable safety profile with no DLTs, opening up the potential to be a best-in-class combination for second-line plus DLBCL and one with potential accessibility across care settings. As a single-agent therapy in third-line plus DLBCL, ZYNLONTA has a profile of rapid, deep and durable efficacy as well as manageable safety with simple and convenient administration. We are focused on executing on our strategy to expand ZYNLONTA's usage into earlier lines of DLBCL therapy in combination and into indolent lymphomas. Our ongoing Phase III LOTIS-5 study in second-line plus DLBCL patients is a confirmatory trial of ZYNLONTA in combination with rituximab, a treatment community physicians are comfortable using and one that is considered a backbone of DLBCL therapy. Not only does this combination offer the potential of competitive efficacy and a favorable safety profile, but it also is a nonsystemic chemo regimen that avoids the irreversible toxicities associated with chemotherapy, a class that is still widely used in second-line plus DLBCL. Our LOTIS-7 trial is a Phase Ib study in patients with relapsed or refractory B-cell non-Hodgkin lymphoma and is the focus of today's discussion. Today, we will review initial results from 29 patients treated and evaluated for safety, 18 of which were evaluable for efficacy. Initial results demonstrate promising efficacy data with a 94% best overall response rate and a 72% complete response rate with a manageable safety profile, including no high-grade CRS or ICANS. ZYNLONTA is also being evaluated outside of DLBCL with compelling data from Phase II IIT studies in both follicular lymphoma and marginal zone lymphoma just presented recently at ASH. As reported in relapsed or refractory high-risk follicular lymphoma, the combination of ZYNLONTA with rituximab demonstrated a 97% best overall response rate and a best CR rate of 77% in the 35 patients evaluated. In relapsed or refractory marginal zone lymphoma, ZYNLONTA monotherapy demonstrated a 91% overall response rate and 70% complete response rate in the 23 patients evaluated. We believe these results demonstrate clear value for patients in these indolent lymphomas, and we plan to engage with NCCN and regulatory authorities to discuss the path forward once more mature data is available. The DLBCL treatment landscape is evolving. We expect that bispecific antibody-based therapies as well as ZYNLONTA in combination with rituximab will move to the second-line setting by 2026, if approved by the FDA. We also see polatuzumab usage continuing to increase in the frontline setting, but subsequent use is less likely. Though the efficacy is promising, CAR-T use remains limited due to accessibility barriers and use of chemotherapy persists despite limited durability and some irreversible toxicities. As physicians make treatment decisions based on efficacy, safety and accessibility in the context of individual patient considerations, ZYNLONTA delivers on all 3, which we believe positions it well for use in combination in second-line plus DLBCL in the future. Beyond the frontline setting, when you look at each class from an efficacy, safety and accessibility standpoint, clear differences emerge. In this space, CAR-T has the highest efficacy, but it comes with high rates of CRS and ICANS and can only be administered in specialized centers. As a result, only about 20% of patients get a CAR-T and that number has essentially stayed flat. That means the other 80% of patients are left seeking other therapies. Chemotherapy, with which most physicians have extensive experience still plays a prominent role in the treatment paradigm, but with low durability and some irreversible toxicities. It is expected to decline in favor of novel systemic chemo-free regimens. What is expected to grow over the next year are bispecific-based therapies. They have shown high rates of efficacy, but still have high-grade CRS and ICANS in some cases. Current combinations with bispecifics generally include chemotherapy, which can have irreversible toxicities or polatuzumab, which is being embedded as a frontline therapy, making it less likely for retreatment. At the same time, ADCs and other antibody-based therapies, including ZYNLONTA, typically have safety profiles allowing use across care settings and increasingly competitive efficacy profiles are expected with novel combinations. Based on the evolution in this space, we believe the 2 segments we are targeting with LOTIS-7 and LOTIS-5 in bispecifics and ADC combinations have the potential to grow at the expense of cellular therapy and chemotherapy. We believe novel combination therapies that offer the promise of efficacy approaching CAR-T levels with a manageable safety profile and accessibility across care settings will have the potential to disrupt the treatment paradigm, offering better options for patients. Now let's take a deeper look into our rationale for exploring the combination of ZYNLONTA an anti-CD19 ADC with glofitamab and anti-CD20 CD3 T cell engaging bispecific antibody. These 2 approved highly potent single-agent drugs offer important and complementary mechanisms of action in DLBCL, which target 2 different B cell surface antigens while delivering a potent payload and activating T cells. Given this, we expect to see additive or synergistic efficacy. In addition, there are no known overlapping non-hematologic toxicities between the 2 agents. And based on the dosing regimen, believe we have the opportunity to lower CRS rates and grades. The design of this trial includes 2 parts. In Part 1 dose escalation was conducted across non-Hodgkin lymphoma patients at 3 dose levels of ZYNLONTA with glofitamab or mosunetuzumab. As we shared earlier this year, we cleared both arms with no DLTs. In Part 2, dose expansion is moving forward in second-line plus DLBCL with ZYNLONTA at 2 doses, 120 micrograms per kilogram and 150 micrograms per kilogram, which is the initial dose approved for ZYNLONTA as monotherapy, combined with the approved dose of glofitamab as monotherapy. The primary endpoint is safety and tolerability with secondary endpoints of efficacy, PK and immunogenicity. We initiated Part 2 enrollment earlier this year and are in the process of dosing 20 patients in each cohort to address Project Optimus. Now as we turn to the data, we are truly encouraged by the initial results of the study. We believe this early efficacy data supports the combination of ZYNLONTA and glofitamab in second-line plus DLBCL. A 94% overall response rate was seen in the 18 patients evaluable for efficacy with 13 of 18 or 72% achieving a complete response based on Lugano criteria. Of these 13 patients, all but 1 maintained a CR as of the data cutoff. Although most patients achieved their best response early, 5 converted from an initial assessment of stable disease or partial response to a complete response, which is similar to what we saw in prior ZYNLONTA trials, including our approval study LOTIS-2. Additionally, these observed responses were strong across patients with different numbers and types of prior therapies and across histologies. The safety data is also encouraging as we observed the combination was well tolerated with a manageable safety profile and no DLTs across all 29 evaluable patients. No high-grade CRS or ICANS were observed in Part 1 and Part 2 and no grade 5 treatment-emergent adverse events were reported. Overall, we are excited about these initial efficacy and safety readouts. For further detail on the LOTIS-7 trial results, I will now turn the call over to our Chief Medical Officer, Mohamed Zaki. Mohamed?

