Iovance Biotherapeutics, Inc. (IOVA) Earnings Call Transcript & Summary

All right. I [ would ] ask if this thing is on, but obviously, it is. Good evening, everyone. My name is Friedrich Finckenstein, and I'm the Chief Medical Officer of Iovance. So welcome to our in-person and virtual event to review the clinical data highlights for our lead TIL therapy, lifileucel, in advanced melanoma. The results, as I'm sure you're aware, were presented earlier today by our lead investigator, Dr. Amod Sarnaik of the Moffitt Cancer Center, during a rapid oral presentation at the SITC meeting. The presentation includes efficacy results in 153 patients. across 2 consecutively enrolled cohorts on study C-144-01. These results are the basis for our ongoing biologics license application, or BLA, submission for lifileucel, which we are very excited about. The Iovance leadership team is grateful to be joined by Dr. Sarnaik and a panel of key opinion leaders within the field to hear their perspectives on the data. This is the agenda for today's call. Let's see -- that works too. That's good. First, I will give a very brief introduction and introduce our key opinion leaders in attendance. After that, Dr. Sarnaik will reprise his oral presentation of our C-144-01 clinical trial of lifileucel. And then Dr. Madan Jagasia, Executive Vice President, Medical Affairs at Iovance, will moderate a multidisciplinary KOL panel. We will then open to a question-and-answer session. We'll try to get to as many of you as time permits. Live webcast viewers have the option to submit questions online using the Ask Question tab on the upper right-hand corner of the webcast page. Here, you in the room, you will not have that option. You are here in person. On the next slide, Slide 3. I'll remind everyone that today's event will include forward-looking statements. You can follow along with the webcast presentation or access the slide deck in the Investors section of our corporate website at iovance.com. Before I hand the call over to the physicians, I would like to frame the opportunity for lifileucel patients with advanced melanoma. In the U.S. alone, there are nearly 8,000 deaths from advanced melanoma each year. After treatment with anti-PD-1 immunotherapy and BRAF/MEK inhibitors, if appropriate, there are no FDA-approved treatment options. Available care with chemotherapy offers only 4% to 10% objective response rate and about 7 to 8 months median overall survival. Based on the treatment numbers, you see on the right panel of this slide, there is a significant unmet need for patients after anti-PD-1 therapy. With that as background, I would like to welcome our KOLs participating in today's event. First, I will introduce Dr. Amod Sarnaik. Amod is a surgical oncologist in the Department of Cutaneous Oncology immunology program and melanoma center of excellence at Moffitt Cancer Center and has an appointment as Professor of Oncology and Surgery at the University of South Florida. He is the presenting author at SITC at this meeting and our lead C-144-01 investigator. Dr. Sarnaik, we look forward to your presentation as well as some additional details from C-144-01 that did not fit within the 8-minute rapid oral presentation that were allotted to our presentation at SITC. Following Dr. Sarnaik, we have assembled a panel of key opinion leaders within the multiple disciplines that are involved in TIL therapy. I call this the TIL triumvirate. They consist of a medical oncologist, a cell therapist and a surgeon to provide color and context of the data. They may also describe how they see lifileucel fitting into the melanoma treatment paradigm. Joining us today, we have Dr. Allison Betof Warner, Assistant Attending Physician and melanoma medical oncologist at the Memorial Sloan Kettering Cancer Center. Dr. Betof Warner is part of the TIL Working Group, a consortium of experienced key opinion leaders that collaborates in educating a broader network about TIL therapy. She has significant experience with Iovance's TIL clinical studies. Earlier today at SITC, she presented a trial-in-progress post for highlighting the design and objectives of our first-in-human study of genetically modified TIL IOV-4001. Dr. Miguel Perales, who is also at Sloan Kettering, is here to provide the cell therapists perspective. He is the chief adult bone marrow transplant service at MSK. Dr. Perales has deep experience with cell therapy and in operationalizing the first CAR-Ts to come to the market. To offer the surgeon's point of view, Dr. Martin McCarter has joined us from the University of Colorado Cancer Center. He is the Surgical Director for the Esophageal and Gastric Multidisciplinary Clinic as well as the Vice Chair for Strategy and Program Development Department of Surgery for the UC Health Cancer Care Anschutz Medical Campus. Thank you to the experts for participating and to everyone for joining in person and virtually. I look forward to the discussion. And Amod, I hand the podium to you. Thank you.

