Good morning, ladies and gentlemen. Welcome to the ADC Therapeutics EHA 2025 LOTIS-7 conference call. At this time, all lines are in a listen-only mode. Following the presentation, we will conduct a question-and-answer session. If at any time during this call you require immediate assistance, please press star zero for the operator. This call is being recorded on Thursday, June 12, 2025. I would now like to turn the call over to Marcy Graham, Investor Relations and Corporate Affairs Officer for ADC Therapeutics. Marcy, please go ahead.
Thank you, Operator. Today we announced an update to the data in our LOTIS-7 trial, which will be presented at the European Hematology Association Congress, or EHA. The press release and the slide presentation we will use on today's webcast are available on the Investor 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 our corporate strategy and our ZYNLONTA franchise, including our plans for expansion. Our Chief Medical Officer, Mohamed Zaki, who will discuss the progress made with our LOTIS-7 clinical program and provide trial updates. Also joining us on today's call is Dr.
Juan Alderuccio, Associate Professor of Medicine and Hematology at the Sylvester Comprehensive Cancer Center at the University of Miami, who specializes in the study and treatment of patients with lymphoma and is a principal investigator on the LOTIS-7 trial. Dr. Alderuccio will take us through the details of the EHA presentation. We will then open the call to questions. Before we begin, I would like to remind the 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. As an approved 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. Beyond our current indication, we believe ZYNLONTA has the potential to reach significantly more patients while growing the commercial opportunity by expanding use into earlier lines of therapy in DLBCL and 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 drug 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 is also a non-systemic 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 I-B study in patients with relapsed or refractory B-cell non-Hodgkin lymphoma and is the focus of today's discussion. Today we will review updated results from the study being presented at EHA with a subsequent oral presentation at ICML. ZYNLONTA is also being evaluated outside of DLBCL with compelling data from phase II investigator-initiated trials in both follicular lymphoma and marginal zone lymphoma, recently presented at ASH. Additional data from the phase II IIT in relapsed or refractory marginal zone lymphoma will be presented at ICML next week, with the abstract going live on June 15th. Looking at the overall DLBCL treatment landscape, whether in the second or third-line setting, there are two main segments. The first are complex therapies, which require unique infrastructure and expertise to handle logistical requirements and patient management. This includes therapies like CAR-T, transplant, and bispecifics.
The second are more broadly accessible therapies, which all physicians can administer in the outpatient setting, including therapies like ADCs, monoclonal antibodies, and chemotherapy. Bispecifics have already been approved in the third-line plus setting as monotherapy, and there's currently a 60/40 split between the complex and broadly accessible segments, respectively. In the second line, where bispecifics have not yet been approved but were recently added to NCCN guidelines for use in combination, the split is closer to 25/75. We believe the emerging clinical profile of ZYNLONTA plus glofitamab in the LOTIS-7 trial positions us well among complex therapies, and at the same time, the clinical profile of ZYNLONTA plus rituximab, seen in the safety run-in portion of the LOTIS-5 trial, can differentiate us among more broadly accessible therapies. ZYNLONTA has the potential to disrupt the relapsed or refractory DLBCL market and unlock significant growth in both segments.
We believe the initial LOTIS-7 efficacy data give us the opportunity to be highly differentiated versus bispecific monotherapies and emerging bispecific combinations. The initial LOTIS-5 data demonstrated a 50% complete response rate, which is double that of our monotherapy data in third-line plus DLBCL. Although only 20 patients, we believe that the full trial data are consistent with the safety run-in portion, this positions us well against other broadly accessible therapies. ZYNLONTA combinations have the potential to unlock significant growth by doubling our addressable patient population, by expanding into the second line, capturing higher market share with differentiated efficacy, and increasing the average duration of therapy. While ZYNLONTA is currently approved as a single-agent in third-line plus DLBCL, we believe ZYNLONTA has the potential to be the backbone therapy for combinations, raising the bar for efficacy in second-line plus DLBCL.