Thanks, Ameet. LOTIS-7 is a very important study, and we are encouraged by the promising data shown thus far. In terms of safety, we now have initial data on all 29 patients dosed with ZYNLONTA plus glofitamab across Part 1 and Part 2 of this trial. Of that, 18 second-line plus DLBCL patients dosed with ZYNLONTA plus glofitamab at one of the expansion doses are efficacy evaluable as of the data cutoff. The patient population assessed for safety includes all patients from Part 1 dose escalation and Part 2 dose expansion as of the data cutoff. The baseline patient characteristics are generally representative of the patient population in this disease setting. Thus far, the safety profile observed was well managed during the study and consistent with the known safety profile of the 2 approved agents. The most frequently observed Grade 3 and 4 adverse events were neutropenia, followed by lymphopenia and hypokalemia. Furthermore, we observed a low discontinuation rate due to treatment-emergent adverse events. Of note, the safety profile was generally similar between doses tested during expansion, which is important as we consider project Optimus. Next, taking a look at CRS and ICANS specifically, to date, the overall rate of CRS was approximately 34%, most of which were grade 1 and no Grade 3 or higher CRS was observed. The CRS rate is lower than that seen with glofitamab monotherapy. All cases of CRS fully resolved with standard treatment, and there was no requirement for pressors or ICU admittance. There were 2 cases of low-grade ICANS, both of which fully resolved primarily with corticosteroids. One patient resumed treatment and ultimately achieved complete response. Looking at baseline characteristics specific to the 18 efficacy evaluable patients, population assisted in this study is generally similar to other second-line plus DLBCL trials. As Ameet shared, we have seen promising data in the 18 efficacy evaluable patients. As of the data cutoff, the best overall response rate observed was 94% with a high complete response rate of 72% across the 2 expansion doses tested according to the Lugano criteria. As you can see, looking at the swimmers plot, 12 of the 13 complete responses have been durable and remain in complete response as of the data cutoff. Most of the patients who responded achieved a response quickly at the initial assessment. In addition, it is important to highlight that 5 patients whose initial assessment was stable disease or partial response converted to a complete response over time. Although still early days, these are very encouraging results. And if they persist, could be practice-changing for treatment of second-line plus DLBCL patients. Going forward, we expect to fully enroll the 40 patient expansion with 20 patients per dosing cohort in the first half of 2025. We anticipate sharing more mature data on additional patients with longer duration in the first half of 2025. As more mature data becomes available, we plan to engage regulatory authorities on next steps in late 2025 or early 2026. Next, I will turn the call back over to Ameet for closing comments. Ameet?