Thank you. Well, thank you for the kind introduction. The title of the talk is lifileucel monotherapy in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapy. This is a pooled analysis of consecutive cohorts, as Friedrich said, C-144-01 study. The patient population description is shown here. Patients have unresectable metastatic melanoma treated with more than one line of prior systemic therapy that includes PD-1 blocking antibody. And if the tumor has an activating mutation, the BRAF 600-codon, a BRAF inhibitor with MEK inhibitor. The eligibility criteria for these 2 cohorts were identical. This was a prospective single-arm multicenter study consisting of 4 cohorts. We focus here on sequentially enrolled Cohort 2, which enrolled 66 patients and the registrational Cohort 4, whose enrollment goal was 75, but enrolled 87 due to rapid enrollment. The primary endpoint for both cohorts was an independent review-assessed objective response rate by RECIST 1.1 criteria. As there was no limit on the number of prior therapies, the population was heavily pretreated. In terms of the schema, harvested tumors were shipped to a central GMP facility for a 22-day lifileucel manufacturing process. The manufacturing process was the same between the 2 cohorts. All patients received a nonmyeloablative lymphodepletion, a single lifileucel infusion and up to 6 doses of IV bolus interleukin 2, and there was no further treatment planned after that. The data cutoff contained in this presentation was July 15, 2022. This consort diagram was not included in the original presentation due to time constraints. On the left, you can see that 189 patients were enrolled in the tumor harvest set, 156 patients received lifileucel, and those patients comprised the safety analysis set. And at the bottom left in green, 153 patients received lifileucel and was analyzed for efficacy, which was the full analysis set as defined by the protocol. The median number of TIL infused was 21.1 billion cells. Lifileucel was successfully manufactured within the specification described in the protocol in 94.7% of patients. And I believe this to be an excellent result, especially given that it was a heavily pretreated patient population. This slide depicts the baseline patient and disease characteristics. Although statistical comparisons between Cohorts 2 and 4 were not planned nor conducted and should generally be avoided, some potential differences were known in terms of higher disease burden in Cohort 4. For example, there was a higher proportion of patients with more than 3 tumor lesions as well as an elevated LDH that was higher in Cohort 4. Nevertheless, across both of these cohorts, patients had a relatively high burden of disease as manifested by a median sum of target lesion diameter of 97.8 millimeters. Patients were also heavily pretreated with a median of 3 prior lines of therapy, and the majority demonstrated primary resistance to prior anti-PD-1 therapy, indicative of a highly treatment refractory disease state. However, the summary statistics do not present the full story of the prior treatment. This plot is called the Sankey plot that depicts therapies that each individual patient received prior to the line of lifileucel. The diagram demonstrates the high complexity of the prior treatments that the patients had. The very first line of treatment is depicted graphically as color-coated bars all the way to the left of the figure. Each subsequent line of therapy is shown as you move from left to right. The green huge colored bars represent the treatment that contained immune checkpoint inhibitor therapy. This is either a monotherapy or in combination with other therapies. For each line, lifileucel is shown in the turquoise blue bar. In the second column from the left of the screen, showing the second line of treatment, the relatively small turquoise bar at the bottom of that line to demonstrates that only 11% of patients had received only 1 prior line of therapy before the use of lifileucel as line of therapy #2. This illustrates that most of the lifileucel was given far later on in the course of therapy. On the other hand, most patients received multiple immune checkpoint inhibitor-based regimens shown in the green hued bars prior to receiving lifileucel. There was a median of 2 separate lines of immune checkpoint inhibitor containing therapy before the lifileucel was given. Seeing the data in this way really underscores how heavily pretreated the patient population actually was. The treatment emergent adverse event assessment started at day 0. This was the day after completion of lymphodepletion. The most common non-hematologic treatment-emergent adverse events included chills, fever, including febrile neutropenia, hypophosphatemia, hypotension, fatigue and diarrhea. There was expected laboratory assessed grade 3 and grade 4 leukopenia, lymphopenia and neutropenia. This is bone marrow suppression of the white cells from the lymphodepletion. The frequency was 100%, but this is given -- sorry, this is expected given the lymphodepletion. Of note, most of the adverse events were transient, manageable and consistent with the known established safety profiles of lymphodepletion and interleukin 2, and this has been described in other clinical trials of TIL that includes lymphodepletion. At the bottom of the figure, as seen in the histogram, the incidence of new adverse events for patients decreased rapidly over the first 2 weeks of lifileucel infusion, there was relatively sparse new adverse events after 2 weeks, and this is one of the benefits of a treatment not requiring multiple cycles of systemic therapy. In terms of response, the objective response rate by independent review is 31.4%, and that included 9 complete responders and 39 partial responders. The median time from resection for the tumor harvest to lifileucel infusion was 33 days. In this waterfall plot, 79% of patients had a reduction in disease as indicated as the negative deflection of the bars from the 0 baseline approximately in the middle of this graph. This demonstrates that the vast majority of subjects had a decrease in some tumor lesion measurements. This slide shows a forest plot that demonstrates different risk factors or different factors and characteristics and what the likelihood of response was to lifileucel. The forest plot demonstrates that response to lifileucel was observed across all the different subgroups analyzed, including BRAF mutational status as well as the PD-L1 tumor proportion score. This is different compared to PD-1 antibody-based therapy, which patients tend to respond with higher PD-L1 expression. This highlights the fact that TIL cell therapy has a mechanism of action while still immunologically based that is separate from PD-1 blockade. Additionally, for patient characteristics, the sum of the target lesion diameters above the median as well as an elevated LDH, both known negative prognostic factors for patients were each independently correlated with a lower response to lifileucel. Patients with the sum of target lesion diameters below the median, which is a good feature and normal LDH, also a good feature, had a greater likelihood of response to lifileucel than those with either or both adverse factors being higher. This does suggest that the earlier use of lifileucel in the course of disease progression after immune checkpoint inhibitor may provide a greater benefit for patients. In the swimmers plot, the blue triangles indicate initiation of a partial response and the green triangles indicate initiation of a complete response, while 39 of the 48 responders or 81% achieved response at the time of the first disease assessment, which again was at 6 weeks. Many of these observed responses deepened over time with some late best response conversions or, if you will, improvements. For example, there were 7 patients who initially had a partial response that improved to a complete response over time. These are the bars where it went from the blue triangle to the green triangle. 10 patients improved from stable disease to partial response. This is indicated by the blue triangle being after the first 6 weeks. Notably, 2 of the conversions to complete response occurred more than 2 years after lifileucel. And remember, there is no additional or subsequent treatment after the lifileucel infusion. This indicates that patients can derive clinical benefit at a very long time after the end of active treatment with this technology. The slide on the left shows the median duration of response Kaplan-Meier curve. The median duration of response was not reached at a median follow-up of 36 months. The proportion of patients with the duration of response more than 12 months was 54.2%. The proportion of patients with duration of response more than 24 months was 41.7%. These data demonstrate the durability of response. And if you look at the very tail end of the Kaplan-Meier curve, there were 2 patients who are at or beyond 4 years. So this updated data set demonstrates that there's continued durable responses for patients at many years after treatment. This graph is using landmark analysis methodology to stratify patient response at the time point of 6 weeks, which, as you recall, is the time of the first disease assessment. Patients achieving a response at 6 weeks depicted by the blue curve had a significantly superior overall survival compared to those patients who were not achieving a response at 6 weeks in the red curve. These data demonstrate that early responses do have prognostic value. However, you can see even on the red curve, it does plateau the end of the curve, indicating that even without a response at 6 weeks, there still are some patients who derive clinical benefit from lifileucel. This Kaplan-Meier curve demonstrates overall survival. The median overall survival for the group as a whole was 13.9 months and the landmark 12-month overall survival rate was 54%. One can see at the tail end of the curve, the plateau that we commonly look for with immunotherapy. Therefore, these patients with treatment refractory disease can still derive the very long-term clinical benefit from lifileucel therapy that was not achieved by the prior line of immune checkpoint inhibitors. So many of you saw the conclusion slide that I presented at the SITC conference presentation today. So I'd like to give you some of my own personal takes. In my opinion, the outcomes associated with this trial exceeded my preconceived expectations. I was thinking that we were selecting patients with a very poor tumor biology, and I was very happy to see that these responses have held up over time. In terms of response, lifileucel has clearly beaten the historical approved treatment options that would include chemotherapy, which, as we all know has not as good of a response and certainly not nearly as durable. Most people who even have a response for chemotherapy does not last longer than 6 months or late-line checkpoint inhibitor recycling. Checkpoint inhibitor recycling is a phenomenon we see all the time when we see cancer patients with melanoma at our cancer center, and it is extremely frustrating. We're really, really hungering for a different line of therapy and this drug with a different mechanism of action meets that goal. And most importantly, we can now see that these results are durable. As an active surgical oncologist, I can say that surgeons will be taking a very active role in this technology and will need to be educated. And I also interested to hear with the medical oncologist and the Board think about the use of lifileucel, as I would recommend having lifileucel be given very soon after progression after the initial immune checkpoint inhibitor line. We all realize that it's much easier to recycle checkpoint inhibitors than to give TIL, but given these data, we have to do what's right for the patients, and I hope to hear what the sentiment is of others. I'd like to thank you for your attention, and I'd like to turn things back over to Madan.

