Welcome to the LOTIS-5 presentation conference call. At this time, all lines are in 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 Tuesday, June 2nd, 2026. I would now like to turn the conference over to Nicole Riley. Please go ahead.
Thank you, operator. Today we issued a press release announcing results from our phase III LOTIS-5 pivotal trial. 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, and our Chief Medical Officer, Mohamed Zaki, who will discuss our LOTIS-5 trial results. We will 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 forms 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, Nicole. Before we get into the details of the LOTIS-5 study, as a reminder, ZYNLONTA is an approved single-agent therapy in 3L+ DLBCL. As monotherapy, ZYNLONTA has a well-established profile of rapid, deep, and durable efficacy, as well as manageable safety with simple and convenient administration. Since FDA accelerated approval in 2021, ZYNLONTA has been used in treating approximately 5,000 patients in the U.S. Beyond our current indication, we believe in the potential to reach significantly more patients by expanding use into earlier lines of therapy in DLBCL and into indolent lymphomas, offering physicians options that address the unique treatment choices in each disease category. As a reminder, LOTIS-7 is our phase I-B trial combining ZYNLONTA with the highly effective bispecific glofitamab in 2L+ DLBCL patients.
Here we continue to be encouraged by the promising data shared to date, which we believe demonstrates the potential for ZYNLONTA plus glofitamab to be a best-in-class combination in a highly competitive market. Today, we will share with you the results of LOTIS-5, our phase III confirmatory study of ZYNLONTA in combination with rituximab versus R-GemOx in patients with 2L+ DLBCL, as well as our planned regulatory next steps. I will now turn the call over to our CMO, Mohamed Zaki, to discuss these results in detail. Mohamed?
Thank you, Ameet. As noted, LOTIS-5 is our randomized open label phase III confirmatory study of ZYNLONTA in combination with rituximab versus R-GemOx in transplant-ineligible 2L+ DLBCL patients. The trial enrolled a total of 420 patients, randomized 1:1, with 210 patients in each arm. The primary endpoint of the trial was progression-free survival. The key secondary efficacy endpoint was overall survival. Other secondary endpoints included overall response rate, complete response rate, duration of response, duration of complete response, safety, PK parameters, immunogenicity, and patient-supported outcomes. ADC Therapeutics was blinded throughout the study. The study utilized both an unblinded independent data monitoring committee to regularly review safety as well as a blinded independent review committee to adjudicate response or progression for each patient.
Looking at baseline characteristics, the patient population enrolled was generally balanced between the two arms, with the exception of more European patients in the test arm and more rest-of-world patients in the control arm. Of note, the study enrolled more than 60% primary refractory patients and more than 40% refractory to last therapy across both arms. Let's look at summary of the key efficacy results. The study met the primary endpoint of PFS with a statistically significant hazard ratio of 0.73 and a two-sided p- value of 0.008. No detrimental effect was observed on the key second efficacy endpoint of overall survival. The OS hazard ratio was 0.96 and was impacted by the earlier use and higher rate of new anti-lymphoma therapy in the control arm.
A higher CR rate was observed in the ZYNLONTA plus rituximab arm. In addition, a longer duration of CRs was seen. Importantly, a higher proportion of CRs were maintained at 24 months in the ZYNLONTA plus rituximab arm. Finally, the results seen in the North America region were consistent with the overall study results. Going deeper into the results, as noted, the study met the primary endpoint of PFS per independent review committee with statistical significance, and a hazard ratio of 0.73 and two-sided p- value of 0.008. Median PFS was 6.1 months for ZYNLONTA plus rituximab versus 4.7 months for R-GemOx. Looking at the Kaplan-Meier curve, you can see good early separation that was maintained throughout the entirety of the curve with a long tail, as reflected by the event-free rate.
You can see here at 18 months, the event-free rate is 25.1% versus 14.7%, and at 24 months, it is 23.2% versus 9.5%, favoring the ZYNLONTA plus rituximab arm. Looking at PFS by investigator assessment, results showed a hazard ratio of 0.65 with an improvement in median PFS of 5.5 months in the ZYNLONTA plus rituximab arm compared to three months in the control arm. The difference seen between this PFS assessment and the PFS assessment by IRC is mainly driven by lower early censoring in the investigator-reported data. The main reason for early censoring were starting new anti-lymphoma therapy without confirming progressive disease, no post-baseline assessment, or consent withdrawals. Additional analysis evaluating time to treatment failure, or TTF, is typically used to mitigate the impact of early censoring. TTF accounts for time to progressive disease, death, new anti-lymphoma therapy, or discontinuation from any other reason.