Thank you, Mohamed. As you've seen today, we believe we have multiple ways to grow beyond our initial approval as a single-agent third-line plus treatment option for patients with DLBCL. We believe there are 3 key areas of growth to achieve our target of $500-plus million in peak annual ZYNLONTA sales. The first is in the currently approved third-line plus market, which is highly fragmented with no standard of care. The current indication is now commercially profitable, and we believe ZYNLONTA is well positioned to achieve $80 million plus in peak revenue. We also see the opportunity to triple revenues with potential expansion into the second-line plus DLBCL setting with our ongoing LOTIS-5 trial combining ZYNLONTA with rituximab by doubling the number of patients and increasing the duration of therapy by approximately 50% and see additional potential with indolent lymphomas. And our third opportunity for growth is in earlier lines through combination with glofitamab. Our LOTIS-7 trial has the potential to further expand our usage in second-line plus DLBCL with the potential to transform the future lymphoma treatment paradigm, becoming a backbone therapy in DLBCL. We believe this should put us well on the path to unlocking tremendous value in the company. We thank you for joining us today for this important update on LOTIS-7 dose expansion and the potential for additional growth we see with ZYNLONTA. We will now take questions. Operator, please open the line.

[Operator Instructions] Your first question is from Eric Schmidt from Cantor.

Congrats on a wonderful data set and thank you for the detailed presentation. Ameet, maybe on your comments on the commercial opportunity here, you make the case that there's room in the DLBCL treatment paradigm for ZYNLONTA-based combination in second line. Obviously, you've got this combination, the LOTIS-7 study. You also have the LOTIS-5 study that will read out next year in combination with rituximab. How do you think about differentiating between those 2 and which patients might be appropriate for either? And then second part of the question, what do you think the time lines are towards getting a LOTIS-7-like approach onto a compendia listing and NCCN guideline?

Okay. Thank you. That's a great question. Thanks, Eric. So as you mentioned, we do have our LOTIS-5 study, which is a combination of ZYNLONTA plus rituximab, which is on track to complete enrollment this year, and we expect it to read out later next year, which would mean an approval likely later in 2026. We think this is going to play a really important role because when you look at the community where bispecific adoption has been quite low, there's still a lot of R-based chemo use and R-based regimen use. And so going along with the Rituxan-based use, replacing the chemo or other agents like R2 with a very potent ADC, where we hope to see better efficacy than what the current standard of treatments are can play a big role. And I think cannibalize quite a bit of the use of the existing ADC and monoclonal antibody use as well as some of the chemo use. Now over time, as bispecifics get more manageable and safer and can be managed more across the community, I do think that adoption will improve over time. I think LOTIS-7 is particularly well positioned in that setting because not only do we think we can have efficacy on the upper end of any bispecific combination, we also think the tolerability and safety profile may be more manageable, particularly given what we're seeing in terms of the non-additive overlapping toxicity so far that we haven't observed any as well as the only low-grade CRS and ICANS. So we do think over time, as bispecifics do grow across different care settings, LOTIS-7 is going to be particularly well positioned. In terms of the timing, it's hard to predict right now, Eric, because we're obviously going to complete enrollment of the 40 patients in the dose expansion in the first half of the year, allow that data to mature by the end of next year or early 2026, we plan to engage with the FDA on what the path forward be. And then based on that data, we'll be able to report kind of more specific time lines. But there's a lot of interest in the study, and the study is progressing well. I think once we have the engagement with the FDA, we'll have more clarity on what the path forward will be and what the exact time lines could be for an approval and launch.