Thank you, Amod, for that. Wonderful presentation and giving us the extra color on the data compared to what we heard at SITC this morning. So with that, I would like our panelists to come to the front row over here. So what I hope to do is go over some question and answers with our panelists. I've classified the questions into a few different buckets. The first theme is going to be, what do the panelists think about the data? What are the key questions. The second is, how do they look at this data and anticipate the uptake and integration into standard of care. The third theme is going to be, obviously, evaluation of a TIL patient is very different than just firing up a recycle of checkpoint inhibitor. How do they look at streamlining all of that in their individual centers? How do you go from evaluating a patient to delivering the therapy in a time-compressed manner. How are they actually thinking about that? And assuming that we are believing in all of this data, how is that going to change their practice and how does that translate into potential demand for lifileucel. So those are the 4 buckets under which we'll be discussing the questions.

So with that, let me start with Allison. As a medical oncologist specializing in melanoma and more recently, the emerging blend of cell therapy solid tumor physicians. You've just seen the entire data set. What is your key takeaway when you look at lifileucel in these 153 patients, most treated with anti-CTLA-4 was 86%. More than half had received combination anti-CTLA-4 and anti-PD-1. What are your key takeaways for us?

I think my biggest key takeaway is, these are heavily pretreated patients. I think as Dr. Sarnaik pointed out, there are very few options for these patients. In our clinic, their median survival is measured in 6 to 9 months. The lifileucel data just doubled that overall survival. We have been desperately looking for an option for PD-1 refractory melanoma patients. That does not involve giving them checkpoint inhibitor that they've already seen and progressed on. Unfortunately, that and chemotherapy are often my only options for patients. taking all of that in mind, this is the -- in my mind, the go-to therapy for PD-1 refractory patients.

Miguel, so MSK has a model that seamlessly integrates cell therapy across both solid tumor and heme malignancy. Could you describe your experience and role in overseeing the various paths of the 2 therapy program?

Yes. So this is something that we've been doing now for over a decade. And so when CAR-Ts will first commercialize, we really sort of planned ahead of time and decided from the onset that we would have a cell therapy service that would manage these patients, got all the stakeholders together to make sure that we had a seamless rollout of commercial CAR T-cells, even though we had experienced clinically with the investigational CAR T-cells. And so now we're at a point where in 2022, we actually have a dedicated cell therapy service on the inpatient service, which is now taking care of all patients receiving cell therapy CAR T-cells, liquid tumors, solid tumors, TILs. In fact, Allison and I are both members of that service. And we've also just rolled out the outpatient component of that. So we really have a dedicated service of physicians and APPs and coordinators and the whole team who takes out of these patients. I do think it's important to realize that it's not one size fits all and that other models may work at other centers. But this is a model that works for us. I know that several of the other large centers are sort of using this combined approach.

Martin, the role of the surgeon in TIL cell therapy is critical. So in your experience, what percentage of patients with -- who have received anti-PD-1 can undergo an adequate tumor resection for TIL manufacturing. And a follow-up, how do you select lesions? What's the type of procedure because these patients not only have to have a surgery, but in 3 weeks when we are done with manufacturing and the product is released, they have to be up and ready to receive lymphodepletion. So as a surgeon, how are you thinking about that?

Well, I would say regarding the percentage of patients who might be eligible beyond progressing on PD-1 inhibitor, I'd say the majority of them will likely be a candidate, if they were fit enough to withstand a checkpoint inhibitor, they're likely to be fitting up to withstand a procedure to collect some tumor. And then as far as how we select the tumor, a number of us have been working on that and recently have published some guidelines on how to select these patients. It's developed out of the NIH experience and now into the more broad experience of multiple centers doing this. There are a bunch of key things that we look at. We often, as you just heard, we meet as a group, it's a team effort. And we work to select those tumors that are most likely to yield a high number of TIL cells. We also try to figure out which ones we can get well doing that in the least invasive way possible. And some of these patients it's a simple procedure in the clinic, even if it's a skin lesion. If not, it's generally an outpatient procedure to collect some tumor.

So moving on to uptake and integration to standard of care. Allison, back to you. Given the results of the C-144-01 study and should lifileucel receive regulatory approval, how would you envision integrating TIL cell therapy into patient of care? And I have sort of 2 buckets over here. If you see a patient who has received anti-PD-1 monotherapy and is recurring or progressing and a spare patient who has received anti-PD-1 and anti-CTLA-4 combination as frontline, how would you sequence lifileucel for these patients?

