Good morning, everyone. Welcome to Day 2 of the Needham Healthcare Conference. I'm Ami Fadia, Biotech Analyst here at Needham. It's my pleasure to be hosting ADC Therapeutics for the first session of our Day 2. Ameet Mallik, welcome. Thank you for taking the time to do this presentation. Just a quick reminder for our listeners, if you want me to ask any question on your behalf, feel free to send it over through the dashboard, and I'll turn it over to Ameet.
Thank you, Amy. I appreciate the opportunity, and welcome, everyone. I look forward to sharing with you a little bit about ADC Therapeutics. Nicole, if you can go to the next slide. ADC Therapeutics is a commercial-stage pioneer in the field of antibody-drug conjugates. We have specialized capabilities that are end-to-end with a variety of different technologies, whether they be payloads, linkers, conjugation chemistry. We have been working a lot on next-generation, highly potent ADCs. We have an approved product in Zynlonta as well as an early-stage solid tumor portfolio. We have been delivering on our strategy with a very strong team, and we have a cash runway that goes into the second half of 2026. If you go to the next slide, our portfolio really is, as I mentioned, centered on two different pillars. The first is on hematology.
Where we have an approved product is Zynlonta, which is approved in the third-line plus DLBCL setting as a monotherapy. It's already commercially profitable, meaning that the sales that we generate more than offsets all of the commercialization, medical affairs, headcount, and cost associated with the product. The much bigger opportunity as we move into earlier lines of DLBCL and into indolent lymphomas. We have our LOTIS-5 study, which is combined with rituximab. It's a phase III study. We have our LOTIS-7 study combining with bispecifics, and we have indolent lymphoma studies. In addition, we have our second pillar, which is our solid tumor platform using our novel exatecan-based payload.
It's a differentiated platform using a very novel hydrophilic linker, and we have four different targets that are in the IND enabling stage: PON6, PSMA, which are the two most advanced in that group, but also NaPi2b and ASCT2. We're in the process of advancing one of those candidates to IND, but more broadly, looking for research collaborations to finance a broader portfolio to move forward. This is just an overview of the pipeline that I mentioned. As you can see, the majority of the activity is really around Zynlonta, coupled with this early-stage pipeline I mentioned in solid tumors, which is beyond the IND enabling stage and now progressing towards IND. This is just some of the leadership team that we have.
It's a very experienced team with 20 to 30 years of experience both in pharma and biotech, multiple critical experiences that people have had with very large-scale leadership as well as kind of very agile leadership in biotech. Very excited about the team that we've been able to build, not only at a leadership team level, but across the whole organization with really proven expertise, all the way, again, from preclinical research through commercialization. Let me dive into Zynlonta now. Zynlonta, as I mentioned, is approved right now as a monotherapy in the third-line plus DLBCL setting. It really is ideally suited across care settings for our patients in that relapsed refractory setting. It's a CD19-directed ADC that's indicated, as I mentioned, as a monotherapy for treatment for patients with relapsed refractory large B-cell lymphoma with two or more prior lines of therapy.
It's really third-line plus DLBCL. Now, there's a few features of the product that are important to note, especially as we get into combinations. These attributes really differentiate the product. First, it has really rapid, deep, and durable efficacy. The median time to the CR is only one and a half months. You achieve a CR very quickly. Overall, as a monotherapy, even in this very late-line setting, we have deep responses. 48.3% overall response rate with a 24.8% complete response rate. Those CRs are very durable. Of course, getting deep response is important, but durability is key. We have a median duration of response that wasn't yet reached, even with two years of follow-up for those CRs. We have a very manageable safety profile.
We don't have any CRS or ICANS, like you see with other therapies, or cumulative irreversible toxicities, like what you see, again, with chemotherapy and other therapies that are often used in this class. Very accessible because it's just a fixed duration dosing, Q3-week dosing, with no ramps or inpatient stay requirements. It is very, very convenient for physicians to administer to patients with a simple 30-minute infusion every three weeks. Again, typically, what you're seeing in monotherapy is three to four cycles; in combination, can be up to eight cycles. Now, here's the strategy. We're playing in a relatively small space today, which is that third-line plus DLBCL setting as a monotherapy. The strategy is really to expand the use of Zynlonta. First, we want to expand into the second-line setting in combination.
