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

Good day and thank you for standing by. Welcome to the Iovance Biotherapeutics ASCO Update Call. [Operator Instructions] As a reminder, this conference call might be recorded. I would now like to turn the conference over to your host, Ms. Sara Pellegrino, Vice President, Investor and Public Relations.

Thank you, operator. Good afternoon and thank you for joining our conference call to discuss the clinical data updates at ASCO 2021 for lifileucel in 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 Dr. Omid Hamid, Chief of Research Immuno-Oncology at The Angeles Clinic and Research Institute. Dr. Hamid is recognized nationally and internationally as a key opinion leader in immuno-oncologic drug development and melanoma therapeutics, and we are very fortunate to have him join us today. Our Chief Financial Officer, Jean-Marc Bellemin, will also provide a brief financial summary, and then we will hold a question-and-answer session. Dr. Friedrich Finckenstein, our Chief Medical Officer; and Dr. Madan Jagasia, our Senior Vice President, Medical Affairs, are also available for the Q&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, Sara, and good afternoon, everyone. We are pleased to host today's call to highlight our 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 TIL therapy in multiple indications as well as earlier lines of therapy, including Iovance cell therapy in non-small cell lung cancer as well as TIL therapy combined with pembrolizumab in 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 FDA feedback 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're going to achieve our new target time lines of our 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 Dr. Omid 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, Dr. Hamid 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-1 inhibitors, other checkpoint inhibitors, bispecifics and targeted agents. He has presented the research done at The Los Angeles -- at The Angeles Clinic at major national international meetings and published manuscripts, abstracts, reviews on immunotherapy, targeted therapy and melanoma care. Dr. Hamid has been a principal investigator in our C-144-01 clinical study and lead author on several of our publications and presentations at medical meetings. We are very pleased he could join us today to review the data for lifileucel. Dr. Hamid, 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. Lifileucel is a cryopreserved autologous tumor-infiltrating lymphocyte therapy in patients with advanced melanoma, and we are evaluating the evaluation of impact of prior anti-PD-1 therapy in this cohort. On Slide 3, you'll see the study design of C-144-01. This is a Phase II multicenter study to evaluate lifileucel for metastatic melanoma in a patient population that was unresectable or metastatic melanoma treated with greater than 1 prior systemic therapy, including a PD-1 antibody; and of course, as important, if BRAF V600 mutation positive, a combination targeted approach. We'll be speaking about Cohort 2 that look to use the cryopreserved TIL product for 60 patients. As it occurred, 66 patients were recruited in this cohort. Primary end point was efficacy per investigator initiated -- assessed overall response rate and the secondary end point is safety and additional parameters of efficacy. Key eligibility here: having 1 tumor lesion resectable for TIN -- TIL generation; ECOG performance status, 01. The patients were enrolled from April 2017 to January 2019. No concomitant cancer therapy was permitted. Image-evaluable disease was required and all responses required confirmation. This is a data cutoff 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-1 or anti-PD-L1. 53 out of 66 patients had, had an anti-CTLA-4. And of those 34 patients had, had concurrent anti-PD-1, anti-CTLA-4. 15 patients had BRAF and MEK inhibitor, and all patients had progressed on anti-PD-1 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 the 3.3 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-2 regimens. You can see most patients received 5 or 6 doses of interleukin-2, and 6 is maximum. A decreasing frequency of adverse events over time is indicative of the potential benefit of this therapy. You -- 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 80.3% with a median duration of response that's not reached. Responses were demonstrated in patients who received prior anti-CTLA-4 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 TIL infusion, various levels of LDH and various visceral metastases patients respond. 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 asserts in those 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, then 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 TIL was manufactured from tumors regardless of location of resection, visceral, lymph node/skin subcutaneous and other not assigned locations. And the amount of TIL was equivalent in each site. Also, target lesion sum of diameter reductions were seen across the range of TIL total cell dose. So not quite associated with the amount of TIL infused. When you look at unit variable analysis for duration of response of lifileucel, although cumulative duration on prior anti-PD-1/anti-PD-L1 was not associated with achieving a response, it was associated with duration of response. When you look here, prior anti-CTLA-4 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 lifileucel duration of response. There are variables from the univariable analyses were examined using the best subset approach. And 2 parameters were identified here, baseline LDH and also cumulative duration on prior anti-PD-1 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-1 and for each 6-month decrease in exposure to prior anti-PD-1/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 lifileucel will be nearly doubled. So in conclusion, Slide 12, in heavily pretreated metastatic melanoma patients who progressed on multiple prior therapies, including anti-PD-1 and BRAF/MEK inhibitors, lifileucel 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 reduction in sum of diameter since the last cutoff 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 anti -- prior anti-PD-1 therapy maximizes duration of response to lifileucel treatment. All newly diagnosed patients should be closely monitored for progression on anti-PD-1 therapy because early intervention with lifileucel at the time of initial progression on anti-PD-1 agents may maximize benefit. Now I'd like to present some of the initial data of the safety and efficacy of lifileucel in combination with pembrolizumab PD-1 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. IOV-COM-202 was a prospective, open-label, multicohort nonrandomized, multicenter Phase II study evaluating TIL therapy in multiple settings and indications. Cohort 1A, which we report here, enrolled patients with immune checkpoint inhibitor-naive advanced melanoma that's Phase III unresectable or Stage IV metastatic for a combination of lifileucel and pembrolizumab. The key eligibility criteria here, of course, naive to immune checkpoint inhibitor, less than 3 lines of prior systemic therapy, good ECOG performance status, having a resectable lesion for manufacturing and then evaluable, measurable lesions for response assessment. Efficacy was objective response rate and safety here will be presented. The data cutoff, 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 lifileucel infusion and interleukin-2 post infusion of up to 6 doses, and then continuing pembrolizumab on the approved every 3- or 6-week dosing, end of therapy then and 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. 85.7% of patients had greater than 3 lesions and that 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, 85.7%. One patient with stable disease for a disease control rate of 100%. The median number of TIL 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 in target lesions 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 for RECIST for 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 mutation, patient 3 had a non-E mutation and patient 6 had a V600E mutation. Patient 6 had seen dabrafenib 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, a PET CT 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 trial that patients had initial response and then had deepening responses over time and the complete response patients here. And also, you can see here that the patients are out many months, all out 6 months and then some out here at past 16 and 21 months. So in conclusion, early data here suggest the response rate for lifileucel plus pembrolizumab may be additive in patients with immune checkpoint inhibitor-naive advanced melanoma with a 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 lifileucel can be safely combined with pembrolizumab. These encouraging data confirm the potential feasibility and activity of the combination in early-line treatment of patients with advanced melanoma. And with that, I'll conclude, and thank you for your time.