I think what we saw from Dr. Sarnaik's data today and as we've traced through the history of lifileucel is that patients who have the smaller volume disease are going to do better. That is sort of universally true in oncology, but it holds true for TIL as well. And so in my mind, that argues we should do this as soon after PD-1 progression as we possibly can. The way I will approach this, should this be FDA approved as patients get single-agent PD-1. If they have small volume disease, they're not progressing quickly. I would take them straight to TIL. The response rates that we see in this trial exceed that for the response rates of treating a PD-1 refractory patient with ipi plus nivo, right? That has been published, that response rate is 25% to 29%. And the durability is not great in that cohort as we've seen historically. And so if I had a patient with small-volume disease, I think that argues that I would take them straight to TIL and know that I still could treat with ipi plus nivo later if I needed to. If I had a patient with larger volume disease or one who was progressing quickly, I was nervous about that period of time between progression. I would probably harvest them right away, give them a dose of ipi plus nivo as a bridge. If they're in that 25% that respond, fantastic, then we've reduced their volume of disease and increase the likelihood that they're going to respond to TIL. And if not, we're getting them to TIL as quickly as we possibly can. I think one of the key questions, and I will come back to the -- if they got ipi plus nivo, I will just say, as long as they are fit, TIL is definitely the next step. And I think one of the key questions we've been asked is -- and that the regulators will need to tell us is whether or not patients should get BRAF plus MEK before they get TIL. And I think it's very clear that we should be taking patients to TIL as soon as we can. BRAF plus MEK has a short duration of response for the patients who respond, we know that the response rates are high, but the median duration of response is short. This is a onetime treatment that has a durable response rate. So using your targeted therapy in the second-line setting doesn't make a lot of sense for most of these patients. And I think all of the data just suggests that if this is more widely available and FDA approved, we will be taking our patients to TIL in the second line.

Miguel, this question is for you. And so as some of you in the audience may or may not know this, but the cell therapy physicians, the PharmDs affiliated with cell therapy programs, the nurse practitioners, the PAs, the coordinators, the administrators. They all roll off to a professional society called American Society of Transplantation and Cell Therapy, or ASTCT. Miguel Perales is the incoming President of ASTCT. So Miguel, you all have mastered this at MSK. As the incoming President of ASTCT, how do you see this playing out at a national landscape?

Well, I think in many ways, we've made sort of life easy for you, right? Because we've gone through already 6 CAR T-cell products, which have been FDA approved, and we've rolled them out to our centers and gone through the onboarding and sort of the integration of that into the clinical flow. And that the ASTCT level, obviously, we represent the community of physicians who treat these patients and the centers and the patients. And so the society has very much taken the lead in terms of providing educational materials, but also engaging with regulators, engaging with CMS in terms of reimbursements. And really, I think one of the things we saw early on with CAR T-cells were a lot of questions about reimbursement and particularly in Medicaid patients and the society has taken a lead role in advocating to make sure that we put the right reimbursement framework in place so that we can actually treat the patients at the center. So we're very much committed at the ASTCT level to continue to support the field of cell therapy, the patients and the center and TIL as the next cell therapy.

So just as a reminder, lifileucel is already mapped to DRG 18 based on the IPPS ruling for '21. So as Miguel was thinking about CMS reimbursement, remember, lifileucel already mapped to that. So once we get approved day 1, it's covered from a CMS standpoint, just as a reminder. Next question is to Martin. So you are a proficient and excellent till harvester, I created that lexicon earlier today. So what are the top 3 to 4 key learnings or best practices that you would communicate to the larger surgical community? And what tools are needed to educate the surgeon as we try and sort of launch at multiple centers.

So I think the key thing is that multidisciplined assessment to make sure everybody is on board with what the most high-yield tumor is going to be. And so that requires the team approach, the radiologist, the medical oncologist and the surgeon. And then as far as executing that, it does take some educating of the general community. And the surgeons we remove a lot of tumors for symptomatic reasons that may not be curable, but we're going to be taking those out. And you want to do that in the least invasive way, at least more midway you can. So getting that education out to the other providers of how to select those patients and how to do that in a least invasive way is going to be one of the keys. And again, we've -- as Dr. Sarnaik mentioned, through the society Surgical Oncology, we have some educational sessions there. And then we've had a few publications as well that have described how to go about this.

So switching gears to timeliness of delivering care and care models. Allison, this one's for you. So some of you may or may not know that, but Allison is going to be directing the melanoma program at Stanford starting in a few months. So Allison, as the incoming melanoma person at Stanford, how do you foresee building a TIL service line, which expedites the evaluation of the patient from initial consult to lifileucel infusion?

It's one we've been working really hard on as a cellular therapy service at Memorial and I think have learned some key lessons along the way, which is, first and foremost, the importance of integrating the solid tumor oncology with the cellular therapy physicians and making that either the same doctor in my case, as someone who literally treats melanoma on Wednesdays and cell therapy clinic on Mondays or really having the multidisciplinary meeting conference every week where we're talking about these patients and managing them together. What we do now, we bring in patients for in a trial setting consent and screening. They are able to do all of that in 1 to 1.5 days. They meet with the surgeon the same day. They do their presurgical testing all in one big package. At which point, we have a surgical date, the next visit is for their surgery. And so this is all sort of, for lack of a better word, sort of working in progress as tumor board. It's all happening in real time. The surgeons and I are talking during their evaluation, their presurgical testing, their scans, what's the lesion we're going to go after. They then walk down and see the surgeon make sure that the surgeon feels that that's appropriate after seeing the scans and seeing the patients. And so really, what we have found is the need for this to be a truly interdisciplinary working live model. And I think the other lesson along the way is, for those of you who have less experience with melanoma is that melanoma is a very rapidly progressing disease. And so this is something that needs to be done. It needs to be done very quickly. And we've really figured out through this sort of multidisciplinary clinic that we can get patients in and through this process actually quite quickly and usually to surgery within a week or 2 from the day that we identify them. And I think that, that will be critical to the success of these types of programs.

Miguel, next question is for you. So you've obviously organized the CAR T-cell program. You've seen the workflows over there. What can the TIL service lines learn from the CAR T-cell? Do they have to reinvent the wheel? Is it a plug and play? How do you think about that?

I think, obviously, the one big difference that I see is the surgical piece of it, and you've heard how Allison has sort of integrated that. But once it comes to the cell therapy component, it's very much the same thing. I mean we've already gone through this multiple times, as I mentioned, and we've been doing this now at the centers that do CAR T-cells, which there's at least over 100 of them treating adult patients in the U.S. that have been doing this for more than 5 years. So the workflows are established, the reimbursement, the finance piece is established and then the whole coordination of care is very much established. So I think you basically just use the same team who does that and sort of integrate the multidisciplinary approach for melanoma today and other tools, other diseases in the future.

All right. So Allison, back to you. So what proportion of patients with post PD-1 melanoma at your center do use see being appropriate candidates for TIL cell therapy. And if lifileucel is approved, how do you see that that's going to change the field? And would you use it at second-line therapy? And how does that affect like the demand? I know there are multiple questions baked into this.

