Status Update

Jun 6, 2021

Slides

Good day and thank you for standing by. Welcome to the iovance Biotherapeutics ASCO Update Call. At this time, all participants are in a listen only mode. Later, we will conduct a question and answer session and instructions will follow at that time. As a reminder, this conference call might be recorded. I would now like to turn the conference over to your host, Ms. Sarah Pellegrino, Vice President, Investor and Public Relations. Thank you, operator. Good afternoon and thank you joining our conference call to discuss the clinical data updates at ASCO 2021 for lifileucel and advanced melanoma. For today's agenda, our incoming Interim President and CEO, Fred Vogt, will do a brief introduction and corporate update. Then the highlight of today's call will be the clinical data update presented by Doctor. Omid Hamid, Chief of Research Immuno Oncology at the Angelus Clinic and Research Institute. Doctor. Hamid is recognized nationally and internationally as a key opinion leader in immunologic drug development and melanoma therapeutics, and we are very fortunate to have him join us today. Our Chief Financial Officer, Jean Marc Bellamine, will also provide a brief financial summary, and then we will hold a question and answer session. Doctor. Frederick Finkenstein, our Chief Medical Officer and Doctor. Madan Jagassia, our Senior Vice President, Medical Affairs, are also available for the Q and A session. Before we start, I would like to remind everyone that this call will contain forward looking statements regarding Iovance's clinical results, goals, business focus, business plans, clinical trials and regulatory plans and results, manufacturing capabilities, regulatory feedback and guidance, collaboration, cash position and expense guidance and future updates. Forward looking statements are subject to numerous risks and uncertainties, many of which are beyond our control, including the risks and uncertainties described from time to time in our SEC filings. Our results may differ materially from those projected during today's call, and we undertake no obligation to publicly update any forward looking statements. With that, I will turn the call over to Fred Vogt. Thank you, Sarah, and good afternoon, everyone. Are pleased to host today's call to highlight a very compelling clinical data for lifileucel in advanced melanoma and our first look in early line melanoma treatment with lifileucel in combination with pembrolizumab. We're really excited about our pipeline and the potential for Till therapy in multiple indications as well as earlier lines of therapy, including IVAN Till therapy in non small cell lung cancer as well as Till therapy combined with pembrolizumab and additional indications such as cervical cancer as well as updates on head and neck cancer. While we aren't providing guidance today, I assure you that we're actively looking at the appropriate means to get more data out across many of our programs soon and we'll provide updates when available. Finally, before we review the data, I would like to address some of our recent updates regarding and the potency assays for lifileucel with respect to our BLA filing. We are confident that we can resolve the FDA's questions regarding our potency assays for products for future commercial use. We think we have an understanding of recent FDA feedback and based on that we are working on a path forward to complete additional assay work in the near term. We believe we can achieve our new target timelines for a meeting with FDA in the second half of this year and planned BLA submission in the first half of next year. The additional assay work is our top priority and we look forward to providing more detail and updates when possible. Now I would like to introduce Doctor. Amit Hamid As the Chief of Translational Research and Immunotherapy at the Angeles Clinic and Research Institute, a Cedars Sinai affiliate and the Co Director of Cutaneous malignancies at Cedars Sinai Medical Center. Doctor. Ami has been instrumental in bringing novel therapeutics to first in human trials from first in human trials to the clinic for patient benefit, including immuno oncologic therapies such as PD-one inhibitors, other checkpoint inhibitors, bispecifics and targeted agents. He has presented the research done at the Los Angeles at the Angelus Clinic at major national and international meetings and published manuscripts, abstracts, reviews on immunotherapy, targeted therapy and melanoma care. Doctor. Hamid has been a principal investigator in our C-one hundred and forty four-one clinical study and lead author on several of our publications and presentations at medical meetings. We are very pleased you could join us today to review the data for lifileucel. Doctor. Jamey, please go ahead. Thank you so much for that lovely introduction. I'd like to thank Iovance and my co contributors in this trial for allowing me to present this data that was so wonderfully presented by James Larkin earlier this morning at the oral session for melanoma. Lifolucil is a cryopreserved autologous tumor infiltrating list of site therapy in patients with advanced melanoma. And we are evaluating the evaluation of impact of prior anti PD-one therapy in this cohort. In Slide 3, you'll see the study design of C144-one. This is a Phase 2 multicenter study to evaluate lipolucel for metastatic