This analysis also shows a meaningful difference in favor of ZYNLONTA plus rituximab with a hazard ratio of 0.64 and a median TTF of 5.19 versus 2.76 months. Turning to the key secondary endpoint of overall survival, there was no detrimental effect observed. The overall survival had a hazard ratio of 0.96 with a median of approximately 12.2 months in both arms and did not achieve statistical significance. The OS results were likely impacted by earlier use and higher rate of new anti-lymphoma therapy in the control arm. Of note, the main cause of death in both arms was progressive disease. Moving to overall response rate, the ORR was 58.1% in the test versus 45.2% in the control arm. Importantly, the CR rate was 39.5% in the ZYNLONTA plus rituximab arm versus 26.7% in the control arm. The median time to best overall response was 44 days in both arms.
The median time to complete response was 49 days with ZYNLONTA plus rituximab as compared to 65 days with R-GemOx. The duration of response was 9.2 months versus 7.7 months, and duration of complete response was 16.8 months versus 12.3 months, both in favor of ZYNLONTA plus rituximab. Importantly, a higher proportion of CRs were maintained at 24 months, 48.5% versus 16.7%, also in favor of the test arm. Turning now to a summary of the key safety results. The overall treatment- emergent adverse events, or TEAE, rates were similar between treated arms. Similar rates of overall Grade 3 or higher TEAEs greater than 5% were observed across both arms. Hematologic TEAEs were higher in control arm, whereas infection, hepatotoxicity, and edema effusion were higher in the test arm. SAEs, TEAEs leading to study drug withdrawal, and Grade 5 events were higher in the test arm.
Of note, the majority of Grade 5 TEAEs in the test arm occurred in patients aged 75 years or older. In this study, TEAE reporting window was defined as 105 days after the last dose of the study treatment or start of a new anticancer therapy, whichever is earlier. The rate of TEAEs were impacted by the longer overall TEAEs observation time in the test versus control arm. This difference was primarily driven by the higher rate of an earlier switching to subsequent therapies in the control arm. Going deeper now into safety results. The total TEAE rate was similar between the two treatment arms. Similar rates of total Grade 3 or higher TEAEs were observed across arms. As noted, SAEs, TEAEs leading to study drug withdrawal, and Grade 5 TEAEs were higher in the test arm.
When it comes to Grade 5 TEAEs, 13.2% were in the test arm versus 4.6% in the control arm. Of these, six or 2.9% and two or 1% were deemed to be treatment-related by investigators in each arm respectively. The majority of Grade 5 TEAEs in the test arm occurred in patients aged 75 years or older. The highest observed Grade 3 or higher TEAEs, more than 5%, were hematologic, followed by infection and infestation, hepatic toxicity with gamma-GT increase as the primary driver, and edema effusion. Hematologic TEAEs were higher in the control arm. Infection, hepatic toxicity, and edema effusion were higher in the test arm. Looking at analysis from the start of treatment to key safety events helps better explain the impact of the safety observation period on the rate of TEAEs reported.
This analysis showed the median time to key safety events, including any Grade 3 or higher TEAEs, serious TEAEs, or TEAEs leading to study drug withdrawal, was longer in the test versus control arm. This showed more event-free time in the test versus control arm. Here, you can also see the rates of TEAEs impacted by the longer overall TEAEs observation time in the test versus control arm. Longer overall TEAE observation time led to more reported events with ZYNLONTA plus rituximab. This difference was primarily driven by the higher rate of and earlier switching to subsequent therapies in the control arm. Looking at overall treatment- emergent Grade 5 events, the median age of patients with Grade 5 TEAEs was 76 versus 74 years old in the test versus control arm.