I guess I'm wondering, Ameet, if I can follow up on the LOTIS-7 study. Does it make sense to continue enrollment beyond the first 40-patient cohort and get a somewhat larger cohort for publication and compendia listing?

Yes. We're going to explore, I think, whether it makes sense to keep expanding that or for example, there could be also a more adaptive Phase III design where there could be an interim look as well. So I think there's different ways in which we may be able to get earlier data looks, which could be suitable to submit to NCCN. I think you would need a larger data set than 40 patients likely. But when you look at other data sets in Phase II, they're oftentimes in the 100 range. So we are -- we will explore other options to get a larger data set that may be suitable for that setting.

Great. Congrats, again.

Yes. Thanks, Eric.

Your next question is from Michael Schmidt from Guggenheim.

Yes, great early data update here. Congrats on that. Yes, I had a question on the swim lanes actually on Slide 19. So I'm seeing that some patients came off therapy, especially patient 9 came off pretty early, but most of the patients that came off actually still had a CR later on. And I'm just curious if you could just comment on those -- on this dynamic. It's very interesting, obviously, to see patients stopping therapy and maintaining a complete response? And then any preliminary thoughts on recommended Phase II dose at the 150 microgram dose, the efficacy obviously seems even higher than in the overall population. Just curious if you feel comfortable with the safety profile, especially at the 150-microgram dose. And then yes, maybe similar to Eric's question, perhaps one step further, if you think about potential randomized Phase III studies in the future, obviously, still some time until then, but would a regulatory study perhaps randomize relative to or against glofitamab alone or perhaps one of the older legacy products? Just curious if you have any preliminary thoughts on that.

Okay. Thanks, Michael. So 3 questions that you had. The first was around treatment discontinuation and the persistent CRs even post treatment discontinuation. The second question, it was around the dosing and how we would pick the different dosing between 150 and 120. And if we already had clarity with the recommended Phase III dose and the third was around a potential control arm in Phase III. So I'm going to turn it over to Mohamed to answer all 3 of those questions.

All right. So in terms of the swimmer plot, it's actually a very good feature for ZYNLONTA because it crosses the payload, crosses the DNA, and that's irreversible. So we actually have seen the same phenomenon in LOTIS 2 for single agent that in spite the discontinuation of treatment that the complete response remains ongoing. And actually, it's very favorable by investigators because of the thinking towards fixed duration treatment. You don't keep treating people until a very long time. Patient #9, specifically, that's a very unique case. That patient was dosed and end up having appendicitis and unfortunately, had a hemicolectomy and then came back to the hospital and his assessment was CR. So the CR observed is actually 1 dose of the 2 drugs that -- but the assessment happened much later after the patient recovered from surgery. That's in terms of the swimmer plot. In terms of our dose selection, it's -- as you see, it's a benefit risk. And I would say it's too early right now to see a difference. What we can see, the 2 doses are pretty effective. The safety profile seems very similar between the 2 so far. So as we -- the data grows and we see end discussion definitely with the agency and Project Optimus and the clinical pharmacology, we'll be able to decide better on what dose to go forward. Third question about Phase III is the most important question for me because it's a very dynamic landscape right now, second line plus. And the typical -- if, for example, STARGLO, Glofit-GemOx gets approved, then that could be an option. But it's very important for no matter what control arm you use to be available in many places, global studies are not only in the U.S. So we have to make sure whatever it is, there is multiple options, could be investigator choice between different choices. More studies could get approved other -- in between now and then. So I would say it's a discussion with the agency also will be more clear on what control arm to use for the Phase III.