ZYNLONTA is a systemic chemo-free option, which can be combined with the highly effective bispecific glofitamab and the most widely used agent, rituximab. We believe ZYNLONTA plus glofitamab in LOTIS-7 and ZYNLONTA plus rituximab in LOTIS-5 are complementary approaches to addressing unmet needs in the two key treatment segments. At this point, I'd like to invite Mohamed to share a bit more with you about our LOTIS-7 trial. Mohamed?
Thank you, Ameet. Let's take a deeper look into our rationale for exploring the combination of ZYNLONTA, an anti-CD19 ADC, with glofitamab, an anti-CD20, CD3 T-cell engaging bispecific antibody. These two highly potent single-agent drugs offer important and complementary mechanisms of action in DLBCL, which target two different B-cell surface antigens while delivering a potent payload and activating T-cell. Given this, we expect to see additive or synergistic efficacy. In addition, there are no known overlapping non-hematologic toxicities between the two agents. By dosing ZYNLONTA prior to glofitamab, it is our hypothesis that this dosing schedule has the potential to debulk the tumor and lower CRS rates and grades. The design of the trial includes two parts. In part one, dose escalation was conducted across non-Hodgkin lymphoma patients at three dose levels of ZYNLONTA with glofitamab or mosunetuzumab in the third-line plus.
In part two, dose expansion moved forward in second-line large B-cell lymphoma with ZYNLONTA at two dose levels, 120 mcg/kg , and the currently approved monotherapy dose of 150 mcg/kg , combined with the approved monotherapy dose of glofitamab. We have dosed the initial 40 patients, 20 in each cohort, for the dose optimization and selection. ZYNLONTA is being given prior to glofitamab to potentially debulk the tumor in the first cycle, and then both agents are given together in subsequent cycles. The primary endpoint is safety and tolerability, with secondary endpoints of efficacy, PK, and immunogenicity. As of the current date of April 14, initial data suggest the combination of ZYNLONTA plus glofitamab is generally well tolerated with a manageable safety profile in large B-cell lymphoma with no DLTs at either 120 mcg/kg or 150 mcg/kg dose during dose escalation. Dr.
Alderuccio will provide more details here, but it is important to note that neutropenia, a known adverse event of each drug, was the most common treatment-emergent adverse event of grade three or higher. We have not observed an additive effect when it comes to neutropenia. The overall rate of neutropenia was approximately 24% in this study, which is similar to the average reported in the approved prescribing information of each drug separately. In addition, we observed lower rates of CRS compared to glofitamab monotherapy label. All CRS and ICANS events observed were low-grade, with the exception of one grade three CRS event at 120 mcg/kg . Importantly, no grade five treatment-emergent adverse events have been observed. Turning to efficacy, we observed an overall response rate of approximately 93% and an unprecedented complete response rate in this setting of approximately 87% per Lugano criteria.
Of note, 25 out of 26 patients with complete response remained in CR as of the data cutoff. In addition, we observed conversions over time with 12 patients converting from stable disease or partial response to complete response in this study. Based on the scientific evidence available and in alignment with the Data Safety Monitoring Committee, we have selected the 150 mcg/kg dose for expansion to 100 patients. Of note, 150 mcg/kg is the approved starting dose of ZYNLONTA for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. As I mentioned a moment ago, in this study, safety was manageable in both doses. However, we observed a lower rate of CRS of any grade at the 150 mcg/kg dose compared to the 120 mcg/kg .
In addition, both doses showed high level of efficacy. However, the median time to complete response was shorter at the 150 mcg/kg dose at 42 days as compared to 80 days at the 120 mcg/kg dose, which is an important factor in treating aggressive lymphoma. Finally, from a clinical pharmacology perspective, we observed an increased predictive probability of having a high complete response with the 150 mcg/kg dose compared to the 120 mcg/kg dose. The impressive efficacy and manageable safety profile seen to date in this trial with the combination of these two potent anti-cancer agents with unique mechanisms of action is encouraging. The data reinforce our belief in the potential for this regimen to change the treatment paradigm for patients with second-line plus DLBCL.