We have our LOTIS-5 study, as I mentioned, which is looking at Zynlonta plus rituximab. It is currently a phase 3 study that is fully enrolled, which we expect could read out by the end of this year. If you look at the safety run-in data, because we were approved via accelerated approval, we did a safety run-in before we went into the randomized portion of the study. That 20-patient safety run-in data showed an overall response rate of 80% with a CR rate of 50% and no new safety signals versus the monotherapy. We are also looking at the combination of Zynlonta plus the bispecific glofitamab. We have seen very promising initial efficacy data, 94% overall response rate with a 72% complete response rate in the initial 18 efficacy-available patients. Also, very manageable safety profile.
I'll go through more of the details in the 29 patients that were available for safety. Beyond DLBCL, we're also expanding into indolent lymphomas. We've demonstrated very strong data in that setting as well. Recently at ASH in December, data was presented looking both at Zynlonta plus rituximab in the high-risk relapsed to refractory FL setting. In that setting, in the first 35 patients available, Zynlonta plus rituximab demonstrated a 97% overall response rate and a 77% complete response rate. There was also a poster presentation with Zynlonta monotherapy in relapsed refractory MZL, marginal zone lymphoma, where in the first 23 patients available, there was a 91% overall response rate and a 70% complete response rate. We've really seen consistently strong efficacy as we've been moving Zynlonta both in combination as well as into different settings of care.
Now, how does this translate into an opportunity? As I mentioned today, we're really playing in that third-line plus monotherapy. That's really the smallest part of what the opportunity is. Typically, sales have been in the $16-$18 million range post the bispecific entry. We finished the year with $69 million in sales, which was the same as what we had the prior year. We've kind of been stable in that range. The real big opportunity comes as we move into different lines of therapy and combination. With our second-line plus Zynlonta plus Rituximab opportunity, that will take the total opportunity for Zynlonta to $200-$300 million. When you think about it, you're doubling the number of patients. We're increasing the duration of therapy by over 50%. The efficacy we expect to get much better than the monotherapy.
All those factors start leading to an opportunity that can get into the $200 million-$300 million range. When you look at bispecifics, with both an approval and compendia listing, we could take this opportunity to $500 million-$800 million in total for the brand. Bispecifics will no doubt be the biggest segment of the relapse refractory segment. We believe we have the chance to have best-in-class efficacy and safety profile with our bispecific combination with glofitamab. I'll review some of that data in this presentation. Beyond DLBCL, we also have an opportunity in indolent lymphomas where we're pursuing both regulatory strategy and compendia strategy. With that opportunity, that could be an additional $100 million-$200 million opportunity.
In total, we believe that the peak revenue opportunity for Zynlonta will go from where we are right now, which is $69 million last year, to roughly a $600 million-$1 billion opportunity, again, depending on the clinical profile and how the competitive landscape evolves over time. As you dive deep into the competitive landscape, there really are four classes of drugs that exist in that second-line plus setting. First is cell therapy. These are really dominated by CAR-T. There is still some transplant, but the majority is CAR-T, which have really strong efficacy. Typically, you see CR rates that are 65%-70% and with a long tail. The durability is quite good with CAR-Ts. The safety profile is a little bit tougher, and they are less accessible because you only have about 150 CAR-T accredited centers in the US.
Because of the need to be at or near the hospital for roughly a month with someone with you, it's not very accessible to many patients. CAR-Ts have about 20% share, and that share has actually remained quite flat over the last couple of years. On the other extreme, you sort of have chemotherapy, which is actually the least effective therapy, only about 25% CR rate. Doesn't tend to be very durable either. The safety comes with some irreversible toxicities like neuropathy and other irreversible toxicities, but it's very easy to give. Physicians are comfortable with it, especially in the community. It's still actually used quite a bit, more than you would expect given the efficacy difference with some of the other therapies. Bispecifics are emerging and really expected to become the biggest class of drugs in that relapse refractory setting.