All right. If I miss any of them, just remind me. So I think, first, thinking about the percentage of patients. So that's going to be a moving target. I think when we first started until I was thinking it would be about 30% of our patients knowing that there were going to be delays in the surgery and then they had to go through the manufacturing process and we had to get a patient through that period of time. In the approved setting and now more recently with bridging therapy, we can take much sicker patients right, harvest them, give them some type of bridging therapy to span that gap during the manufacturing time. So that 30% that I originally estimated has now, I don't know, doubled as an estimate. I think that's going to continue to evolve. I also think that as -- we are a tertiary quaternary referral center. The sooner we get those patients referred to us, the more of those patients we will be able to treat, right? So as we are able to get the word out to community doctors, smaller centers that are treating melanoma that may or may not be doing TIL themselves, right? But instead of getting the fifth, sixth, tenth line, I saw referral, right, if we're getting the second third line referral, right, a much higher percentage of our patients are going to be able to go through the TIL process. So I think that those are key things that just shifted that dynamic drastically. And I think with the data that we've now seen that treating smaller volume disease earlier is probably better. I think that does drive the referrals to the TIL centers and gives people a reason to refer their patients earlier. So I think that percentage is going to go up pretty considerably. I do -- as I said earlier, I think for most many patients, this should or will be a second-line therapy. Certainly, patients who started an academic center, I expect that this will be their second line therapy for most of them as long as they don't have brain metastases and other limitations. It's those referrals that may get later line because we don't get to see them before that. What part of your question did I forget?

No, you nailed it all. So a question for Martin. So it sounds like Allison is moving towards second-line therapy. So I see kind of the number of patients increasing can surgeons keep up? Can surgeons scale up as far as harvesting on the tumors?

Well, as surgeons, we certainly love the opportunity to operate in patients, particularly if we have a chance to provide a cure, where previously that didn't exist. So I actually think most of us in the cancer world would do anything to try to find a curative therapy. And so I have to believe that most of the people are going to be very interested in participating. In particular, if it's a relatively simple outpatient procedure that provides a cure. I mean, as a surgeon, that's a rare entity. And that's something that would be a win-win for everybody.

So the last question was trying to do like a quick 15 to 30 second round-robin. So we'll start from Dr. Sarnaik. How do you currently communicate with community oncologists? And if lifileucel comes to market -- when it comes to market, what is your message to the community oncologists?

So my program does extensive outreach. I come from the state of Florida, the Sunshine State. We have really high volumes of melanoma, yet they all seem to come to Tampa. I've treated people from the East Coast, from the Panhandle even Southern Georgia, Alabama, Mississippi. We have extensive media outreach. We have a whole team of people who communicate with the community dermatologists to get us the surgical patients perform metastasis as well as get to the medical oncologists who do not want the community medical oncologists, in general, do not really want to treat melanoma patients that are refractory to PD-1 antibody. They were for them basically to us. And that includes the main private practice medical oncology group, for a medical clinic. They sent all the patients to us. So they come to us.

Excellent. Miguel, when the lifileucel is a market, what's your message because you probably have established relations with community oncologists who are sending your lymphoma patients for CAR T-cells. So hopefully, over time, melanoma equal cell therapy sort of becomes a paradigm. So what's your message to medical oncologists?

I mean I actually think listening to what we're hearing here, they have a better referral pattern in melanoma than we do in the hematologic malignancies because we have more lines of therapy. And so we actually probably have a harder time getting those patients in for CAR T-cells. So maybe I should talk to you and you can tell me but I mean we have established networks, obviously, of referral. And I think it's communicating the fact that, as you heard from Allison, these patients need to be seen quickly. And certainly, when we get a referral for CAR T-cells, our goal is to see the patient that weak and unless there's a clinical reason not to and push them back a week or so. So it's really the fact that we're available to take account of the patient and make sure they get the right treatment, right.

So Allison, 30-second elevated pitch to community oncologists.

We all hate giving patients treatment that we know they're very unlikely to respond to, including chemotherapy and recycling checkpoint inhibitors, and we finally have another option. And I think that's the answer. Nobody wants to give a patient a treatment that has side effects that they can look a patient in the eye and say chances are, this really isn't going to work for you. But it's the only thing I can do. And now the sooner they refer those patients to us, we have another option or we will, hopefully, have another option.

Martin?

Yes. Well, I would say we also have a referral center that is well-known for its clinical trials. And so if patients are progressing on PD-1, they're often preferred down. I think the key message is getting that out a little bit earlier so that we get them at a lower disease burden and have a better chance. The other thing for those community practices, this is -- it takes a village to run this. And so for them, knowing that we've got the expertise already in place. It's an easy referral the thing to set up for us as opposed to trying to do this out in the community, just build on the existing platform that's there. I think that's an easy message for them.

Excellent. All right. So with that, we conclude the moderated Q&A. So the Iovance team would really like to thank the panelists Amod, Allison, Miguel and Martin for really sharing your perspectives and giving this -- the physician voice that it needs. For the open Q&A in the last 10 minutes or so, just a reminder to the live webcast viewers that submit your questions using Ask a Question tab. So put your hands up, Sara and Jen will moderate, and I'm going to be sort of the triager of appropriate questions will come to the appropriate panelist. Questions and I think what I would request is, let's use the physician's time wisely, questions that have been asked before of Iovance management. I'm going to request that you all touch base with the IR team.

Mark Breidenbach from Oppenheimer. This one is for Dr. Sarnaik. You showed us that beautiful plot of the patients' journeys, the sort of treatment history is very stunningly illustrated in a graphic. Can you point to any kind of material differences between the Cohort 2 and Cohort 4 journeys that you would want to highlight? And I'm just curious if that manifested in any significant changes to safety profile between the 2 Cohorts?

So to answer your question, I think there was a time gap between Cohort 2 and Cohort 4, and there was no other reasonable TIL trial to put patients on. So when Cohort 4 opened, at least I'm talking about my center, there was a huge influx of patients, who are sitting at home waiting for some treatment. So that's one reason why the disease burden may have been higher. In terms of safety, I don't really think that there was a material difference between Cohorts 2 and 4. Am I correct on that?

Yes.