Infection was the leading cause across both arms and was higher in the test as compared to the control arm. The main type of infection in the ZYNLONTA plus rituximab arm was bacterial. Of all Grade 5 TEAEs, 59% versus 22% occurred in patients aged 75 years or older in the test versus control arm respectively. The treatment exposure of Grade 5 treatment-emergent adverse events was a median of four cycles for ZYNLONTA plus rituximab and a median of two cycles for R-GemOx. Considering the overall safety profile observed with the combination of ZYNLONTA plus rituximab in patients aged 75 years or older in this study, we expect physicians would consider potential mitigation actions that might include assessing the immune system before treatment, considering prophylaxis, and being proactive in treating infection. Taken together, I look forward to discussing these trial results with the FDA in the coming months.
Now, I would like to turn the call back over to Ameet.
Thank you, Mohamed. Looking ahead, based on the totality of the LOTIS-5 data shared today, we plan to conduct a pre-sBLA meeting with the U.S. FDA in August with a planned sBLA submission, as well as presentation at a medical meeting to follow in the fourth quarter 2026. Separately, I'd like to share that our LOTIS-7 phase I-B trial remains on track to be fully enrolled in the second quarter of this year, and we continue to anticipate data readout later this year. In addition, the phase II IITs in marginal zone lymphoma and follicular lymphoma are expected to read out between the end of this year and middle of next year. Before we move to Q&A, we would like to extend our gratitude to the patients, investigators, and clinical teams, as well as to all our employees who contributed to this important trial.
We can now open the line for questions. Operator?
Thank you. Ladies and gentlemen, we will now begin the question and answer session. Should you have a question, please press star one on your touch-tone phone. You will hear a prompt that your hand has been raised. Should you wish to decline from the polling process, please press star two. If you're using a speakerphone, please lift the handset before pressing any keys. One moment, please, for your first question. Your first question comes from Eric Schmidt of Cantor. Your line is already open.
Thank you for taking my question, and appreciate the very comprehensive update here. In terms of the Grade 5 treatment-emergent adverse events, it looks like in the ZYNLONTA plus rituximab arm that the total rate here is a little more than maybe double what you saw in LOTIS-2 and also higher than what we've seen from LOTIS-7. Is there a rationale in your mind for why we're seeing a higher absolute rate of Grade 5 events? Is it patient selection? Is it combination with rituximab? Is it entry criteria? Any thoughts?
We believe that one of the main likely reason of higher observed Grade 5 in the test versus control, or versus others, the reporting or the observation period in the control arm was much longer compared to the test arm, which have contributed to more. Can you hear me well, sorry?
Well, Mohamed, I was.
In the test-
My question was more just about the absolute rate of Grade 5 events at about 13% here in this study. I think in LOTIS-2 it was much lower, at about 6%. I don't think we've seen anything like that even in LOTIS-7. Wondering what about these patients or this trial has an elevated rate in your mind?
Yeah, I think one of the things, and I'll turn it to Mohamed. One of the things is you had a large portion of patients, over 40%, that were over 75 years of age. Most of the patients with the Grade 5 events happened in that over 75 population, mainly due to infections. Obviously, for LOTIS-2 it's the same agent, so it's a different regimen. For LOTIS-7, to your point, in the first 49 patients reported, we saw quite a low rate of Grade 5 AEs, only two of the 49 patients, so mid-single digit.
In addition, as I mentioned to you also, LOTIS-2 has reported treatment-emergent adverse events within 30-day window. This trial has reported into 105-day window. Again, the more observation time, the more adverse events you will see in the control arm. A comparison between trials sometimes is hard in order to have single-agent, single-arm versus randomized trial.
Thank you very much.
Your next question comes from Maury Raycroft of Jefferies. Your line is already open.
Hi. This is James on for Maury. Question. Just going on the Grade 5 imbalance, what gives you confidence that the FDA will be willing to address this through label language with age-based restriction, for example, rather than viewing it as a benefit-risk gating issue? Is there any precedent either in DLBCL or broader hema- onc for an age-based label restriction? Just adding on to the last question, did you see any infection risk in the patients less than 75 years old? Was there a difference there between treatment and control?
Yeah. The majority of Grade 5 TEAEs in ZYNLONTA arm was in the elderly patient population, and we believe that the longer overall the observation time also have contributed to more reporting in the test versus control. Also, the difference was primarily driven by higher rate and earlier switching to subsequent therapies. That's why you have shorter reporting in one versus the other. We can't really speculate on what the label will be at this time. However, in hematology, there's several labels that actually address specifically 75 years or older for special warning and precautions on how to manage those. KOLs typically know how to treat elderly slightly different than the typical patient you will see non-elderly, or non-75 years or older.