With that, it is my pleasure to pass the presentation over to the principal investigator on the LOTIS-7 study, Dr. Juan Alderuccio.
Thank you, Mohamed. Baseline characteristics in this study are representative of the second-line plus diffuse large B-cell lymphoma patients' population and similar to other studies in this space. Among the 41 safety evaluable patients, there are a few characteristics that are important to highlight. The median age in this study is 71, with a range of 26 to 85 years of age. The study enrolled patients with large B-cell lymphoma, including de novo diffuse large B-cell lymphoma, transformed follicular lymphoma, high-grade B-cell lymphoma, and grade three-B follicular lymphoma, all considered to be diffuse large B-cell lymphomas. Median prior lines of therapy was two, with a range from one to five. This study includes a number of difficult-to-treat large B-cell lymphoma patients. Nearly 20% of patients presented as double or triple hit. 19.5% of patients received prior CAR-T, which is in line with other trials done with bispecific combinations.
Patients refractory to prior therapy were well represented in this study, with 51% of patients refractory to primary therapy and 49% refractory to last prior therapy, both of which were slightly higher in the 150 mcg/kg compared to 120 mcg/kg dose. Safety was analyzed in the 41 large B-cell lymphoma patients who received at least one dose of loncastuximab plus glofitamab. Most notably, as Mohamed mentioned earlier, when looking at grade three or four treatment-emergent adverse events occurring in more than 5% of patients, neutropenia was the most common at 24.4%, which is similar to the rate of neutropenia reported in the prescribing information of each drug separately. We are not seeing any additive effect here. Beyond that, to date, the type of TEAEs observed are consistent with the known safety profiles of each drug separately.
The rate of serious TEAEs was similar across both doses. Only three of the 20 patients who experienced serious TEAEs discontinued treatment. To date, the combination has shown a manageable safety profile and no new safety signal was observed. A total of six patients discontinued due to adverse event, three of which were serious TEAEs. Overall, the numbers are small, with three each for loncastuximab and glofitamab. For loncastuximab, we saw one case each of pericardial effusion, generalized edema, and pleural effusion. For glofitamab, we saw one case each of ICANS, polyneuropathy, and febrile neutropenia. It is important to consider the profile and management of cytokine release syndrome and ICANS when using bispecific therapies. In this study, we can see that overall rates and all grades of CRS are higher at the 120 mcg/kg dose compared to the 150 mcg/kg dose.
The 120 mcg/kg dose had 55% any grade CRS, primarily grade one and two, with one case of grade three. The 150 mcg/kg dose had 23.8% any grade CRS, all of which was grade one. Grade one and two CRS cases were managed with tocilizumab, corticosteroids, acetaminophen, and/or fluid bolus without ICU admission or pressor support. The grade three CRS case was managed with tocilizumab, acetaminophen, dexamethasone, norepinephrine, and included ICU admission. ICANS were seen in two patients treated at the 120 mcg/kg , and 1 ICANS was observed at the 150 mcg/kg dose. These ICANS were low-grade and primarily managed with corticosteroids. All patients had a complete resolution of symptoms, with 1 patient electing to discontinue treatment and two patients resuming treatment and ultimately achieving a complete response.
Of the 41 treated patients at the time of the April data cutoff, 30 patients had reached the initial disease assessment and were efficacy evaluable. The results observed across those levels were consistent in terms of overall response rate, complete response, and partial response. In this study, we have seen a 93.3% overall response rate and an 86.7% complete response rate. Median duration of response was not reached at the time of data cutoff. Looking now at the swimmer plots, the green bars show all patients in complete response, and the length of these bars shows the durability of each response. The gray bars represent patients who have not yet made it to the first disease assessment, so are not yet evaluable for response. Most responses were observed at initial assessment, which occurred at day 42.