melanoma in a patient population that was unresectable or metastatic melanoma treated with greater than one prior systemic therapy, including a PD-one antibody and of course as important is BRAF V600 mutation positive, a combination targeted approach. We'll be speaking about Cohort 2 that look to use the cryopreserved Till product for 60 patients. As it occurred, 66 patients were accrued in this cohort. Primary endpoint was efficacy per investigator initiated assessed overall response rate and the secondary endpoint is safety and additional parameters of efficacy. Key eligibility here, having one tumor lesion resectable for Till generation, eCOG performance status 1. The patients were enrolled from April evaluable disease was required and all responses required confirmation. This is a data cut out from April 22, 2021. As you can see in Slide 4, the baseline patient characteristics are indicative of the patients that we see in clinic with a male predominance. As far as prior therapies, all patients had seen a prior anti PD-one or anti PD L1. 53 out of 66 patients had, had a anti CTLA-four and of those, 34 patients had concurrent anti PD-one anti CTLA-four, 15 patients had BRAF and MEK inhibitor and all patients had progressed on anti PD-one therapy. You can see here that this is a high risk population with 41% of patients having elevated LDH with the sum of target lesions being a significant and then 3 point 3 mean prior therapies and high tumor burden at baseline. When you look at treatment emergent adverse events in Slide 5, you can see that the adverse event profile was consistent with underlying advanced disease and the safety profile of lymphodepletion and interleukin-two regimen. You can see most patients received 5 or 6 doses of interleukin-two and 6 is maximum, decreasing frequency of adverse events over time is indicative of the potential benefit of this therapy. As you see here, there were no new safety signals after 2 months. The majority of toxicities are acute and then resolved. When you look at the grade toxicities, clearly the initial toxicities are due to the lymphodepleting regimen and then the rest from interleukin 2. So a therapy that you give to the patient and then they resolve the adverse events and move on. Efficacy is shown here on Slide 6 with an objective response rate of 36.4%, complete response rate of 4.5% and a disease control rate significant at 80 0.3%, with a median duration of response that's not reached. Responses were demonstrated in patients who received prior anti CTLA-four and BRAF MEK inhibitors and response was seen regardless of BRAF mutational status, PD L1 expression on tumor or time from stop of anti PD L1 therapy to Till infusion, various levels of LDH and various visceral metastases patients' response. Here is the efficacy in a waterfall plot on the next slide. 81% of patients had a reduction in tumor burden, 11 patients had further sum of diameter reductions since the last cutoff on April 2020. And you can see here that these were seen in patients as the asterisk denotes patients with BRAF V600 mutation. This is again reflected in our swimmers plots. You can see early in our responders at the first imaging time point at 6 weeks, response was seen, response was durable and patients went from initial response in a partial response to complete response, and then responses continue to deepen over time. Slide 9 shows the Cohort 2 biomarkers. It's important here to show appropriate amount of Till was manufactured from tumors regardless of location of resection, visceral, lymph node, skin subcutaneous and other not assigned locations, and the amount of Till was equivalent in each site. Also target lesion cell of diameter reductions were seen across the range of Till total cell dose. So not quite associated with the amount of Till infused. When you look at univariable analysis for duration of response of lifilevelucel, although cumulative duration on prior anti PD-one, anti PD L1 was not associated with achieving a response, it was associated with duration of response. When you look here, prior anti CTLA-four use, BRAF mutation status, baseline ECOG, baseline LDH and the location M1C or M1D was not associated with duration of response. Multivariable models look for independent predictors for leaflet cell duration of response. Here are variables from the univariable analysis were examined using the best subset approach and 2 parameters were identified here, baseline LDH and also cumulative duration on prior anti PD-one and anti PD L1. This cumulative duration was a stronger predictor for duration of response when we looked for each 3 month decrease in exposure to prior anti PD-one and for each 6 month decrease in exposure to prior anti PD-one, anti PD L1. As you can see here, a hazard ratio that is significant and does not cross 1 that showed for each 6 month decrease in exposure, the duration of response to lipula cell will be nearly doubled. So in conclusion, Slide 12, in heavily pretreated metastatic melanoma patients who progressed on multiple prior therapies including anti PD-one and BRAF MEK inhibitors, lifelicel treatment resulted in a 36.4% overall response rate with a median duration of response not reached at 33.1 months of therapy. Responses deepened over time. We saw 11 patients demonstrating further reductions in some of diameter since the last cut off in April 