Up to this point, they've only been approved as a monotherapy in the third-line plus setting. As they move into combination in the second-line setting, you see efficacy in that 58-62% range from a CR standpoint. Durability, as a monotherapy, looked good. You will see how that plays out in combinations. The safety is, of course, better than a cell therapy, but you still have CRS and ICANS, which oftentimes requires hospitalization. You see the penetration in the community, although it started much more limited than what you would see in the academic setting. That, of course, hampers some of the accessibility in that broader kind of community setting. Nonetheless, as they move into earlier lines with multiple combinations, this is projected to kind of grow the class.
ADCs and monoclonal antibodies, which there are a number that have been approved in a second-line setting, typically have efficacy up to 40% CR rates. There's, again, an opportunity here, not only as a class themselves, but across ADCs plus bispecific combinations to really expand the opportunity. Today, the efficacy is worse in bispecifics, but again, there's an opportunity to really improve that. The safety, of course, is better than a cell therapy and a bispecific, and they're very accessible. Like chemotherapy, really any physician can administer these products. That's a big advantage. You can see we're really playing in the two segments that are projected to grow: bispecific-based combinations and ADC-based combinations.
With our LOTIS-7 and LOTIS-5 trial, we believe we have a chance to really disrupt the treatment landscape and to lead in the two segments of the market that are projected to grow. Ultimately, physician treatment choices are not just driven by efficacy because if they were, CAR-T should have 100% share. At the end of the day, physicians are always balancing the treatment of efficacy, safety, and accessibility based on those individual patient considerations. Not only in terms of the clinical profile of the patient, but the accessibility that that patient has to different centers. If we go to the next slide, I'll dive a bit deeper now into LOTIS-5, which is our confirmatory phase 3 study of ZYNLONTA in combination with rituximab, again, in that second-line plus DLBCL setting. These are second-line plus DLBCL transplant ineligible patients.
The primary endpoint's PFS, but of course, a lot of other key endpoints like overall survival, ORR, CRR, duration of response, and other key factors. As I mentioned, we did a safety run-in. Given that the accelerated approval was based on the monotherapy, we did a safety run-in where the first 20 patients showed an 80% overall response rate and a 50% CR rate, no new safety signals. We have now since completed the randomized portion of the study that was done by the end of last year. We are now waiting for the events to happen. We expect top-line results could happen by the end of this year once the 262 prespecified PFS events are reached. Of course, the timing is events-driven. The exact timing is going to depend on when we hit those events. Once we do, we plan to then submit to regulatory authorities soon after.
When you look at the competitive landscape on the lower left, you can see that LOTIS-5, whereas a monotherapy, we have about roughly a 20% CR rate, which is more akin to chemotherapy, of course, more durable without all the side effects. You can see how LOTIS-5 can bring the therapy, if the data holds at 50%, to be really the best in class outside of the CAR-T and bispecific combinations. We know that not all patients are going to have access to or be suitable to a bispecific or CAR-T. Also, many of them, unfortunately, will progress. For all those patients, having a best-in-class combination like LOTIS-5 really provides a great opportunity for us. One of the things we did was to look at some quantitative market research because, as you know, there's a lot of different classes coming in.
There's a number of bispecific combinations getting approved. There's the ECHELON-3 data that came out. There is a lot of new combinations coming out. We asked independent market research companies to do quantitative market research to really sort of anticipate where is this market moving and where is it expected to go. In the second-line setting, you can see CAR-Ts, which are just over 20% share, are expected to be roughly stable. Within that 78% share today, most of those are either ADC or antibody-based therapies or chemotherapy, which is still actually used quite a bit. What you can see is CAR-Ts are expected to be roughly stable. Bispecific-based combinations are expected to become the biggest part of the market. Together, CAR-Ts and bispecifics capture about 50% of the market.