Yes. Michael, as you're probably aware, up to this point, all the Phase II studies have been R-GemOx, all the bispecific combination studies are ZYNLONTA plus rituximab LOTIS-5 study. I think that will be one of the big discussions with the FDA is where is the control arm moving forward and what control arm is really accessible worldwide to conduct global studies.

Your next question is from Kelly Shi from Jefferies.

Congrats on the progress. First question on efficacy and safety. So the response rating looks very encouraging. Curious on durability front, what would assure this combo regimen as the therapy to go in second-line DLBCL? And on safety, can you inform us, any community centers were included in LOTIS-7 trial? And do you think the current safety profile that community doctors would also feel comfortable adopt this treatment regimen? And also maybe if prophylaxis such as toci and steroid are allowed on the trial?

Okay. There are few different questions. One is around the durability of the efficacy. The second is our community centers included in this trial? And then third, you mentioned, do we think that this profile would allow for use in the community over time? And fourth question you asked was around is there any prophylactic use of toci and other things. So I'll turn it to Mohamed to answer those questions.

So in terms of the durability of response, currently, we are very encouraged with the fact that 12 out of the 13 complete responses remain in CR as of the data cutoff date with 4 PRs still ongoing with the possibility of changing to CRs over time. It's a little bit too early to have a median for duration of response at this time, but it's trending towards a long and sustained duration of response. The second -- one of the questions about prophylaxis that this goal did not require prophylaxis neither for Part 1 or Part 2. As a matter of fact, in Part 1, during the safety assessment period for DLT that was prohibited actually from use. So technically, we did not proactively prophylaxis for this trial. In terms of community, would you like?

Yes. I think in terms of the community use, Kelly, the -- the recruitment of this trial is mostly at academic centers, but there are some community centers also involved in the study. And I do believe that this profile, if it persists, both from an efficacy standpoint, but of course, more important from a safety standpoint, I think it would be conducive to use across the community. I mean, so far, what we've seen is quite manageable levels, rates and grades of CRS and ICANS, they've been able to be treated with standard treatments. And when you look at other things like neutropenia, we haven't seen evidence of any additive toxicity. And most of the other grade 3 and events that you see are at pretty low levels and are really consistent with the no profiles of the 2 safety profiles of both drugs. So we do feel that if this profile persists, this would be amenable not only for the academic setting, but more broadly in the community.

And I also have a follow-up, if I may. So the response rate looks pretty high. And curious if you check the CD19 and CD20 antigen expression level in the second-line settings before the treatment and if low expression on either of the target was presented in patients. And so my question actually is whether the CD19 ADC, CD20 bispecific approach could also bring additional benefit for better capturing the tumor cells to drive deep response.

Okay. So your first question, Kelly, was around do we require any kind of CD19 and CD20 screening to understand what the antigen expression is prior to this. So I'll turn that to Mohamed.

No, we did not require that, but it's actually a typical markers to be looked at for patient biopsies as hospitals. But per protocol, we did not require a pre-measurement of any of those antigens. Was there another?

And the second question, Kelly? Around the CD19, CD20 bispecific?

Yes. So to clarify, it's not actually screening patients. You clearly have you check the expression level. So therefore, because you have both CD19 and CD20. So if there are any like low expression or maybe lost antigen, this approach can actually better capture the tumor cells to drive quick response?

Yes. But there was no reports that came to us about loss of antigen or anything like that from the treating physician to be very honest with you. We did not hear anything from them about antigen loss post those or as they come to the trial. So -- and I think the data pretty much shows that there is definitely an engagement for the 2 drugs together as you can see how the responses are ongoing. So the [ KOLs ] are very encouraged that the 2 drugs together could provide a higher benefit of each drug separately.

And your next question is from Roger Renza from RBC Capital Markets.