2020. We've seen conversion from a partial response to complete response at 24 months post infusion on a patient still on trial. And what came out of this evaluation, shorter duration of prior anti PD-one therapy maximizes duration of response to lupilacil treatment. All newly diagnosed patients should be closely monitored for progression on anti PD-one therapy because early intervention with lifilacil at the time of initial progression on anti PD-one agent may maximize benefit. Now I'd like to present some of the initial data of the safety and efficacy of lifilecel in combination with pembrolizumab PD-one inhibitor for immune checkpoint inhibitor naive patients with advanced melanoma. And again, I'd like to thank the investigators for allowing me to show you and present this information. IOCOM-two zero two was a prospective open label, multi cohort, nonrandomized, multicenter Phase II study evaluating Till therapy in multiple settings and indication. Cohort 1a, which we report here, enrolled patients with immune checkpoint inhibitor naive advanced melanoma that's Phase 3 unresectable or Stage 4 metastatic for a combination of lisilisil and pembrolizumab. The key eligibility criteria here, of course, naive to immune checkpoint inhibitor, less than 3 lines of prior systemic therapy, good ECOT performance status, having a resectable lesion for manufacturing and then a valuable measurable lesions for response assessment. Efficacy was objective response rate and safety here will be presented. The data cut off April 29, 2021. The schema, as you can see here, from screening to enrollment, the patients received an initial pembrolizumab administration and then went on to lymphodepletion chemotherapy with day 0 lipocell infusion and interleukin-two post infusion of up to 6 doses and then continuing pembrolizumab on the approved every 3 or 6 week dosing end of therapy then an efficacy follow-up. As I showed you on the previous trial, the baseline patient characteristics were similar. The majority of patients here had had no prior therapy. Again, these are 7 patients, male preponderance. The prior systemic therapies in these patients, one with chemotherapy, one was targeted BRAF and MEK inhibitor. And the majority were Stage 4 metastatic. PD L1 positives were 57% of the patients. And again similar, a 42% LDH above baseline and a high tumor burden as you can see here. 85 0.7% of patients had greater than 3 lesions and the high tumor burden as I've noted before. Efficacy is presented here on Slide 17. You can see an objective response rate, 6 out of 7 patients, 85 point 7 percent, one patient with stable disease for a disease control rate of 100%. The median number of Till infused was similar to the prior study and the median follow-up here was 8.2 months. Slide 18 shows best percentage change from baseline of all evaluable patients and median number of pembrolizumab doses here in these patients, 10. You can see here there was 1 unconfirmed complete response and 2 patients who had partial response that went on to have a confirmed response paresis per PET evaluation. There are 4 patients with BRAF mutation. And then as you can see on the spider plot here, early deep and durable responses in patients that are going out past month 21. And these patients with the asterisk, these are the patients who had CR based on a FDG PET scan. Let me show you these 3 patients with complete response. As you can see here, these 3 patients, 2 had BRAF V600 mutations, patient 3 had a non E mutation and Patient 6 had a V600E mutation. Patient 6 had seen zibrafenib and trametinib for 5.2 years with a partial response and discontinued for progressive disease. When you look on the right, you can see here that initial imaging was done by CT scan in all of the patients and in patient 3 and patient 6 after an extensive amount of confirmed response as PETCT was done again in patient 3 at 10.5 months and month 13 that confirmed a complete response by PET negativity and again in patient 6 at month 6. So these are not early PET scans done. These are PET scans done after a significant amount of confirmation of response. Slide 21 shows the swimmer plot here and you can see that the time to first response on these patients was at initial imaging on the majority. What we've seen is similar to what is seen in the single agent trials that patients had initial response and then had deepening responses over time in the complete response patients here. And also, you can see here that the patients are out many months, all about 6 months and then some out here past 16 21 months. So in conclusion, early data here suggests the response rate for alicelacel plus pembrolizumab may be additive in patients with immune checkpoint inhibitor, naive advanced melanoma with overall response rate of 85.7%, complete response at 42.9% with responses deepening over time. Most patients had a high disease burden at baseline. And we've shown that lefilacil can be safely combined with pembrolizumab. These encouraging data confirm the potential feasibility and activity of Thank you, Doctor. Ahmed. So let me comment very briefly on our current financial continue to execute towards a BLA submission and prepare for commercial launch while advancing our pipeline. So let me turn to Slide 28, please. I will begin with our cash position. As of March 31, 2021, Iovance held $610,200,000 in cash, cash