You can see that Zynlonta, as it would be if, again, the data holds at 50% with strong durability, you can see that the physicians project roughly a 14% share for Zynlonta plus rituximab. Given that Zynlonta, not only do you have more patients in that second-line setting, what we're seeing is a higher duration of therapy. Typically, instead of the three or so cycles that we get with Zynlonta monotherapy, we see about five cycles we expect to see with Zynlonta plus rituximab. When you couple the greater number of patients plus a longer duration of therapy, each of these share points is worth roughly $15 million. You can see how 14% translates to a lot. Even if we only got 10% share, that's a roughly $150 million opportunity just in the second-line setting. It is a pretty significant opportunity for us.
Not all patients are going to have access to bispecifics and CAR-T. Not all are going to be suitable for them. Many are going to also, unfortunately, progress. You get to the third-line setting where we can play in the 50% in the second line where patients do not get access to or are not suitable for CAR-T or bispecific. When you get to the third-line setting, that also includes patients that have also progressed post them. In the third-line setting, you can see that, again, bispecifics and CAR-T will play a big role because these therapies can be sequenced. You may get a CAR-T second line and then a bispecific third line or vice versa. Nonetheless, you still see that therapy Zynlonta combination really expected to take a lot higher share. We are roughly 9% share, 9-10% share.
It is expected to more than double based on this market research because, of course, the efficacy going from 25% CR rate to roughly 50% CR rate puts us closer to chemo from a response rate, although, of course, more durable and safer, but to one in which you could be kind of best in class amongst those non-CAR-T bispecific therapies. Again, here, even if we took the share down and said, "What if it was only 15% share, 14% share?" That could still be $150 million another opportunity.
You can see how getting to $200 million-$300 million, given that we have a better efficacy profile, we're doubling the number of patients, we're increasing the duration of therapy by more than 50%, there's a real place for Zynlonta to play, not only in the second-line setting, but in the later line settings as well, and to gain share versus where we are today as a monotherapy. Now I'm going to turn to LOTIS-7. We're really excited about this. This is the combination that we look at with Zynlonta with the bispecific-based therapies. We did a dose escalation where we looked actually across NHL patients, both at Zynlonta plus glofitamab and Zynlonta plus mosunetuzumab. We looked at the full doses of those bispecifics with three different doses of Zynlonta: 90 micrograms per kilogram, 120 micrograms per kilogram, and the approved dose of 150 micrograms per kilogram.
We had cleared all the doses, no DLTs with any of the combinations. We decided to move forward with Zynlonta plus glofitamab since they're both approved agents in DLBCL and really two of the most potent agents that have been approved in DLBCL. We're looking at two different dose levels, the 120 micrograms per kilogram and the approved 150 micrograms per kilogram dose of Zynlonta with the full dose of glofitamab. What you can see below is in terms of how they're dosed, obinutuzumab, as per the label of glofitamab, is given on day one. Then Zynlonta is given on day two to debulk the tumor. You do the step-up dosing of glofitamab. From cycles two to eight, you give both therapies concomitantly on the same day. They're both every three-week dosing. Zynlonta can be given for up to eight cycles, glofitamab for up to 12 cycles.
Cycles 9 to 12, if the patient's still on therapy, would only get glofitamab. This was the design of the study. Again, we completed the dose escalation, and we're currently in dose expansion right now. I'll share some of the initial data that we shared in December. This was with a data cutoff as of November 20. We had 29 patients in the safety available population because, of course, we can include some of those patients not only in the dose expansion, but in the dose escalation across the different histologies. You see baseline patient characteristics, which are very similar to the other bispecific studies. You see whether it be the histology, the IPI scores, Ann Arbor stage, you see it's a good representation of risk status. There were immediate prior lines of therapy of two, and prior CAR-T therapy was about 24%.