Twenty-five out of twenty-six patients who achieved a complete response have maintained that response after the data cutoff. Twelve patients converted from an assessment of stable or partial disease to complete response over time. At this point, the longest response in this study is more than a year. Complete responses were observed regardless of prior therapy. Of the six patients previously treated with CAR-T and undergoing response assessment, five achieved a complete response. The median time to complete response was shorter in the 150 mcg/kg at 42 days compared to the median time to complete response in the 120 mcg/kg dose at 80 days. Median time to complete response, along with the safety differentiation and pharmacokinetics modeling, supported the recommendation of the DSMC, of which I am a member, to move forward with the 150 mcg/kg dose of loncastuximab tesirine for further expansion.
While still early, these data are highly encouraging. I would now like to turn the call back to Ameet.
Thank you, Dr. Alderuccio, for walking us through the LOTIS-7 trial update. We are encouraged by the data and look forward to expanding enrollment to 100 patients at the selected 150 mcg/kg dose. Within our current indication, our commercial strategy is focused on relapsed or refractory DLBCL patients who need a treatment with a fast, durable response, and a manageable safety profile, which can be administered in the outpatient setting. We believe LOTIS-5 has the potential to take ZYNLONTA to $200 million-$300 million in peak sales as we expand into the second-line setting. This is driven by doubling the patient population, extending the duration of therapy, and improving the clinical profile versus our current indication as a monotherapy.
With LOTIS-7, we estimate we can expand the total opportunity for ZYNLONTA in DLBCL to $500 million-$800 million in peak revenue, with regulatory approval and compendia listing. If the data persists, we believe ZYNLONTA plus glofitamab has the potential to transform the future lymphoma treatment paradigm by becoming the preferred bispecific combination in the second-line plus DLBCL setting. Additionally, in indolent lymphomas, there is a clear unmet need in both the relapsed refractory marginal zone lymphoma and relapsed refractory follicular lymphoma settings. We are encouraged by the initial data seen in the phase II IIT suggesting that the ZYNLONTA regimen could provide significant benefit in these indolent lymphomas. We believe the indolent lymphomas opportunity could provide additional peak revenue of $100 million-$200 million with regulatory approval and compendia listing, primarily driven by marginal zone lymphoma.
Taken together, we believe ZYNLONTA has the potential to reach peak revenues of $600 million-$1 billion in the U.S. Across the LOTIS-7, LOTIS-5, and marginal zone lymphoma ZYNLONTA programs, we expect to have multiple data catalysts in the remainder of 2025 and 2026, with potential approval or compendia listing for all of these in the first half of 2027. With LOTIS-7, we intend to share fuller, more mature data toward the end of this year and expect to complete enrollment of 100 patients at the 150 mcg/kg dose in the first half of next year. We plan to engage with regulatory authorities starting later this year while we simultaneously pursue publication and a potential compendia strategy.
For LOTIS-5, we expect to reach the prespecified number of PFS events by the end of this year, with top-line results and a potential BLA submission in the first half of next year. With indolent lymphomas, we expect additional phase II IIT data to be shared at medical conferences this year and next by the lead investigators. Beyond the use of ZYNLONTA, we are excited to see the advancement of our exatecan-based PSMA targeting ADC, with potential completion of IND-enabling activities toward the end of this year. Overall, we believe we have multiple value-driving catalysts within our cash runway. We can now open the line for questions. Operator?
Thank you. Ladies and gentlemen, we will now begin the question and answer session. To ask a question, you may press the star followed by the number 1 on your telephone keypad. If you're using a speakerphone, please take off your handset before pressing any keys. To withdraw your question, please press the star followed by the number 2. With that, our first question comes from the line of Kelly Shi with Jefferies. Please go ahead.
Congrats on strong data, and thank you for taking my questions. I have a couple of questions to Dr. Alderuccio. Maybe firstly, based on this durable complete remission rate, I mean, complete response rate at approximately 6 months-7 months of immediate follow-up time, would you be able to predict the overall survival benefit based on previous clinical trial experience? Do you see a good correlation of complete response rate to overall survival for lymphoma therapies? Thank you.
Okay. Thanks, Kelly, for the question. Dr. Alderuccio, I think the question, Kelly, you're asking is really about the durability of the CRs and the potential for that to translate over time into overall survival benefit and what the correlation between CRs and OS is. Dr. Alderuccio, could you handle that?