Congrats on the really nice data. Maybe just a few for me as well. As you see this data with glofit, are you set on a specific CD20 for potential registration enabling? I know this is early, but as you think about options to explore other bispecifics aside from glofit, if you choose that route, do you think any bridging would be necessary and how you could potentially leverage the LOTIS-7 as this matures? And then secondarily, as Roche is working on SKYGLO and the Glofit-R-CHOP in first line, how do you think that could play into the competitive dynamic with Glofit being used in first as a combination there? Congrats again.

Thanks, Greg. Two great questions. So yes, to answer your question around use potentially with other bispecific combinations, I would say we're very open to be combining across with any bispecific. We're sort of agnostic. We think that the concept of an anti-CD19 ADC like ZYNLONTA can be a backbone. It can really be combined across any of the bispecifics. We're, of course, furthest along right now in terms of the study with glofitamab. But of course, as you know, also in Part 1 generated some pretty encouraging data combining with mosunetuzumab. We have a couple of ITs plans now to combine ZYNLONTA with Epcoritamab that will start soon, one in the U.S., one in Europe. So we are doing different things to continue to explore the use of ZYNLONTA across different bispecifics. In terms of how we can leverage the data, I think, of course, you'd still have to do some exploratory work with each of the drugs, but we've certainly learned a lot in terms of how we're dosing in advance to reduce some of the peripheral B cells and debulk the tumor, how to combine these drugs well. So there are definitely learnings that we can apply as we think about other settings. And Greg, just remind me again of the second question, sorry.

Yes, absolutely. Just with respect to Roche's SKYGLO and exploring glofit with Pola-R-CHP in first-line, how you think that could play out in the competitive dynamic with glofit use in first line there?

Yes. So you're right. I mean there are a couple of frontline studies being both with Epcoritamab and with glofitamab. It really in the higher IPI score. So that's the population that they're looking after for the frontline studies. Obviously, the bar in frontline is pretty high. We know that it took 20 years from R-CHOP until we got to [ Pola-R-CHP ] which had showed some improvement, obviously, from an efficacy standpoint. Polivy is also generally pretty tolerable for our frontline setting. So I think what it will be interesting to see is what does the efficacy look like, how tolerable is it for what patient subgroups? I think there's a lot still to be seen in the data. And obviously, we haven't seen any mature data for any of those trials. I do think though, because an anti-CD19 therapy has never been exposed in the frontline setting. I do believe this combination is still going to play a big role. We do know that there's recycling of CD20-based therapies even today, from front line to second line and subsequent lines. And typically, they need to be reactivated with other mechanisms of action. So we do believe the powerful combination of a CD19 ADC with a CD20 CD3 bispecific can play a role even if bispecifics potentially are approved in the frontline setting.

That's great. Very helpful. And while we have you, I know this is the focus on LOTIS-7 today, but I just want to give you a chance to comment a bit on the platform and early-stage candidates as we think about what's in store for '25.

Yes. We're excited about our early-stage solid tumor platform. So as you know, it's all exatecan based. We have a very novel linker, and we've shown a pretty compelling preclinical data where we have a very large therapeutic index. We mentioned that we have 4 programs that are sort of at the IND-enabling stage, one of which we are going to fund on our own to get to complete the IND and move to the clinic. The other ones we're actually exploring different research collaborations to make sure that we can advance a broader set of portfolio, I think, in a very capital-friendly way. So we don't -- we're allocating most of our resources towards ZYNLONTA, but we're allocating a small portion of our resources to make sure that we could advance a broader solid tumor portfolio. So we're excited about the early data. Things are progressing towards IND, particularly for one of our lead programs. And then I look forward to sharing more in 2025 on what some of the next steps will be for our programs there.

Congrats, again.

Thanks, Greg.

Your next question is from Brian Cheng from JPMorgan.

First, just go back to the earlier question on your swimmer plot on Slide 19. It seems like some of your complete responders and treatment at various time points, specifically 3 of your best CRs turn CR after they discontinue treatment. So did those patients start another therapy after your combo discontinuation? And how confident are you that those CR conversions are driven by your combination? And I have a follow-up.

Okay. That's a great question. I'm going to turn that to Mohamed.