In addition, we see quite a few patients that were refractory to primary therapy or to last prior therapy. This is a pretty tough patient population and very similar, again, to what you've seen with other bispecific-based combination studies. If you look at the next page, this is just an overview of the safety. Now, what we know is most of the adverse events are actually not overlapping between glofitamab and Zynlonta. For most of the grade 3, 4 adverse events of special interest, you see kind of one-off events, which are all adverse events that are either attributable or unknown with either glofitamab or with Zynlonta. No surprises there. What we were pleasantly surprised by is where there is overlapping toxicities on some of the heme toxins.
Each of the products, glofitamab and Zynlonta, have neutropenia with grade 3 or 4 or higher, roughly of 30%. You see we saw something very similar in the combination. We did not see additive heme tox so far in this initial patient set. Also, the discontinuation rate was relatively low, which was good to see within this trial so far. Now, CRS and ICANS is obviously one of the downsides within the bispecifics. We were pleased that if you look at the CRS rate, overall, it was half the level of what you see with glofitamab monotherapy. We had 34.5%, which is roughly half of the 70% level that is in the label of glofitamab. Most of that was grade 1 and could be managed with acetaminophen. There were a couple of grade 2 cases as well, which could be managed with tocilizumab, corticosteroids, and fluid bolus.
We did not have any requirement for ICU admittance or pressure support, which is important. Also, ICANS, there were two cases of low-grade ICANS. Both patients had complete resolution of their symptoms. One patient resumed treatment and ultimately achieved a CR and still remained in a CR as of the follow-up that we shared in December. Both patients could just be managed primarily with corticosteroids. If this profile keeps playing out, this is really encouraging to make bispecific-based combinations more accessible across the community setting. When you look at efficacy, we were really pleased to see the efficacy because, as I mentioned, if you look at all the competitive bispecific data that ends up being in that 58-62% range from a CR standpoint, obviously, not just response that matter, durability. I will show you some of that initial data on the next slide.
If you look at just the response rates, overall response rate across the two dose levels of 94% with a 72% complete response rate. This right now is really encouraging to see north of a 70% CR rate in these initial 18 patients. Again, if this data holds, we think it has a chance to really be a best-in-class bispecific combination and really to change the treatment paradigm in that relapse and refractory setting. This is a Swarmers plot. What you can see is really durable. Twelve of the 13 CRs remained in CR as of the data cutoff. Only one patient progressed. Most of those patients, about eight of those patients, had CRs at the initial assessment. Five patients did convert from either a stable disease or a PR to a CR over time.
That is one of the phenomenons we know with Zynlonta is when we're giving you these response rates, they're the best overall response as of the data cutoff. When I quote the other competitor data, it was the best overall response rate throughout the whole course of the study. There is always a chance that you can have conversions. We know with Zynlonta, even in the monotherapy study, about 25% of patients who started as a partial response ultimately converted to a complete response. You can still, we still have those four partial responses that are all currently ongoing when we did this data cutoff. Now turning to indolent lymphoma. This is marginal zone lymphoma. Marginal zone, there are about 3,000-4,000 relapsed refractory marginal zone patients in the US. Very few options for these patients.
There are only two approved therapies, a couple others that are in the compendium and NCCN preferred guidelines. You can see that if you look at the lower left, the response rates, really only complete response, it's only up to about 29%. The biggest class of these drugs is really the BTK inhibitors, which are also not fixed duration. Patients have to keep taking the BTK inhibitors for the duration of their treatment. That is another downside. Right now, there is a phase two IIT that is being conducted by Dr. Lossos at University of Miami. This is a 50-patient multicenter study of which 23 patients were enrolled and then evaluable for this presentation that happened at ASH. Overall, response rate of 91%, CR rate of 70%. This is really outstanding.