Yeah. Thank you. Thank you for the question. This is a critical question about enlarged B-cell lymphoma. Yeah, the high number of CRs seen in the trial in LOTIS-7 is encouraging. We know that complete response by the Lugano criteria, that was the criteria used in this study, is a strong surrogate of durability. As the current data cutoff, 25 out of 26 CR patients remain in CR. In addition, CRs have been shown to be durable with each drug individually in heavily pretreated third-line plus single-agent loncastuximab and glofitamab. I agree that we need longer follow-up, but the current results are encouraging, and I think it's highly encouraging that these complete responses will translate in a survival benefit.
Thank you. And also a follow-up is efficacy. This initial data showing the efficacy actually could surpass CAR-T. But could you also comment on the overall tolerability profile, including CRS, ICANS, but also neutropenia or myelosuppression, those immune cell-related toxicities of ZYNLONTA glofitamab combo? And make a comparison to other therapies in lymphoma. How would you assess the plausibility for this combo regimen to be broadly used at community centers? Thank you.
Yeah, this is another important question. Oh, I'm sorry.
No, no, go ahead, Dr. Alderuccio, please.
Yeah. So yeah, these agents independently have been approved for already a few years, and people are more and more comfortable dealing with the unique toxicities. What is important to highlight is that the toxicities of this combination were not higher than the single-agent toxicity reported on each trial independently. We did not see any addition on or a cumulative effect or higher effect of this combination on the rate of neutropenia, ICANS, or CRS. I think that is the first point that is important to remark at the current follow-up and with the current number of patients enrolled. Regarding the question about if these agents will be adopted in community centers, I think that while broadly accessible therapies have traditionally been used in community centers, uptake of bispecific is already occurring in more sophisticated community centers.
Over time, I expect to see bispecific combinations more broadly adopted in community centers, as they have shown a better clinical profile as in this trial. I think the initiation of loncastuximab before glofitamab was a smart decision in the study schema because this appears to have decreased the toxicity of glofitamab.
Thank you. One more, if I may. Could you help us to understand the rationale of the synergy between CD19 ADC and CD20 T-cell engager? Why this combination can achieve efficacy better than CAR-T? Is it due to different modalities, different mechanisms of action, and the broader epitope coverage? Could you help us to understand the reasons behind? Thank you.
Yeah. So maybe, Mohamed, you could first talk mechanistically about the two molecules and how they fit together. And then Dr. Alderuccio, if you have anything else to add, that'd be great as well.
Sure. In terms of the mechanism of action of each drug separately, first, I want to highlight there are two potent agents. Each one is approved on accelerated approval. The second part that is important here, they actually target two separate antigens expressed in the B-cell. One is the CD20, and the other one is CD19, which could bring a complementary mechanism of action. More importantly, the activation of the immune system by each drug, typically, of course, the glofitamab activated the immune system, possibly creating adaptive immunity with memory cells. Also, ZYNLONTA kills the cell through immunogenic cell death by apoptosis that also activates the immune system, creates adaptive immunity, and memory cells. Now, earlier, as we've shown by each drug separately, the median duration of complete responses has not been reached after two years for ZYNLONTA and after three years for glofitamab, with limited duration of cycles used.
It tells you that the resistance of CRs without treatment could possibly be actually by the immune system activation that lasts for much longer than the actual treatment itself. That is pretty much it. Dr. Alderuccio, please feel free to add if you'd like.
Yeah. No, I agree. These are highly effective agents independently that have been shown in phase II studies. And the mechanism of action is independent of one or the other. Loncastuximab is an ADC with a cytotoxic payload and glofitamab an anti-CD20, CD3, T-cell engaging. I think it's a synergistic effect between both agents that is the one that triggers the efficacy and the results that we have seen in the current presentation.
Thanks very much. Congrats again.
Thank you, Kelly.
Your next question comes from the line of Michael Schmidt with Guggenheim. Please go ahead.