equivalent investment and restricted cash, inclusive of $42,900,000 proceed raised through our ATM offering. As a remember, the total ATM offering is for up to $350,000,000 This strong cash position is expected to be sufficient into 2023 to deliver on our pipeline programs with no immediate need to access capital at or near the current stock price. We will continue to focus on investment in 4 key areas to ensure the growth and strength of our value creation: 1st, advancing our current clinical programs and indications 2nd, scaling up our manufacturing capacity to support our clinical manufacturing while preparing for expected commercial supply in 2022 3rd, ensuring the launch readiness and 4th, maintaining a strong balance sheet and cash position. I will now hand the call back to the operator to kick off the Q and A session. Thank you. Our first question is from the line of Ben Burnett from Stifel. Your line is now open. Hey, thank you very much and appreciate the update. Actually, I have a question about the disclosure of the pivotal Cohort 4 melanoma data. I think in the past disclosing this was gated by the BLA filing. I guess, is that still the case? And is there any chance that we could get the results of Cohort 4 earlier than that? Hi, Ben. This is Fred. Yes, that's correct. We had gated to the BLA filing. Given all the recent events, we'll take a look at that, of course. I don't have updates for you today, but that's something that we're thinking about. Next question is from the line of Michael Yee from Jefferies. Your line is now open. Hi, good afternoon. Maybe two quick ones, one for the doctor and one for the company. Maybe, Doctor. Ahmed, you could talk about Doctor. Hadid, sorry, you could talk about maybe how this data stacks up with other combination regimens, obviously, LAG-three data here at the conference. And your analysis of PD-one, does that imply you should expect for a long duration of therapy early in first line? I mean, what do you think the implication is of that analysis? And then maybe for the company, I know that you just talked about potentially unblinding cohort 4. Does that have to do with trying to get agreement on passes and not wanting to have all of that information assays, you just need to ask the FDA if that would be okay? Maybe just clarify that comment for us. Thank you. Yes. Why don't I go first, Michael, and then I'll hand it over to Doctor. Hamid. On the assay related to the Cohort 4 data, it's one of many factors we're considering as we consider what to do with that data. But the BLA timing was our primary driver for that because of the need to cut the data and do all the work prior to the BLA. For Doctor, I'll give the second question to Doctor. Amit. Just note that this call is really about Iovance's Till therapy and not so much about some of the other things that he's involved with. Doctor. Mead, would you be able to answer that? Yes. So thank you so much for that. Let me just tell you that, number 1, I'm not only a physician researcher, but I run a very robust clinical practice where I see a significant proportion of patients 4.5 days in clinic. So I would say when you look back at this first line data, what you notice is that these are the patients that are going to become that came to lipolystel. These are the patients that have progressed on these therapies. When you look at LAG-three, the data presented by Paula Assierto post PD-one, way back when 3 years ago, the response rate was like 11%. When you look at the data in KEYNOTE-six, post pembrolizumab, the response rate to anti CTLA-four therapy was 15%. And when you look at the response rates to ipinivo post PD-one, it's somewhere between 20% to 30%. But this population of patients that you're looking at have progressed on those therapies and you're not expecting them to respond in as robust way as they have done to lifilevelacel with a 36.4% response rate. Now something that wasn't presented here has been presented before and that's the checkpoint refractory population, the patients that don't respond initially. These were about 80% of the responders to this therapy. And now you're looking at trying to find answers to patients who would never respond to an immune checkpoint inhibitor. What you're seeing here is an early indication of a different paradigm when you're looking at patients who really have shown you that they're not going to respond or benefit. We know that 25% of patients that respond to anti PD-one therapy then subsequently progress. So what I'm saying here is there's enough patients looking for this. And if this was available, the patients would want it. Now the combination first line data is interesting here where you look at these patients who come in with the best performance status and then ability to move forward. So it may be that you're looking here on a way to synergize these therapies at a time where the patient has less tumor burden, a lower LDH and is more able to tolerate this therapy, therefore expanding what has been an exclusion for some patients, age, comorbidities and getting this therapy to a wider range of patients. What that means for other combinations is unimportant in relation to reviewing this data and understanding its importance and role in melanoma care and therapy. We have our next question from Mark Breidenbach from Oppenheimer. Your line is now open. Hey, guys. Thanks