So I think the safety issues, they're short-term and not likely to cause permanent damage to the patient even if they do have a higher disease burden. Does that answer your questions?

Yes, it does. And maybe one quick follow-up for you and Dr. Betof Warner. If you had to change one thing about lifileucel, if you had to improve one aspect of it to make it more palatable for patients and providers. It would be the IL-2? What would you want to update?

Well, if I had a genie bottle, I would vote for getting rid of the lymphodepletion. Now there are some downstream consequences to that. But if you maintain efficacy, I would vote to get rid of the lymphodepletion. I think the IL-2 is manageable. I think if you have experienced clinicians who know when to stop the IL-2. Direct toxicity to IL-2 is relatively transient because the half of IL-2 is like 15 or 20 minutes. Now the toxicity on the regimen may linger a little bit longer because the IL-2 is affecting the TIL and the TIL obviously, we want them to persist. So you do get some effects of toxicity after the IL-2 has stopped. However, once reconstitution of the bone marrow occurs, a lot of this toxicity goes away. So if you didn't have the lymphodepletion, I think we'd be able to treat more patients and we'd also potentially be able to maybe give another cycle or 2 of infusion if need be for a little boost. So I don't know...

Allison and then Friedrich, if you have any comments.

I would love to get rid of the lymphodepletion, but if I had a genie bottle to make this better, I would say I would get rid of the IL-2, but for a different reason. I also think the IL-2 is very manageable with some experience we can learn to do this very easily, knowing when to stop is the key. I think the challenge is the rest of this really could probably be done as an outpatient. Even the lymphodepletion could probably be done as an outpatient. The IL-2 requires a patient in the hospital. And if I could get patients out of the hospital, we could treat a lot more patients. So if I had a genie bottle, that's what I would do.

Friedrich, any comments on -- you'll be hearing that, let's get rid of lymphodepletion. Not so easy, right?

It's all a question of clinical development and where you put your efforts, right? Obviously, this is something where we can't just like start dialing down several things at the same time. And then in the end, we want to learn what was right, what was wrong. So we're going to have to do that step by step and in a prudent way that allows us to actually decide whether that was right or not. So that's going to be stepwise, but obviously something that is explorable, and it's something that we're thinking about because we hear this, and we don't necessarily disagree. Madan, if I may though?

Yes, please.

If we can just bring Slide 10 back up because there was a question around differences between Cohort 2 and 4 and what their prior history was right. If you just look at that this extended summary. So this is a little bit extended beyond what was in the presentation earlier today. Just on the lower, kind of like on the lower right part of the slide, if you compare just the prior lines of therapy, the prior lines of ICI, the proportion of patients that had prior CTLA-4 or combination is pretty smack on the same. There is no big difference. So really, the difference is the tumor load, the tumor burden and LDH, which is again. Madan and I still discuss whether it's a measure of tumor burden or something else on top of it. Madan is probably, right? But really what probably is going on here is that just the decision-making on who was being enrolled to this study with prior knowledge of Cohort 2 data influenced and just let patients with more tumor load that were just more advanced, although the prior history might not have been that difference.

I also think the comfort on the part of the medical oncologists treating sicker patients as we made it through Cohort 2 and we learned that we could get patients through this, then we were willing to enroll later line and sicker patients than we might have been willing to consider for Cohort 2 just because we didn't have the experience. So I think that there's also that.

From a prospector drug developer, that's something that'll be often seen.

All right. Next question.

This is Peter Lawson from Barclays. And I guess, a question for Dr. Perales and Dr. Warner, just around this -- the way you kind of combine TIL and CAR T-Cell delivery, what are the hurdles for CAR T-Cells to centers to adopt TIL therapy? And how many centers, do you think are kind of going in your direction or are there kind of hurdles that prevent them?

So the question is centers who are doing CAR T-Cells today are not willing to do TILs or what the challenges will be?

Yes, just like that's the split and if there are challenges.

I mean I think there's just going to be different models. I mean, at Memorial, we've chosen sort of the uniform approach because we think that's more efficient. It means that you have one nursing team taking care of these patients. You have one team of physicians and you have one team of advanced practice providers. There are certainly other centers where they may choose to have it more separate. I mean even in the CAR T space, there may be sensors well lymphoma and myeloma separate and maybe the tools are going to be separate. And so I think each center has to decide what's the best model for them. But I think from us, it's a much more efficient system where we work together. And we use the lessons, we've learned doing CAR T for 10 years to integrate novel cell therapies, including TILs.

I think one thing we've learned in the process is the importance of -- if this is going to happen sort of with cellular therapy being sort of the central coordinating service, having the solid tumor oncologists, the disease-specific experts involved and heavily involved in that process is really important. There are things that are unique to solid tumors that people who haven't taken care of solid tumors in a long time are less equipped to deal with brain met pops up and is bleeding, things like that, that are somewhat unique to our patient population. I think the other thing, and the way we've seen other centers do this, and we've talked quite a bit about this amongst the TIL working group, right, is that many, especially melanoma services actually have much more experience with IL-2 than cell therapy centers or cell therapy services. And so it really, I think, is dependent on the center and the way that the center works together. Our model works really well, but that also involves physicians like me learning about CAR T and getting CAR T certified and being able to administer CAR T as a nonhematologist and so this is going to work differently at different places.

Next question?

Asthika Goonewardene from Truist Securities. Dr. Perales, I was wondering if you could kind of comment on, what we've seen auto CAR T use and some of that's in the outpatient setting as well, amidst in the outpatient setting. But we know you need a good amount of monitoring and follow-up after the patient has been infused for the next 2 or so weeks. How would you compare the follow-up with TIL with the follow-up required and the monitoring required for CAR-T? That's one. And then to Dr. Warner and Dr. Sarnaik, I just wondering if you could kind of tell us, what proportion of melanoma patients who are fit enough to get PD-1 are also fitting up to get TIL and then what portion of melanoma patients who are fitting up to get nivo plus ipi are also fit enough to get TIL?