Thank you, Dr. Hamid. So let me comment very briefly on our current financial and cash position to end this presentation, which the cash strongly position Iovance to 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 $610.2 million in cash, cash equivalent, investment and restricted cash, inclusive of $42.9 million proceed raised through ATM offering. As a reminder, the total ATM offering is for up to $350 million. 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 investments in 4 key areas to ensure the growth and strength of our value creation: first, advancing our current clinical programs and indications; second, scaling up our manufacturing capacity to support our clinical manufacturing while preparing for expected commercial supply in 2022; third, ensuring launch readiness; and fourth, maintaining a strong balance sheet and cash position. I will now hand the call back to the operator to kick off the Q&A session. Thank you.

[Operator Instructions] Our first question is from the line of Ben Burnett from Stifel.

I 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?

Ben, this is Fred. Yes, that's correct. We had gated the BLA filing. We're -- given all the recent events, we'll take a look at that, of course. I don't have any updates for you today, but that's something that we're thinking about.

Next question is from the line of Michael Yee from Jefferies.

Maybe two quick ones, one for the doctor and one for the company. Well, maybe, Dr. Omid, you could talk about -- Dr. Hamid, sorry, you could talk about maybe how this data stacks up with other combination regimens, obviously, LAG-3 data here at the conference. And your analysis of PD-1, does that imply you should expect for long duration of therapy early and 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 the assays and not wanting to have all of that information out before the assays, you just need to ask the FDA if that would be okay? Maybe just clarify that comment for us.

Yes. Why don't I go first, Michael, and then I'll hand it over to Dr. 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 Dr. -- I'll give the second question to Dr. Hamid. Just note that this call is really about Iovance's TIL therapy and not so much about some of the other things that he's involved with. Dr. Hamid, would you be able to answer that?

Yes. So thank you so much for that. Let me just tell you that, number one, 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 lifileucel. These are the patients that had progressed on these therapies. When you look at LAG-3, the data presented with [indiscernible] to post-PD-1, way back when 3 years ago, the response rate was like 11%. When you look at the data in KEYNOTE-006 post pembrolizumab, the response rate to anti-CTLA-4 therapy was 15%. And when you look at the response rate to ipi/nivo post-PD-1, 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 lifileucel 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 are not going to respond or benefit. We know that 25% of patients that respond to anti-PD-1 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 this combination first-line data is interesting here where you look at these patients who come in with the best performance status and the 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.

I find it really striking that you're still seeing tumor shrinking this long after a onetime 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 TIL 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.