When we talk to physicians, they say if you can get over 40% and you maintain good durability with a good safety profile, given that this is an indolent lymphoma, that would be outstanding data. We are excited about this. University of Miami and City of Hope are enrolled. Emory recently is on board too. Additional sites will be coming on board as well to enroll the full 50-patient study. Once we have the results of this and data is published, we plan to pursue both regulatory pathway as well as compendia in parallel. Once again, we have the data sufficiently available from these 50 patients. We turn now to follicular lymphoma. Again, really strong data. This was an oral presentation, the last two ASHs in a row. This data was also simultaneously published in Lancet Hematology this past December.
If you look at the follicular lymphoma data, you look at the lower left, it's obviously a lot more crowded segment than MZL, where there's very few options. Here, you do have a lot of options. CAR-T therapies, which have the highest efficacy, are not always very accessible, typically given in later line settings and have relatively low share because, again, the safety profile that's acceptable in this indolent setting is much different than in a more aggressive lymphoma like DLBCL. These patients tend to progress slowly, oftentimes multiple years between lines of therapy. Many of these patients don't die of the disease. The safety profile really matters a lot.
We're excited that even when we studied in the high-risk population, including more than half the patients who are POD24, meaning patients that progress within 24 months, where the average patient mainly progressed after five years, we saw an overall response rate of 97% with a CR rate of 77%. This study is enrolling now 100 patients. Once we have that study completed, we again plan to pursue both regulatory pathway and compendia in parallel. Once again, the data is available on the 100 patients. Now, beyond Zynlonta, we also have a really growing toolbox with novel payloads, linkers, and conjugation chemistries. This has been built up over the last decade with really strong end-to-end capabilities where we've been able to, with a high degree of success, translate technology and biological ideas into novel compounds. The most advanced of our platforms is a novel exatecan-based platform.
Here's the next slide. Our exatecan really has advantages over traditional topoisomerase-based platforms like DXT, for example. One of the things with exatecan that's tough to work with is it's highly hydrophobic. Because of that, you need a very novel linker system that's hydrophilic enough to create stability within the delivery of the molecule to make sure that we could trace this and release exatecan into the cells. We know exatecan has a lot of advantages. It has higher bystander effect and potency, has a lower risk of multi-drug resistance. We don't see the interstitial lung disease in the monkey studies we've conducted, which you do see with DXT, and we've seen a much higher therapeutic index. We've tested our ADCs against DXT, and we see superior potency, efficacy, and so far better tolerability profiles, especially when it comes to ILD.
We're excited about the exatecan platform. Again, the novel part is really the linker because you have to offset that hydrophobicity of the exatecan. We have four different molecules that are on that IND enabling stage. CLON-VI and PSMA are the most advanced and closest to the clinic. We're moving one of those forward to IND, and then we are seeking a research collaboration in order to advance our portfolio forward as we've only funded these programs up to a point and then really require collaboration to be able to continue beyond that as we're really allocating the majority of our capital right now to Zynlonta. Our strategy in hematology, we focus on the US where we commercialize the product. We have ex-US partners to help commercialize the product as well as to help fund some of the development expense with Zynlonta.
As solid tumors, as I mentioned, the strategy is really to focus on more BD opportunities to unlock the value and to be able to resource and be able to fund a broader portfolio through partnership. These are some of the key milestones. With LOTIS-7, we plan to enroll 40 patients, which are planned currently in the dose expansion in the second quarter. In this quarter this year, we'll also be giving another update with additional patients, not all 40, but a good subset of the data, as well as longer follow-up. In the second quarter of this year, we'll have full data on all those 40 patients with much more mature follow-up in the second half of this year. We plan to engage with regulatory agencies and evaluate compendia strategy in the later part of this year and as we get into 2026.
With LOTIS-5, we expect top-line results by the end of this year. Again, that's events-driven because this is a PFS events-driven trial. We expect it could happen by the end of this year, possible that it goes into early next year depending on the timing of the events. As soon as we get those top-line results, we plan to submit the BLA to the regulatory authorities and expect that we could have potential compendia listing and BLA approval by the end of 2026. For indolent lymphomas, we expect to have more data presentations at medical conferences on the indolent lymphomas. With solid tumors, as I mentioned, we're advancing the portfolio of compounds and in parallel, really pursuing business development right now to fund the early-stage pipeline. I want to thank you very much and open to any questions you may have.