So I think I'll make 2 comments in response to your question. One is we are doing CAR T-Cells outpatient. And so the lymphodepletion, we almost exclusively do outpatient and then depending on the product may admit the patient or not. But we try and do as much as we can outpatient. And so it's very much driven by the CAR and the toxicity profile in terms of time of onset and grade of toxicities that drives that. And in some cases, it's just a matter of do they have a caregiver. So if you're treating an 82-year-old with CAR, their caregiver is probably 82 and then that just doesn't work. So you may admit them for that. In terms of the follow-up, the CAR T follow-up is very much driven by the REMS program of the FDA, which mandates that 28-day follow-up of the patients within the center and a 2-hour rule from being away from the center. But the reality is that in patients with CAR T, most of the toxicity happens early and by 2 weeks, most of that has resolved and we have data from our center showing that if you have resolved your toxicity by day 14, it's not going to recur and you could probably send those patients home by week 3 and not keep them there for the 28 days. Obviously, we have to do that within FDA compliance. So I think for the TILs if you heard, it's very much related to the administration of IL-2. And so you now have a 28-day window that you sort of have to keep the patient. So it's really driven by the clinical management then.

I've been doing TIL for more than 10 years, and I think I readmitted one patient within -- after discharge within the 28 days.

Same one patient.

I'm a surgeon, not a medical oncologist. I'll defer to Allison on that.

I was curious as how you were going to answer that. So I would say the easier question is what percentage of patients that are fit for ipi plus nivo are fit for TIL most. There are some exclusion criteria for TIL like brain mets that I will actively treat every patient with ipi plus nivo. But with our experience now and comfort with doing this, if I feel a patient is appropriate and has appropriate organ function, so renal function, especially, that would be the one difference where I might be willing to treat someone with ipi plus nivo if their kidneys aren't great, but I may be less excited about giving them TIL. But for the most part, if they're fit enough to get ipi plus nivo and withstand that toxicity, they're fit enough for TIL. PD-1 is different, right? We give PD-1 to, I gave it -- the oldest patient was 101. I wouldn't be super enthusiastic in 2022, now maybe in 2024, about taking a 101-year-old through TIL. So that is a lower percentage of patients. It's hard, though, because we're selecting patients for PD-1 monotherapy because they're not that fit, right? So it's not necessarily a fair question. But I would say, if I had to put a number on it like 50%, probably.

That's why I gave the nivo ipi part to you.

Yes. Right.

Just a clarifying comment on the brain mets. So there was actually a paper by Rosenberg around 10, 15 years old patients with asymptomatic brain mets, untreated were treated with 2 cell therapy until cells go into the brain and you get a parenchymal brain mets response. So to sort of keep that in mind. And we're obviously going to be exploring that gradually.

Within the next week or 2.

All right. You spilled the beans on that. All right.

Tyler Van Buren from Cowen. I have a data and then a use question. So regarding the data, was there any correlation on response or duration of response for cumulative prior checkpoint inhibitor treatment, like we saw in Cohort 2 with the pool data. And then just to try to distill all the use questions down for the KOLs assuming lifileucel becomes available later next year, how many patients per month will your center be able to treat? And how might that change over time, and we're going to hold you to it.

So I'll take the PD-1 cumulative duration question, but go ahead, Allison about the potential number of patients. Let's answer that first.

So I would say right now, we're treating about 4 per month. we have a patient admitted pretty much every week going through the process. I think we will probably stay at that number for a little while with an approved product and make sure that the system is running smoothly. One of the limitations, quite frankly, is just the ability to get inpatient beds. That will be -- we live in New York, so it's a problem for us. That will be a limiting factor for us in the number of patients that we can treat. I think it's not so much about getting a patient through the therapy. We're not limiting it in that sense. I think in the beginning, just to make sure that the wheels are turning smoothly, it will be 4 or 5 a month.

So go to your question regarding cumulative prior duration of anti-PD-1 therapy. So when we looked at that in the context of Cohort 2, the multi-varied model selected LDH and prior cumulative duration. But when you combine 2 and 4 together, remember, I think Amol pointed out that there are some small differences between 4 and 2. The multi-varied model now does not include it falls off the model and what really comes into the model is now the tumor size. So it's just basically a manifestation of a larger end models of new change, and this actually makes biological sense.

And keep in mind, it was even in the context of Cohort 2, it was associated with DOR not with the response rate.

Next question.

Reni Benjamin from JMP Securities. Can you talk a little bit about the impact of subsequent therapies on the survival curve. And I guess where I'm kind of going with that also is, if I'm a referring center, am I going to get these patients back and I'll be able to treat them kind of just as much and potentially continue to impact? Or will they be in worse off shape, so I'll try to hold on to them as much as possible?

I think that's a great question. It's one we've been talking a lot about as a melanoma community. Just like CAR, just like anything at transplant, right? We will get these patients through the acute process through TIL and send them back as long as there's another option for that patient, right? Some patients who progress may choose to stay at the center because they have another clinical trial option that may not be available where they came. But every one of our patients has gone back to see their primary medical oncologists who referred their patient to me, at least once, whether that panned out long-term. But I think one of the issues, unfortunately, as we've heard in the PD-1 refractory melanoma space is there just aren't that many good treatment options and patients right now are trial shopping because that's their only option.

And to answer your question, so in the [ Univer ] analysis, [ broad ] lines of therapy, 1 to 3 versus more than 4 have been compared and there's no difference in ORR. Sara, Jen, how are we doing on time?

We got about 5 more minutes.

Ben Burnett from Stifel. I'm a little bit surprised about how much recycling is going on. What is driving that? Is there data that's supporting that the community docs are looking at? And I guess, is there also like a financial component to that.

Really what's driving that is the lack of good other options. I mean, honestly. So I published this when I was a fellow, it's been studied in subsequent prospective trials. The response rate to retreatment with single-agent PD-1 is about 15%, the response rate to retreatment with ipi plus nivo is in the 25% to 29% range. There are patients who did not respond originally who will respond to retreatment. So it's the Hail Mary because we don't have anything else to do, right? Many patients -- I mean, when we talk about the long-term or the patients who get chemo, it's not dacarbazine or TEMODAR. I mean we're talking about 3 agent chemo every 3 weeks, they're very sick, and it's indefinite. And a lot of patients just choose not to do that, and they'd rather take that Hail Mary shot, then get chemo. And there just aren't that many other options. So for the lack of something better and because there has been a published response rate, we do it because we don't have anything else to do.

And I can just mention that in the ipi pembro paper, right, after failing anti-PD-1, if you look at the paper, they divide the patient population into those that were clinical progressors and confirmed progressors. In our study, everybody is a confirmed progressor. In clinical progressors, the ORR was 40% and confirmed progressors, it's 25. And in that same paper, anybody who got more than 12 months of anti-PD-1 had a response rate of 0%.