for the update and thanks for taking my question. I find it really striking that you're still seeing tumor shrinking this long after a one time therapy. And it looks like maybe even a couple of patients are on the cusp of achieving partial responses in Cohort 2. I'm wondering if this is a general trend with Till therapy. Have you seen this not just in melanoma, but in other indications as well? And maybe, Fred, you can give us updated guidance on plans for readouts from additional cohorts in the Basket study and or the cervical cancer trial later this year? Thank you. So if you'd allow me to go first, Fred, I would just say that this is not amazing or not interesting. If you look back on Mike Atkins data on the approval of interleukin 2 for melanoma, even though the response rates to that were much less, these are patients who are durable and have responses. Even Mike discussed running into a patient 30 years later having a response and benefit. This is the whole idea of immunotherapy. These are similar in patients who received only 4 doses of anti CTLA-four therapy and are still benefiting with a partial response that's durable and a completion response that's durable a decade later plus on trials. So we've also seen this in prior Till trial. So what I for us that have been giving these types of therapies, it's not surprising. It's interesting and welcome that we're seeing a higher rate of patients responding and these patients are some of our most heavily pretreated patients, patients who've had prior PD-one, prior BRAF inhibitors, prior anti CTLA-four and that's the majority of patients that come to my clinic. And that's what's going to happen now based on what's been presented at ASCO. These patients will receive standard therapies in clinics and community and will be seeking a therapy that can show high response rate, durable responses and deep response. Yes. Totally agree, Doctor. Hamid. Why don't I go back and just answer the first part of Mark's question there about the indications in our Basket study. So yes, we have obviously a lot of ongoing cohorts in the Basket study. We've just put one of them into this ASCO conference that we just had and Doctor. Just talked about your panel Friday. There's other cohorts running there. We haven't committed to data flow yet on those, but we're working as hard as we can to get those ready. Just note that those cohorts started a little bit later than the frontline melanoma cohort that we were talking about here. So stay tuned on that. We'll come back and as soon as we possibly can to talk about additional data. There was another aspect of the question as to whether we had seen this across other indications. Can I ask Friedrich on our side to step in and talk about that a little bit? Sure. I mean, I don't have a lot to offer to Doctor. Hamme. It's really powerful and also true statements and descriptions there. I think what I can contribute is to point to our data in the CPI naive headed neck cancer cohort that we presented last year at SITC. There is an example that looks very similar to what you're seeing here of a patient who had a response initially observed after on his second assessment and then converted to a CR late at month 9 after Till therapy. So I do think that this is a general feature of immunotherapy, but our data are suggesting that that is true for Till as well and that might be true across tumor types. Next question is from the line of Asikka Goonewardene from Turits Securities. Your line is now open. I want to talk to Hamid, if I may. Doctor. Hamid, the data that was presented today was quite interesting. And just to summarize, for each 6 months decrease in exposure to prior PD-one, the duration of response to the filler cell has doubled. I'm wondering what do you think is happening here? And I was hoping you could maybe speculate in terms of the quality of T cells you'd like to getting as starting material and speculate on the type of tumor that you'd be treating here. And then in the likely event that tepotinib, the LYG3 plus nivo becomes a standard frontline therapy, I know there isn't much data, but could you maybe tell us what you think how that changes the tumor and the TILs? Yes, that's a great question. And I can really see that you've spent the time to try and suss this out. I would say to you that, I mean, it's too early to really speculate. I would more than likely say that what you're what we've seen is an interaction with people who with patients who've received PD-one in extended time and there's some evidence of T cell exhaustion there that we could look to recover. What this points to is further work that will need to be done evaluating the biomarkers on these patients who are on therapy. And it does point to a plan that Iovance and others have had that's visible here, that they're not just waiting on the data to be evaluated by FDA for single agent, they're moving further into first line prior to ICI. And when that data matures, I think we'll have a better answer to give to you. Next question is from the line of Peter Lawson from Barclays. Thanks for taking my questions. So Doctor. Hamed, just as we think about the use of Till therapy in a broader melanoma group of patients, What's the biggest restriction there? Is it the ability to generate TILs or use of IL-two, just your considerations there around the potential expansion of Till