None of the patients are presented with CRs over here have received any additional therapy beyond what we have. Typically, if you're a CR you don't go after it. Of course, you can claim that people might go to transplant or CAR-T post, but none of those patients, this situation happened to them. What was the second part of the question?

Yes. So how confident are we in the durability and that the CRs are because of this combination?

Well, we're seeing very nice durability so far. Of course, I can't speculate what's going to happen, but it seems like all the CRs currently are ongoing except one. So data is promising from that direction. And as we follow it more, we can talk about durability, but this is short follow-up, so I can't really describe more on that. But what I can highlight is that there is 4 patients in PR, and there is another 4 patients in swimmer plot that didn't even make it to the first assessment yet. So I can see a potential for this data to grow and even get better in the future. However, of course, speculating right now is not the right thing to do.

Yes. And then, Brian, in terms of your question, are we confident to do the combination, I'd say, yes, because they're not getting any of the treatment. So these are patients that weren't in a response, obviously, and achieved a response. These are patients who are relapsed or refractory patients, right, who are progressing on disease and are benefiting, obviously, by this combination.

And very important also to highlight that one of the reasons that nobody gets subsequent therapy because per protocol, we're following every one of them for PFS. So if you introduce something else I guess sensor, and that's not allowed. So I just want to reassure everybody that this is continuous with only the treatment that was described by protocol so far.

And maybe just a follow-up, I guess, just from a strategic standpoint, how do you think about incorporating a subcutaneous formulation of bispecific?

Yes. I mean I think for LOTIS-7 right now, we're not planning to do that. I don't think administration is the key thing, to be honest. I think these are both luckily fixed duration therapies. I think -- and on the same schedule. So both glofitamab and ZYNLONTA are both every 3 weeks. As you know, ZYNLONTA is just a 30-minute infusion. So adding these 2 therapies, actually, the dosing works extremely well. I think with other therapies, obviously, like Epcoritamab and [indiscernible] has a subcutaneous dose that would have to be considered. But I think what's most important is having a very powerful efficacy, manageable safety profile with administration that's convenient for the patient. I think every 3 weeks is very convenient when you compare it to other dosing regimens and that can be administered on the same schedule. So I think this is this -- I feel very comfortable with the profile of this combination as well as what the dosing regimen is and the fact that it's a fixed duration dosing regimen.

Your next question is from Robert Burns from H.C. Wainwright.

Congrats on the data. Two questions for me, if I may. So obviously, at ASH, we saw data from the Phase Ib trial evaluating glofitamab plus polatuzumab. And I was just curious to get your impressions of that data, especially in the context of the SKYGLO trial. And considering that the SKYGLO trial is ongoing, do you think it might be more advantageous if you're trying to go into the frontline setting to maybe do ZYNLONTA plus Epcoritamab plus like a mini R-CHOP regimen? Just thoughts there.

Yes. So look, I think the data with glofitamab and polatuzumab is encouraging. The efficacy looked good. It was, as you can see, a more high-risk patient population in terms of what they're -- how they're positioning it. It was a more heavily treated higher-risk patient population. It's a Phase II study. I'm not sure -- I haven't heard of any disclosed plans of moving to Phase III or what the registration pathway be. So obviously, 2 of the same agents that are, as you mentioned, being studied frontline. And both patients, if that gets approved, will be exposed to both glofitamab and polatuzumab. Patients are already, quite a few patients in the U.S., about 1/3, we estimate get polatuzumab frontline. So it's already taken hold quite a bit in terms of frontline treatment. I think we're really well positioned irrespective of what bispecific could potentially get approved frontline, again, which we don't know yet because we're -- it will be the first time a patient would get exposed to anti-CD19-based therapy. So I think having a unique mechanism of a CD19 ADC, of which we're the only one approved positions us in a very unique spot for second-line plus treatment. In terms of frontline strategies, I can't really comment yet because we haven't disclosed anything about any plans for a frontline study. Right now, what our focus is, is on LOTIS -5 and LOTIS-7 to make sure that we have 2 really potent profiles with strong efficacy and manageable safety available for second-line plus DLBCL patients.

Your next question is from Sudan Loganathan from Stephens.