I will say the other thing is sort of this question of if a patient had PD-1 or ipi/nivo are they going to get nivo/rela, right? That's also considered recycling. The best data that we have, which aren't great data, but it's the only data that are out there from [ Paolo Assearto ] from 2017. Looking at response rates to nivo/rela in the second line after PD-1 progression and the response rate is 11%. So we're working with what we have, but it's just because that's the only thing we have.

Madhu Kumar from Goldman Sachs. Kind of 2 questions, 1 related to the trial, 1 related to kind of practical use. So on the trial, when patients progressed on lifileucel and went on to subsequent therapy kind of qualitatively or quantitatively, if you have it, was there a difference in the response to subsequent therapy after lifileucel and to the panel kind of following from that, how do you think about kind of the narrowing of therapeutic options after progression levels, so we could say, for example, I wouldn't want to give chemo after lifileucel because I want to wipe out these TILs I just put into a person. So how do you think about kind of the subsequent therapy after TILs after progression?

So I guess I'll tackle that. This comes to me every day. I think the subsequent therapy, I'll kind of tackle that first. So patients who progress after lifileucel, if they are actively progressing, I'm not worried about giving them chemo because it's going to wipe out the TILs because the tills aren't working for them. So I'm less concerned about that. There is some question about and this is all hypothetical. There are no data about whether sort of having given TIL might make a patient more responsive to retreatment with checkpoint blockade. More to come on that. Some of us are actively looking into that now that we finally have enough patients to look into that. I don't know that we have any hunch as to what the answer is there. For a long time, we just didn't have enough patients to collect the data. Now with the completion of this cohort and now also with the expanded access program, there will be enough of those patients that I think we'll be able to get a sense of what later response rates look like. But I don't think there's hesitation about giving patients later line therapy as long as they are well enough. And it's not that a patient isn't well enough from the TIL process. Unfortunately, it stressed melanoma is a very aggressive disease. At some point for most patients with melanoma, their melanoma will track along and then it will just take off. Those patients, unfortunately, get sick very quickly. And many of them at some point will just become too sick for another line of therapy. But it hasn't been my experience that it's -- they're too sick after TIL to get treatment. It's just at some point, their melanoma just takes off. I have a virtual question from Colleen Kusy at Baird for Dr. McCarter. How do you determine the tumors that are most likely to yield a high level of TILs? And how long does that usually take to get alignment?

Well, some of the criteria that we look at is sort of the solid nature of the tumor. So some of these tumors are cystic or have a dead center. So that may not be as good a yield, but if you have a more solid piece to go for, that's very helpful. And then the ease of access is the other component of it, too. So if it's something on the skin that we take out in the office, that's super easy. If it's something a little deeper that we have to figure out another way to get to, whether it's a sedation procedure or anesthetic to do it. And I'm sorry, the second part of that question was?

How long does that usually take to get alignment?

Alignment with that, I'm not sure about 2 seconds. Usually it's right in the -- the same time we're all together looking at it together and decide, okay, these are our targets, and we'll have a backup plan, too, which is this doesn't turn out to be easy access or falls apart when you take it out, then we have plan B.

It's James Shin from Wells Fargo. This is for Dr. McCarter and Sarnaik. Can you share what percent of your lifileucel patients had lesions that were harvested in the outpatient setting versus requiring general anesthesia in an overnight state?

So it's not 100%, but it's probably 90% to 95%. I agree with the comments that outpatient surgery is far easier to recover from, don't have to worry about giving the lifileucel within 30 days.

Yes, I'd say the same. Most of them have had a general anesthetic but it's usually in our procedure.

Let me add a little bit of color on that. So again, with Dr. McCarter and on with Sarnaik our melanoma surgeons. But if you look at our data and more data to come in the manuscript, 1/3 of our regions, 1/3 of the patients had lymph node and subcutaneous, 1/3 had visceral lesions. So they go to hepatobiliary surgeons with thoracic surgeons. And the third are like soft itch and everywhere, which could be in the outpatient setting, which could be in the inpatient setting. But as surgical oncologist specializing in melanoma, they're obviously -- their experience is more sort of melanoma skewed in terms of skin, subcutaneous lymph nodes. So these tend to be more outpatient.

But even the visceral patients.

Makes sense for that. Yes. Thoracic surgery patients usually go home the next day. We're not doing lobectomies, we're doing [ levator ] resections. And same thing with liver. We're not doing formal anatomic liver resections. These are [indiscernible]. They can go home in a day or 2. And general anesthesia versus IV sedation in this day and age of modern anesthesia is not much of a difference at all.

Last question.

This is Yuchen on for behalf of Mike from Jefferies. 2 questions. First on AEs. I'm looking at the JCO paper and then you have, for example, like neutropenia, 39% Grade 3/4. But on the safety data you report here for pooled, it's 100%. So just wondering how the math works out there.

The reason for that is the definition of treatment emergent adverse event. So when patients get lymphodepletion, they record an AE before day 0. So that's technically not a treatment-emergent event. So that's why there's a discordance in why we updated the data to show that it's 100%, but people will ask, well, if you gave lymphodepleting chemotherapy, how could you have only a 40% leucopenia rate is actually 100%. It falls on the definition of what a treatment emergent adverse event was initiating the adverse event at day 0.

I mean I'm going to ask Dr. Finckenstein to put a little bit of extra color on that.

Yes. If we can go back, I think it's just a question of what we are reporting in the past, we've reported the adverse events, which are the reported asset events, right? As part of this presentation, we decided to really switch to not reporting the hematologic toxicity or the hematologic events as adverse events but as lab abnormalities. So abnormalities or data that we are collecting, they don't depend on how they are being reported. So that's different. You will have -- you will have PIs who simply will not report a lymphopenia as an adverse event because that's the intended effect of the lymphodepletion, right? So there's a little bit of a spread here. We wanted to be fair and just report the lab data. That's what expense the differences.

All right. Well, thank you, everyone, for your robust participation. Excellent questions. Thank you again to all our panelist and Dr. Sarnaik for giving us this precious time today. Feel free to get a beverage or so. And we'll see you soon, I guess. Thank you. Bye-bye.