use in patients? So I would say, good question. I'm grateful for Iovance to be able to bring this to many different centers and hospitals throughout our major issues in the past. As I've worked with Doctor. Mark Farris, who's the co director of our program here and a surgical oncologist is for most people was finding a GCP facility a way to generate Till. So they've overcome that. And the second thing would be the ability for centers that are interested in doing this to be able to bring forth a team and mobilize a team to be able to present this and be able to give this to patients. So this adoptive T cell therapy is for us would have never been accessible if we didn't have this pathway. It took us some time initially to get the hospital involved and the clinical pathways put together. And I think Iovance is working to help the novel centers do that. But if you go back to the understanding and the use of IL-two for patients with metastatic melanoma that was pioneered and worked on with Chiron and others. It's the ability to clearly relate the benefit, clearly relate the therapy and then clearly translate that into action at many different sites. We have our next question from the line of Joe Catanzaro from Piper Sandler. Your line is now open. Great. Thanks. Thanks for the update. Thanks for taking my questions here. So Doctor. Ahmed, you had noted earlier that the patients, melanoma patients refractory to PD-one still represents a sizable proportion of patients. With that as context, I was wondering if for the lipolusopembrolizumab combination, if any of those patients were experiencing increases in their target lesions during the pembrolizumab run-in ahead of Till infusion that markedly reversed after Till infusion? And then maybe one quick one on the potency discussion. Company, you've previously spoken about a front runner assay and a secondary assay that you've provided data around. Can you say whether both of those assays are still in play following the most recent feedback? Thanks. Yes. Why don't I start here, Doctor. Mead, and then I can loop you back in here. So the answer to the second question first, all things are on the table with the FDA. Obviously, we've been talking about additional potency assays that we've developed and getting them in front of FDA, but that doesn't mean that we would not use those in combination with prior assays or alone. We don't we just haven't had that. We have got to that left book discussion yet with the regulator, and we'll update the street as soon as we can. Regarding the first question, maybe Doctor. Amit, I don't know if you want to take that one or maybe Frederic can jump in on that one. Yes. Well, let me take it to the best of my ability. As you can see here, the patients were screened and placed on study and received one dose of anti PD-one therapy and then went on to lymphodepletion chemotherapy. So there was no imaging done in the interim and then there were 7 patients. So I would say that there's really not anything to mention and there wouldn't have been any type of progression from starting therapy and receiving first dose. Next question is from the line of Madhu Kumar from Goldman Sachs. Your line is now open. Hey, everyone. Thanks for taking our questions. So our first one is to Doctor. Hamid. In your experience, have patients who've been on PD-one blockade who discontinued therapy maintain responses? And like how do you think about that aspect of the PD-one naive trial that people can come off therapy and maintain response? Right. Good question. I would put it this way to you that most of the majority of clinical protocols that are written at this time in melanoma have a finite limit of therapy at 2 years. When you look at the KEYNOTE-six trial, they allowed patients to come off early if they had shown a complete response that was maintained for, I believe, 6 weeks. When you look at the data from TECMATE-sixty seven, which was just presented, they have interestingly shown patients who have come off for toxicity initially and never been retreated continuing to have a benefit and a response. So this is something that's very familiar to us who take care of patients with melanoma. And I think it's possible in the same fashion for the patients who are on the combination first line trial. Okay. And then one other question we've gotten from people is, the notion have you seen any studies combining IL-two either a long course or short course IL-two with PD-one blockade and melanoma? And to what extent do you envision that some of the effects can be contributed by just the very short period of IL-two given kind of after Till infusion and how you think about that aspect of the combination of the PD-one naive trial? Look, I'm going to be straightforward here. I can't talk to the PD-one naive trial. It's an early trial of 7 patients. I will say that if you'd looking for data about IL-two combinatorial therapies and look no further than the amazing work done by the cytokine working group, which we're a part of. And so that's aside from what we're talking about today. But clearly, the IL-two experience has shown shown responses that are somewhere under 12% to 15%. And really, the data that was presented in the past was in prior to the checkpoint era. And additionally, I mean, I would you want to compare it and see that this the response rate here is greater by more