Hey, good morning. Thanks for taking my questions. Yeah, congrats. Really nice data update here at EHA. I thought this sort of conversion to CR over time is quite interesting, sort of from either PR or even SD. Is that something that's unique to this combination, or is that seen with glofitamab as well? I know it's a fixed duration regimen, but for modeling purposes, what is a good duration of treatment assumption for this if you account for the need to perhaps treat longer to convert patients to CR over time?
Okay. Thanks, Michael. Two parts to your question. One was about the conversion to CR over time. You saw in the swimmer's plot that 12 of the patients converted, one from SD, 11 from PR, which is why that happens. The second question was about the fixed duration and how many cycles. I'll answer the second part first, and I'll turn it to Mohamed and Dr. Alderuccio for the first question. In terms of the fixed duration of cycles, typically with ZYNLONTA monotherapy, what we're seeing in the third-line setting is an average of three cycles. What we've seen in this trial for the patients who have stopped treatment is an average of six cycles of ZYNLONTA and also an average of six cycles of glofitamab. It is a fixed duration therapy, and yet we see durability continuing beyond that.
Maybe, Mohamed, do you want to start, and then Dr. Alderuccio, you can chime in as well just on why there can be conversions from patients who are initially assessed with a PR, SD, but over time can convert to a CR?
Yeah. As I mentioned in the previous question, the mechanism of action of each drug separately with the activation of immune response maintains the disease control without the need for continuation of treatment. That is actually very encouraging in treating a lymphoma patient with a fixed duration treatment, and the response is maintained. If you see how this happens in each drug separately, when we got approval, accelerated approval, the CR median duration response was not reached for two years by ZYNLONTA in spite of the median duration of number of cycles used was about three. For glofitamab, the same phenomenon with CR median duration response not reached after three years with the median number of cycles for that study was about five. In the current study, the median duration of cycles for each drug separately was six cycles of ZYNLONTA and six cycles of glofitamab.
We are predicting this to be the same phenomenon. The CR is lasting already, and the conversion at the earlier data cut when we showed data in December was five conversions. Now we have 12 conversions. It is actually going exactly where we expect it to go. Dr. Alderuccio, if you'd like to please add anything you would like to add.
Yeah. No, I agree with your statement, Mohamed. I think also it's important to remember that glofitamab, as other bispecific, may produce an initial tumor flare. We based the response on the Lugano criteria, which is a nuclear medicine, a PET-CT-based response criteria. It's possible that the higher uptake that we see in the lymphoma area is compatible with a partial response or a stable disease because of the T-cell infiltration but for the inflammatory reaction that this drug produced and that subsequently the response improved from the stable disease or partial response to a complete response. I think that's also something that can partially explain the reason for these conversions.
Okay. I mean, when we talked to physicians just earlier this week, I think they really like to see this combination approved ultimately, FDA-approved. Yeah, I'm just curious. This 100-patient cohort now that you're expanding into, do you think this could potentially support an FDA filing, or is there the plan perhaps to conduct a larger study subsequent to completing this expanded cohort? Thanks so much.
Yeah. Great question, Michael. So yeah, the plan, as you said, is to expand the 150 mcg/kg in this LOTIS-7 study to 100 patients in total. We know that that will help to serve two key purposes. One is based on different precedents. When you look at three different bispecific combinations that were added in the first quarter of this year to preferred NCCN guidelines, it was based on about 100 patients. We think that's a sufficient number upon publication to be able to submit and hopefully get accepted as a preferred regimen in NCCN guidelines. The other benefit of 100 patients is that it produces a much larger safety database, which is helpful for regulatory discussions. There are two reasons why we're doing it.
Mohamed can speak about we do plan to engage with the FDA in the second half of this year to explore possible regulatory approaches. It's not clear if we're going to do that, but we are going to engage in discussions on what potential approaches can be. Mohamed, do you want to talk how we're thinking about the regulatory approach?