All right. Thank you, Ameet. That was a great presentation. Maybe I want to just dig into the LOTIS-5 and the LOTIS-7 data updates. Perhaps we can start with LOTIS-5, which is ZYNLONTA combined with rituximab. We've obviously seen that 50% complete response rate previously. How do you see that data evolving with kind of the top-line data update? I mean, obviously, that was sort of an initial safety run-in. Help me understand, as investors think about what type of data update we could get, right, as we see more mature kind of data later this year, what's sort of the risk around the response rate data that you've seen previously?
Yeah. I mean, as you mentioned, LOTIS-5 is an event-driven study. We expect to see results once we hit those prespecified number of events.
I think the fact that it's a non-systemic chemo combination really offers Zynlonta and rituximab advance, especially as there's still a lot of chemo use in this setting. The fact that it's fixed duration, has a really strong safety profile, and really convenient dosing to the 30-minute infusion of Zynlonta makes it really kind of widely—I think will make it widely accessible across the different settings. Again, when you look at those non-CAR-T, non-bispecific options today that are approved, and there's really no other anticipated that are not bispecific-based combinations in the future. In that second-line setting, the CR rates are between 25-40%. Remember in that safety run-in, we saw a 50% CR rate. I think anything north of 40% makes this very competitive. We have some buffer, even if we're in a slip, but not that we expect it to.
We expect that we hopefully can maintain that CR rate at 50%. Of course, durability of the CRs matters too. We are going to be reading out a lot of things, but the durability and what we are really pleased is that even as a monotherapy in that third-line setting, with so later-line setting just as a monotherapy, we saw that we never even reached the duration of response for those CRs after two years of follow-up. If we can see not only deep responses, but also durable responses with a manageable safety profile, I think it could be really highly differentiated, particularly as there is still a number of patients that either will not have access to be suitable for or will progress on a CAR-T or a bispecific-based therapy.
Remind us, what's the standard of care duration of response or median PFS for kind of the chemotherapy or all other bucket?
Y eah. It depends on the line of therapy. The PFS in the third-line setting, honestly, for almost everything's Zynlonta, bispecifics, almost everything's around four months, even CAR-T. It's very, very, very short. PFS is not necessarily the best indicator because when you talk to most physicians, they say, "I care about the depth of response and then the tail of the curve." You look at CAR-T, for example, there's some CAR-Ts even in the second-line setting that only have a nine-month PFS. There's other targeted therapies that have a longer PFS. The key is, can you get a really deep response and can you maintain a good portion of them for a long period of time?
Even if it's only 30% of patients that can maintain, but for years, that becomes almost like a functional cure that you see with CAR-T. What we're really looking at is, can we get a lot of patients in deep responses and can you, especially for those patients that get CR, maintain a large portion of them for a long period of follow-up? I think that would be a very competitive efficacy profile.
Is there kind of a bogey for that that you're looking for?
Yeah. I mean, I think if we get north of 40% CR and you have a substantial number of patients that kind of have—again, if we hadn't reached the median duration of response for CR like we saw with monotherapy after two years, I think that would be very, very good in terms of durability.
Okay. That makes sense.
With regards to LOTIS-7, you kind of talked about the data that we've seen so far. I think I'm just sort of trying to play devil's advocate here and say, is there any reason to believe that the data would deteriorate from what you've seen before? Because it obviously looks competitive based on what we've seen so far. You're going to provide kind of an additional update on the patients on which you'd already reported data. As that data matures and you're folding in more patients into the data reported, how do you sort of see that evolve?
Yeah. Look, it's small numbers. Data can obviously go up or down, but I would just say just as much as it could deteriorate, it could also go up.