than a factor of 2. So you can't just say this is IL-two, No one would say that. Hi, Madhu. This is Amida Anjageshia, Senior Vice President for Medical Affairs. I would just like to reemphasize that, that it's highly unlikely that a median of 5 doses of IL-two can affect any sort of a major response just by itself, even if you were to say that these patients so remember, in the Cohort 1a study, right, patients have had one dose of pembro, 2 weeks later they get lymphodepletion and then they get up to around 5 to 6 doses of IL-two. It's highly unlikely that one dose of pembro plus 5 doses of or 6 doses of IL-two is giving you a response that we are seeing of 86% ORR with a 43% CR without the tubes doing anything. It's just scientifically very, very improbable. This is Frederic. Maybe I can just add to this as well as Frederic Finckenstein, Chief Medical Officer at Iovance. Remember, therapeutic IL-two is dosed in repeated cycle repeated cycles of many more doses over a longer time than the 6 doses that we are administering over maximum 3 or 4 days duration. I totally agree with what said here. This is not therapeutic IL-two. This IL-two is administered in order to continue the Till expansion after administration in vivo in the patient. That's its purpose. Next question is from the line of Mara Goldstein from Mizuho. Your line is now open. Great. Thanks so much for taking my questions. Just first on the results looking at those, converted CRs and particularly that late CR. I'm curious if you have any information about what is going on for those patients biologically and how that might translate into practice? And then hello? That's very difficult to hear you. Sorry, is this better? Yes. Could you restate that question? You got partially cut off in the first part. Sure. Thank you. I'm just curious about around the complete responders in the trial and the what might be going on biologically for those individuals and how that might translate into clinical practice? And then secondarily, I did want to ask on the question of assays and new data, whether or not, as you say, everything's on the table, whether de novo data will be required to complete this assay process with the agency? Yes. Let me start with the potency assay question first. By the way, are you talking about Cohort 2 when you say the trial? Yes. Thank you. Okay. All right. So regarding the potency assay and de novo data, yes, some additional data is required. We've been talking with The Street about that. We'll have to we're going to have to generate data packages as part of our interactions with the FDA in the second half of this year. However, we've already done a lot of that work and we have retained samples that we can use to facilitate that process. For the first part of your question, why not Frederic, would you be able to speak a little bit more about the CRs? Yes. I think what I heard was the question what's going on biologically in patients who have CRs or respond to the combination. Was that your question? Think so, Virgil. Go ahead. Yes. So I think one thing to keep in mind when we are looking at Till therapy, these are autologous, non modified T cells. So they it would make sense that they are subject to the checkpoints that are controlling their activity combining with checkpoint inhibitors is perfectly rational and that makes a lot of sense that we would be seeing that you would be seeing at least as we are watching these data potentially even synergistic data. These cells are subject to PD-one mechanisms and blocking them make a lot of sense. And obviously, what lies closest is to use a validated mechanism and approved agents that do exactly that. Does that answer your question? Next question is from the line of Nick Abbot from Wells Fargo. Your line is now open. Hello and congratulations on 2 terrific sets of data here. My question is on the checkpoint inhibitor naive cohort with focus on the 2 patients has progressed. Are you able to characterize the nature of progression? I think we're calling the advanced setting that progression at a single site can be addressed by resectional local regional therapy and those patients remain treatment free? And if that's not the case here, are these patients eligible for resection and retreatment with the new Till product? Thank you. Roger, can you answer that one, please? Yes, I can definitely address the second question. I did progression that we see in patients after Till therapy is often related to the development of new lesions, but not always. All of our protocols allow, if the PI and the patient agree and this is thought to be a benefit for the patient for retreatment after re resection and manufacturing of the new product. I was just going to ask if that was undertaken in these two cases. This is early. This is really hard of the press data. So we're very early in this stage. Next question is from the line of Colleen Cussey from Baird. Your line is now open. Yes, good afternoon. Thank you so much for taking our questions. In the pembro combo, it looks like based on the SUMRIS plot, we're seeing some variability in the amount of pembro given. Can you maybe just talk about how that's determined in this early trial and how you expect in the future combo will be dosed? Frederic, can you answer that one for Colleen? Can you repeat the question, please? I'm having a bad connection here. I apologize. Sorry