Yes. Thanks, Ameet. Thanks for the question, of course. It is important to highlight that the high CR rate unprecedented seen in this study with the manageable safety profile is very encouraging. With the 100 patients enrolled, going to the agency and discussing what's the potential to bring in this regimen quicker to patients in an ethical trial, meaning the control arm has to be a good decision. Now, it is not clear what the control arm could be at the moment because the Argelics are not popular anymore in the U.S. and maybe Western countries and becoming very hard to enroll patients if that's the control. Among others, nothing rises to the level of this number of CRs. During the CAR-T approval, there was a synthetic control arm used in order to approve CAR-T with a single-arm trial with 100-plus patients.
That could be a discussion. Or typically, we could land into a control arm, what's called investigator best choice, between whatever available therapy in a global study having choices where the control arm is available not just in the U.S., in other countries as part of your trial. As Ameet mentioned, we are going to meet with you to discuss the regulatory path with the agency among other things we'll discuss together.
Great. Thank you.
Yeah. And then, Michael, with the financing that we announced also this morning, we're funding the full 100-patient expansion as well as we announced extending the cash fund later 2028. Any further regulatory discussions, I think, would also probably have to be in conjunction with the partners that we have also in the study. Operator, go ahead.
Your next question comes from the line of Eric Schmidt with Cantor. Please go ahead.
Thanks for taking my questions and congrats also on the data update. Maybe two questions, one for Dr. Alderuccio and one for the company. Dr. Alderuccio, if you look forward to a time when you have access to both this combination as well as CAR-T therapy in the second-line, DLBCL patient population, are there subsets of patients that you think would be better served by one or the other treatment paradigm? For the company, actually, Ameet, you just kind of touched on this. How should we think about Roche's future participation in a development program for this combination? What would be a good result for ADCT? Thank you.
Okay. Dr. Alderuccio, do you want to start with how you would think about this in your future treatment paradigm if this becomes accessible as well as CAR-T and other therapies?
Yeah. Thank you. That's a good question that I have been doing myself after starting seeing the data. I think if the data persist, the combination of loncastuximab plus glofitamab would be the preferred bispecific combination option in patients without access or not suitable or who progress after CAR-T. Right now, defining the one population or the other is difficult with preliminary data, but I think it's highly promising. I think also it's important to recall that the current CAR-T that are approved require a process of catheter insertion and a process that will take a few weeks until the product is ready for the patient to receive it. Patients that are quickly progressing, there are rates of further progression and deterioration and potential death if they are not treated promptly.
I think this combination that is off the shelf and the patient can start it quickly the following day if needed is very attractive in that population, patients that require treatment right away. This is a common scenario in relapsed refractory diffuse large B-cell lymphoma.
Yeah. And then with regards to Roche, as you know, since the start of the study, we've worked very closely with them, and we really appreciate the collaboration. Roche is obviously one of the leaders within the lymphoma space. We benefited not only by them providing supply of the product for the clinical trial, but also really valuable insights, both clinical and regulatory insights based on their experience. We really appreciate the collaboration. I can't comment or speculate on what the future will be, but we do look forward to continuing to collaborate and assessing different ways in which we can continue to partner to bring this combination to as many patients as possible going forward. We look forward to keeping you updated as that progresses.
Thank you.
Thanks, Eric.
Your next question comes from the line of Sudan Loganathan with Stephens. Please go ahead.
Hi. Good morning. This is Felix Ampomah for Sudan. Thank you very much for the data, and we are very impressed. I have two questions. What was the reason for the discontinuation rates, and what was the discontinuation rate as of the last time of data cutoff? Number two, the ORR looks very impressive. We wanted to understand which ORR benchmark that you are looking to be on par with.
Okay. Two great questions. Maybe, Alderuccio, I'm going to actually have you start with both of these. The first question, Dr. Alderuccio, was, what are the reasons for discontinuing treatment within LOTIS-7?