Because remember, when I quote response rates of 58-62% for the other competitive-based therapies, that's with longer follow-up. That means that a patient achieved a CR rate at any point of time. If you remember, I've talked about conversion that can happen with Zynlonta from PRs to CRs. We've already seen it in the trial. We've seen it with monotherapy. It is also possible that some of those PRs convert. It could go either way, obviously. That's why we need larger data sets in terms of more patients and longer follow-up.
I mean, so far, what we've seen is very encouraging because to get over 70%, if we are able to maintain that over the 70% CR rate, I think over 60% is already competitive because typically, if you look at the bispecific combinations, they're either combined with chemotherapy, which has an unfavorable toxicity profile, a lot of irreversible toxicity like neuropathy, of which many patients have already been exposed to in the front line, or polatuzumab, which is also used more and more in the front-line setting. Physicians tend to not want to recycle it. The fact that we're not polo, not chemo, is already an advantage. If you're with a similar efficacy range, but you actually are a novel mechanism, there's already an advantage.
If we maintain the over 70% CR rate with a competitive durability and safety profile, I think it has a chance to be not only highly differentiated, but to really fundamentally change the treatment paradigm. We have to let the data play out, obviously, with more patients and more durability. Ultimately, the data is going to tell us the answer. I think if we maintain it, at least this initial data is very encouraging for us.
Okay. You've talked about pursuing sort of both regulatory filing and compendia listing. Can you help us understand sort of the path to compendia listing based on kind of the data readouts that you've laid out for LOTIS-5 and LOTIS-7?
Sure. With LOTIS-5, obviously, we have a full phase three study.
The basis of that phase three study would obviously get presented at Medical Congress, be published. The publication would be submitted right away to compendia. Typically, that happens a little bit before the approval just because it happens a little bit quicker. You typically see phase three studies getting into compendia and then soon after that, after regulatory approval. With LOTIS-7, what we've seen with the bispecific-based combinations, and really almost all the bispecific-based combinations have pursued the strategy, whether it's glofitamab, mosunetuzumab, or epcoritamab, all of those are now currently in guidelines with different combination partners based on roughly 100 patients from a phase one-two study. We see an opportunity with our LOTIS-7 to potentially expand up to 100 patients at the chosen dose level to be able to submit to guidelines.
That'll also form the basis for additional safety data and a larger sample set for us as we kind of then engage with the FDA on potential path forwards for a regulatory strategy. We think there is a faster path forward potentially with the LOTIS-7 in the compendia, as we've seen with all the other competitor bispecific trials, as we engage with the FDA and other regulatory agencies on a potential phase three path forward.
Okay. I'll try to squeeze in one last question in the time that we have left. Obviously, within ZYNLONTA, you have a lot of opportunities for meaningful growth over the next couple of years with what we've discussed. You also have a very interesting ADC platform. You mentioned you're looking for sort of a potential partner to sort of help fund some of the work moving forward.
Just maybe down the line, five years out or so, do you intend to sort of keep some of the ADC portfolio internally and kind of take it to the point of commercialization yourself, or is that something that you think about as a source of partnership and sort of revenue generation through that?
Yeah, I think it all depends. I mean, we certainly have the capability to do it. I think in this environment with the cost of capital, I think it's also just being focused and understanding where you think you can have the greatest chance to win is important. Prioritizing how we allocate precious and expensive capital is really critical. We have really made that choice to do most of that towards Zynlonta.
Over time, of course, as the company gets towards profitability, which we think we can start to do as soon as the end of 2027, because in 2027, you start having not only LOTIS-5 opportunity, potentially LOTIS-7 in guidelines, potentially the indolent lymphomas in guidelines. Of course, we're not going to promote anything off-label, but all those opportunities start to create a bigger opportunity for ZYNLONTA, which can help to fund also the next set of molecules. Certainly in the, I'd say, short to medium term, partnership's going to be key for solid tumor. Over time, I think we may have the ability to invest more on our own as the company gets profitable.
Okay. All right. Looks like we're out of time. Thank you so much, Ameet, for taking the time to be with us today. And thanks to all our listeners.
Yeah, thank you so much. I appreciate it. All right.