So if you'd allow me to go first, Fred, I would just say that this is not an 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-4 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 TIL trials. So what I -- it's -- 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-1, prior BRAF inhibitors, prior anti-CTLA-4. 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, in community and will be seeking a therapy that can show high response rate, durable responses and deep response.

Yes. We totally agree, Dr. Hamid. Why don't I go back and just answer the first part of Mark's question there about the other 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 Dr. Hamid just talked about that on Friday. There's other cohorts running there. We don't -- we haven't committed the 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, and we'll come back and -- as soon as we possibly can to talk about additional data. There was another aspect to 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 Dr. Hamid's really powerful and also true statements and descriptions, but I think what I can contribute is to point to our data in the CPI-naive head and 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 TIL therapy. So I do think that this is a general feature of immunotherapy. But our data are suggesting that, that is true for TIL as well and that might be true across tumor types.

Next question is from the line of Asthika Goonewardene from Truist Securities.

One to Dr. Hamid, if I may. Dr. Hamid, the data that was presented, it was quite interesting when -- but just to summarize for each 6 months, decrease in exposure to prior PD-1, the duration of response to lifileucel 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 might be getting as study material and speculate on the type of tumor that you'll be treating here. And then in the likely event that well, EpimAb, the LAG-3 placebo, 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 flush this out. I would say to you that it's too early to really speculate. I would more than likely say that what your -- what we've seen is an interaction with people who -- with patients who've received PD-1 and 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 the 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 a 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.

Dr. Hamid, just as we think about the use of TIL 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-2? Just your considerations there around the potential expansion of TIL 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 Dr. Mark Faries, he'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 TILs. 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-2 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.

Great. So Dr. Hamid, you noted earlier that patients -- melanoma patients refractory to PD-1 still represents a sizable proportion of patients. With that as context, I was wondering if for the lifileucel-pembrolizumab combination, if any of those patients were experiencing increases in their target lesions during the pembrolizumab running ahead of TIL infusion that markedly reversed after TIL 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 provided data around. Can you say whether both of those assays are still in play following the most recent feedback?

Yes. Why don't I start here, Dr. Hamid, and then I can loop you back in here? So the -- to answer 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 haven't gotten to that level of discussion yet with the regulator, and we'll update the Street as soon as we can. Regarding the first question, maybe -- Dr. Hamid, I don't know if you want to take that one or maybe Friedrich can jump in on that one if...

Yes. Well, let me take it to the best of my ability. As you can see here, the patients that were screened and placed on study and received 1 dose of anti-PD-1 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 the first dose.

Next question is from the line of Madhu Kumar from Goldman Sachs.

So our first one is to Dr. Hamid. In your experience, have patients who've been on PD-1 blockade who discontinued therapy maintain responses? And like how do you think about that aspect of the PD-1 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-006 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 CheckMate 067, 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-2 either a long course or short-course IL-2 with PD-1 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-2 given kind of after TIL infusion and how you think about that aspect of the combination of the PD-1 naive trial?

Look, I'm going to be straightforward here. I can't talk to the PD-1 naive trial. It's an early trial of 7 patients. I will say that if you're looking for data about IL-2 combinatorial therapies, look no further than the amazing work done by the cytokine working group, which we're a part of. So that's aside from what we're talking about today. But clearly, the IL-2 experience has 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 how would you want to compare it and see that this, the response rate here is greater by more than a factor of 2? So we can't just say this is IL-2. No one would say that.

Madhu, this is Madan Jagasia, Senior Vice President from Medical Affairs. I would just like to reemphasize that it's highly unlikely that a median of 5 doses of IL-2 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 1 dose of pembro. Two weeks later, they get lymphodepletion. And then they get up to around 5 to 6 doses of IL-2. It's highly unlikely that 1 dose of pembro plus 5 doses of -- or 6 doses of IL-2 is giving you a response that we are seeing of 86% ORR with a 43% CR without the TILs doing anything. It's just scientifically very, very improbable.

This is Friedrich. Maybe I can just add to that as well. So I'm Friedrich Finckenstein, Chief Medical Officer at Iovance. Remember, therapeutic IL-2 is dosed in repeated cycles of many more doses over a longer time than the 6 doses that we are administering over maximum of 3 or 4 days duration. I totally agree with what was said here. This is not therapeutic IL-2. This IL-2 is administered in order to continue the TIL expansion after administration in vivo in the patient. That's its purpose.

Next question is from the line of Mara Goldstein from Mizuho.

Just first on the results looking at those reported 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?

It's very difficult to hear you.

Sorry, is this better?

Yes. Could you restate that question, please? You got partially cut off on the first part.