Congrats on the data here. My first question is regarding the patients that are still on treatment versus the patients that are not. What was the decision there to be made for some patients that had a complete response still on treatment versus some that are not, 5 or 6 patients that are currently not on treatment? And then secondly, just some clarity on the prior treatment for these patients. Was it R-CHOP or was it the combination of polatuzumab plus R-CHP?

Okay. So I'll turn that to Mohamed in terms of these 2 questions.

Yes. Almost all the patients that you have seen in this swimmer plot for efficacy reasons and for this trial I have seen R-CHOP before. We don't have patients so far that has been exposed to Pola R-CHP before. What was the second part of the question?

Yes. And you probably saw the median prior lines of therapy is 2 in the study. So 72% of patients had 2 or more prior lines of therapy, 28% had one prior lines of therapy. So it was a number of different therapies. You probably saw from 5 patients had prior CAR-T. Obviously, there was a range of anywhere from 1 to 5 prior lines of therapy. So given that 72% had 2 or more prior lines, obviously, beyond R-CHOP, most patients had at least one other therapy. And your second question again?

Yes, it was on the decision on some of the patients that are not treatment ongoing versus some that are regardless of having a complete response. I think I noticed 5 or 6 patients that have a complete response and were not treatment ongoing and then others have complete response and ongoing. So just a decision there for those patients.

Yes, that's a great question. So one thing, and I'm going to turn it to Mohamed to answer. But one thing to note in the trial, ZYNLONTA is given for up to 8 cycles and glofit for up to 12 cycles, meaning it's up to the physician discretion of how long they think the patient needs to stay on therapy post achieving a complete response. But maybe you can comment further.

Yes, that's exactly right. And different patients maybe have what we call completed treatment per protocol, as Ameet mentioned, patient decision, physician decision. But what we know for a fact that very low number of patients discontinued because of adverse events, only 3 patients as we described in the slides, with ICAN, one with pleural effusion and one with pericardial effusion. So there was no involvement from us in any stoppage or treatment decision. This was purely according to the protocol written how patients are being treated. And as Ameet mentioned, it's up to. So some physicians will see a CR after 2 cycles, they said, okay, patient need -- maybe need some treatment holidays. Some others said, no, I want to keep consolidating that with more cycles. So it's really according to the treatment decision, but it's up to 8 cycles for ZYNLONTA and up to 12 for Glofit.

And then one more follow-up. In the case that in the future, glofitamab does move to either first-line therapy or yes, prior therapies, would -- I guess -- and the patient still doesn't have a response, does it still make sense then to have a glofit plus ZYNLONTA in the second line? Or will there be kind of -- will that be looked at a little bit differently if the patient had previously failed on a therapeutic regimen that had glofitamab in the future? Just kind of want to get your thoughts on that.

Yes. I think, honestly, there's not enough data. I mean you have to see is there CD20 expression. What was the reason for the failure? Because obviously, Glofit, if it gets approved in the frontline it would be part of a regimen. But I would say right now, if you look at CD20-based therapies like rituximab, there is a lot of recycling across lines with -- as a backbone therapy changing the other components. I think what's really important for us is that we're the only CD19 directed ADC that's going to be -- that is approved and will be brought into different combinations in the second-line plus setting. But Mohamed, anything else you would add?

No, you said it's right. And typically, the combination have possibly a chance to overcome any resistant for the frontline therapy that could develop according to when we have more data about the presence of CD20 or not in some patient versus the other. But the data is still out there, so we haven't really found out about that. But presence of a CD19 for the first time that is expressed on almost all B cells is a solid reason why I see the combo should be developed.

Great. Congrats again on the data set.

Yes, thank you.

There are no further questions at this time. I will now turn the call back over to CEO, Ameet Mallik. Ameet?

Well, I want to thank you all for joining our call today for the update on LOTIS-7. We look forward to keeping you updated on our progress. Operator, you now may please end the call. Thank you all.

Thank you. Ladies and gentlemen, the conference has now ended. Thank you all for joining. You may all disconnect your lines.