Yeah. Just a quick follow-up. How are you thinking about the read-through from today's update to LOTIS-7? Do you plan to amend the LOTIS-7 protocol at any point, or you just don't see any read-through there?
No, no, we're not planning to amend the protocol. We've already shared, obviously, 49 patients, as I mentioned. In that, the Grade 5 TEAEs was quite low. It was only two of 49 patients, one related and one unrelated. It's quite low. There's nothing we're going to do to amend LOTIS-7.
Great. Thanks for taking my question.
Yeah. Thank you.
Your next question comes from Michael Schmidt of Guggenheim. Your line is already open.
Hey, thanks for taking my question. Yeah, maybe just one more on the Grade 5 rate being higher perhaps than expected. I guess, how do you think physicians will weigh, if approved, the positive PFS benefit? The CRs were really durable, it looks like. How will they balance that with the Grade 5 event risk, perhaps relative to other therapies? Do you still feel confident in the value proposition of the combination in second-line DLBCL?
Great question. First, I want to highlight that this is a trial that met the primary endpoint of PFS. Also, there's no detrimental effect on OS. High CR rate and durable observed, as I mentioned, almost 50% of patients at 24 months kept their CR at that time. It's typically a discussion that we will have with the FDA with planning into the totality of the data and the benefit risk. We would be prepared, of course, to address the positive benefit risk of this regimen for future use.
Given that maybe, Mohamed, you can comment, given that the majority of the Grade 5 is driven by infection, the leading cause of those infections or the leading type of those infections was bacterial. How would a physician manage that or think about how to mitigate that risk?
Typically, a prophylactic antibiotic or use antibiotic during the treatment. Also importantly, that they evaluate the level of immunoglobulins at baseline before they start the treatment, make sure the patient immune status overall, and that's easily treatable by IVIG. There's other methods to address that. Typically, KOLs understand better they're 75 years old and the needs of treatment, and they are able to address that. As I mentioned, several label have already address separately in the label how to talk about or how to treat 75 years or older in the label for hematology.
Thank you. Appreciate it.
Your next question comes from Leonid Timashev of RBC Capital Markets. Your line is already open.
Guys, thanks for taking my question. I wanted to follow up on this imbalance in the follow-up therapies that patients had. I guess when you say novel anti-lymphoma therapies, I guess what exactly are you referring to there? Is there any particular reason there may have been an imbalance there? I think you mentioned that you tried to adjust for that. Can you just talk a little bit more about that analysis as well? Thanks.
Yes. You mean follow-up for safety, right?
You say earlier, switching for next available therapy.
Yeah.
Basically, look, what we saw in this study and in R- GemOx, a lot of times physicians aren't happy with the results and want to switch. We observed in this study, as you've seen in other lymphoma studies as well, is there was a significantly higher rate of prior rates and earlier levels of switching. That's why you see discordance, like for example, you probably saw in the study some discordance between the IRC and investigator assessments because you see basically a lot of that earlier censoring happening because of the much higher rates and earlier switching to next available therapy.
Your next question comes from Sudan Loganathan of Stephens. Your line is already open.
Hey, thanks for taking your question here. This is [Keith Avan] for Sutan. Just a quick one from us. If you could provide your thoughts on how maybe these results have impacted your view and forward strategy within the 2L+ DLBCL space, that'd be great. Thank you.
Yeah, we're moving forward. We're preparing right now a briefing book request to meet with the FDA in June. We intend to have a meeting with them in August, a pre-sBLA meeting to discuss the path forward. That's where we'll share the data and get feedback on how to move this forward. It hasn't really changed our plans in terms of moving LOTIS-5 forward. Obviously, how we move that forward and what the label and other things look like will depend on this conversation with the FDA. We're continuing all the other studies, as I mentioned. LOTIS-7, we'll expect to read out later this year. The IIT studies for marginal zone data by the end of this year and follicular by the middle of next year. All these other studies are ongoing and moving forward.
Ladies and gentlemen, as a reminder, if you have a question, please press star one. There are no further questions at this time. I would hand over the call to Nicole Riley for closing comments. Please go ahead.
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.
Ladies and gentlemen, this concludes today's conference call. Thank you for your participation, and you may now disconnect.