Yeah. I'm sorry. It was muted. The most common reason for discontinuing both agents during the study was physician or patient decision after achieving a satisfactory response such as a complete response, followed by a few additional cycles of consolidation. Additional reasons to stop treatment included reaching the maximum number of cycles of either or both drugs, reaching deep enough responses with intention to bridge to cellular therapies such as CAR-T or transplant that happened in only two patients, and adverse events. Those were the most common reasons.
Okay. Thank you.
Thanks, Dr. Alderuccio. The second question, which is, what do you think would be—I think you were asking—a compelling overall response rate and CR rate for this trial as the study matures?
Yeah. That's a great question. I think a profile with a—so I will say that rather than overall response rate in aggressive lymphoma, as a physician, I am interested in complete response rates. And a profile with a CR rate or complete response rate at or above 70% and comparable durability to what we are seeing with other bispecific combinations would be clinically differentiating from other treatment options. In this trial, the complete response rate was 86.7% with 25 out of 26 patients remaining CR as the data cut off. That gives confidence about the profile of this combination.
Thank you.
Yeah. Thanks for the question. We appreciate it.
Apologies. I was on mute. Your next question comes from the line of Leonid Dimashev with RBC Capital Markets. Please go ahead.
Hi. This is Mitch on for Leonid. Thanks for taking our question.
I'm just wondering if you could provide some additional context on the safety profile of LOTIS-7 compared to the safety profile of glofitamab in prior studies. And why do you think that CRS and ICANS rate are potentially lower at the 150 mcg/kg dose of ZYNLONTA compared to the 120 mcg/kg dose? Thanks so much.
Sounds good. We really appreciate it. Maybe, Mohamed, do you want to take this one, which is just comparing the safety profile, particularly with regards to CRS and ICANS of glofitamab monotherapy versus this combination? And why do you think that the 150 mcg/kg dose does even better than the 120 mcg/kg dose of ZYNLONTA when combined with the full dose of glofitamab?
All right. Thank you, Ameet. And thank you for the question. First of all, I would like to highlight that the label of glofitamab showed 70% any grade CRS with a single agent in the trial that led to the approval. Currently, with the addition of ZYNLONTA ahead of glofitamab to help debulking more than what is already included in the label of rituximab at day one, we added ZYNLONTA at day two and glofitamab for the first time at day eight. And then subsequent cycle, we add those together, seems to have helped in reducing the all-grade any grade CRS. And if you see the differential between the two doses, the CRS rate observed in the 120 mcg/kg is in the range of 55%, slightly or still lower than glofitamab alone showed. However, in the 150 mcg/kg, it is about 23.4%. So significant reduction in the recent CRS.
In addition, the 120 mcg/kg had three grade two's and one grade three. The 150 mcg/kg have only grade one. If you know the difference, grade one is simply using antipyretics like Tylenol, paracetamol, and steroids. Grade three is ICU. We see a very strong benefit from that perspective. The reason the 150 mcg/kg was selected for expansion has three main reasons. As I mentioned, the reduction on the rate and grade of CRS, as seen by the Data Safety Monitoring Committee who oversee the trial in the escalation and expansion and dose selection. That is number one. Number two, the median time to CR is shorter on the 150 mcg/kg at 42 days compared to 80 days at the 120 mcg/kg .
In addition, from a clinical pharmacology perspective, in the modeling, it shows that predictable probability of having a deeper response is more when you actually have higher doses in the first two cycles compared to two lower doses. Pretty much the three elements that usually are used for dose optimization and selection have met. Unanimously, the Data Safety Monitoring Committee recommended 150 mcg/kg to be the dose to move to expansion. I hope that two answers explain the things and address your question.
Yeah. Thanks, Mohamed. Just a reminder, the 150 mcg/kg dose of ZYNLONTA is the approved dose. Essentially, what we're moving forward with now in the continued expansion to 100 patients is the approved dose of both agents.
We have no further questions at this time. I would like to turn it back to Ameet Mallik for closing remarks.
I want to thank you all for joining our call today and for your continued support. We look forward to keeping you updated on our progress. Operator, you may now end the call.
Thank you, presenters. Ladies and gentlemen, this concludes today's conference call. Thank you all for joining. You may now.