about that. So just in looking at the swimmer's plan, it looks like the amount of pembro and the frequency of pembro infusion is variable between patients. I guess how do you expect that to be dosed going forward in the trial? And how would you expect that to impact the response? Yes. So you're looking at the tremor plot and you're seeing the dose indicating the pembro infusion. Again, if you see a patient discontinue in pembro, then that is due to toxicity, which is to a certain extent expected in the patient treated with checkpoint inhibitors. What I find remarkable is that the patients that are actually, although they are just continuing pembro or deepening responses or maintaining that response. I think that is for a long time. That is really important observation. For us currently, I think this is too little data to inform on what we should be doing with this combination. I think we need to generate more data with it. So for now, this study will continue to explore continued maintenance with pembrolizumab and then we will learn from it. Great. Thank you. Next question is from the line of Boris Peaker from Cowen. Your line is now open. Great. Thanks for squeezing me in. Maybe for Doctor. Hamed, I'm curious, are there any mechanisms to assess the expansion of persistence of these Till cells? I know they don't have a conserved antigen like CAR T cells do. And if there is such a mechanism, is there has anybody looked at to see if that persistence or expansion is improved by checkpoint inhibitors or full dose of IL-two versus people that require reduction of IL-two or any other correlation to performance? So I think I just want to reiterate what was said before that the amount of IL-two here is not dosed in a similar fashion in the past as to toxicity. And this is just to expand the T cells only. So we would not be expecting or would not have anyone be doing full dose IL-two and multiple doses up to 12014 in the past. As far as the other assays, I'll leave it to Ionis to speak in relation to what they have done in relation to this product. Hey, Boris, I can talk a little bit about this. We're not Checkpoint, if you're talking about expansion of sales, the impact of Checkpoint doesn't seem to be significant from what we know. If you're talking about ex vivo, for example, I'm not sure if that fully answers your question, but that's what we know as of today. Well, I mean, my general question is, is there any way to monitor these cells once they're injected back into the patient? Can you assess if they are actually persistent for a long period of time or not? Yes. All right. I got you. If you look back at some of our posters, you'll see some of our data that we've done with iReporter, which is a company that offers profiling TCR profiling services. And we do have ways of assessing that, although I don't have any information for you right now on how that affects this particular trial. You can look back and see what we're able to do with the techniques if you look at our posters. Fred, I can just confirm that we are collecting samples for similar analysis as we have presented previously for a melanoma and cervical trial and those data are on our website. Great. Thank you. Securities. Your line is now open. Hey guys, thanks for squeezing me in and congratulations on the data. Respond, is there anything that you can glean from that patient as to why they might not have responded? Is that person still on study with an SD? And have you ever seen, SDs across any of the studies converting to PRs? Frederick, why don't you take this one? Sure. So I think a single patient out of a total of 7 patients is much too early to try and learn any sort of predictive characteristics, but obviously that's something that we're going to continue to explore. This patient stays on trial. We are following patients with standard stable disease. And yes, on other trials, we have seen later conversions to partial relapsedrefractory study Cohort 2, you talked about 11 patients who had further reductions. And at least when I was looking at the slides, it looked like, for example, patient 39 improved to a CR. Should we be thinking about this data now that instead of 3 patients with CR, it could be that we actually have 4 patients with CR? Or how do we incorporate the new patients' data that occurred past the April 2020 cut 2021 cut? Sure. Do you want me to take this question? Yes. Why don't you take that one about the question? Yes. So waterfall plots are showing best overall response regardless of timing. And as you've seen and that's been previously presented in the first and ASR, the additional patient of the 3 CRs converted late and now we are counting this patient as additional CR patient. The patient number 39, although that patient shows a total reduction of target lesion to minus 100%, may not have resolved non target disease and because of that is not formally considered the C outpatient. Got it. Great. Thank you for the clarification. We are on top of the hour. And at this time, I would like to turn it back to Mr. Fred Vogt. Sorry, I was on mute. Apologies. Thank you again for joining the Iovance ASCO update call. A special thanks to Doctor. Ahmed for joining us to present the data. Feel free to reach out to our Investor Relations team if you wish to follow-up. Thanks, everyone. This concludes today's conference. You may all disconnect.