Iovance Biotherapeutics Inc (IOVA) 2022 Q2 法說會逐字稿

Welcome to the Iovance Biotherapeutics Second Quarter and First Half 2022 Financial Results and Corporate Update Conference Call. My name is Andrew, and I will be your operator for today's call. (Operator Instructions) Please note that this call is being recorded. I will now turn the call over to Sara Pellegrino, Senior Vice President, Investor Relations and Corporate Communications at Iovance. Sara, you may begin.

Thank you, operator. Good afternoon, and thank you for joining us. Speaking on today's call, we have Dr. Fred Vogt, our Interim President and Chief Executive Officer; Dr. Igor Bilinsky, our Chief Operating Officer; James Ziegler, our Executive Vice President, Commercial; Dr. Friedrich Finckenstein, our Chief Medical Officer; and Jean-Marc Bellemin, our Chief Financial Officer; Dr. Madan Jagasia our Executive Vice President, Medical Affairs; and Dr. Raj Puri, our Executive Vice President. Regulatory Strategy and Translational Medicine are also available for the Q&A session.

This afternoon, we issued a press release that can be found on our corporate website at iovance.com, which includes the financial results for the 3 and 6 months ended on June 30, 2022 as well as recent corporate updates. Before we start, I would like to remind everyone that statements made during this conference call will include forward-looking statements regarding Iovance's goals, business focus, business plans, pre-commercial activities, clinical trials and results, regulatory interactions, plans and strategies, research and preclinical activities, potential future applications of our technologies, manufacturing capabilities, regulatory feedback and guidance, payer interactions, licenses and 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.

We undertake no obligation to publicly update any forward-looking statements. With that, I will turn the call over to Fred.

Thank you, Sara. And good afternoon, everyone. I'm pleased to highlight our significant year-to-date progress at Iovance. I'll begin with our first planned biologics license application or BLA for our lead TIL therapy, lifileucel and metastatic melanoma. This is our #1 priority on behalf of patients who are eager to see lifileucel approved.

We successfully completed a pre-BLA meeting with the FDA in July, and we are on track to begin the BLA submission this month. The FDA provided favorable feedback on the clinical efficacy data from Cohorts 2 and 4 of the C-144-01 clinical trial include duration of follow-up to potency assay matrix.

The FDA also agreed that the clinical and safety data that was sufficient for a BLA review and provided valuable feedback and advice regarding various parts of the planned BLA submission. Following the pre-BLA meeting, we will commence the rolling BLA submission this month.

The rolling BLA submission is the benefit available under our Regenerative Medicine Advanced Therapy or RMAT designation. A rolling BLA allows us to submit sections of the BLA to the FDA on an ongoing basis.

This process enables the FDA to begin review of submission documents as early as possible as they are received potentially allowing for earlier approval. We expect to complete the rolling BLA submission during the fourth quarter of this year. We are pleased with the outcome of the pre-BLA meeting, which multiple members of FDA senior management team attended.

The FDA is engaged in support of the BLA for lifileucel and we look forward to continuing this level of collaboration throughout the submission and review process. In parallel to BLA-related activities, we are actively preparing to launch lifileucel. Key pre-commercial activities, including medical education, treatment center onboarding, payer engagement, commercial manufacturing readiness and near and long-term capacity planning.

We aim to successfully deliver full therapeutic cancer patients and create value for our shareholders. We are also excited about the advancement of our TIL-cell therapy pipeline. We are recruiting patients across 5 Iovance clinical trials, including the recently initiated trial of our first genetically modified TIL therapy.

Six cohorts of non-small cell lung cancer patients are part of 3 of these active trials, reflecting our focus on that indication. We are also on track to initiate a Phase III trial of lifileucel combination with pembrolizumab in frontline melanoma towards the end of the year.

As noted in this afternoon's press release, we are expecting our C-145-01 -- sorry, C-145-04 study to support BLA submission for lifileucel in cervical cancer, which Friedrich will highlight further. This updated registration strategy reflects FDA discussions and feedback that address the shift from frontline standard of care in cervical cancer.

As we prepare to launch the first onetime cell therapy in solid tumors, we are growing the organization to advance our mission of innovating, developing and delivering TIL therapies. Today, we have nearly 450 employees that bring deep expertise and successful track records of oncology and cell therapy development and commercialization.

The strength within our organization reflects tremendous enthusiasm for Iovance cell therapies and our global leadership in the field. I look forward to addressing your questions later during this call. We'll now ask Igor to discuss manufacturing networks.

Thank you, Fred. Our manufacturing network is dedicated to patient needs and operational excellence with a consistent TIL manufacturing success rate of more than 90% in more than 500 patients treated with Iovance TIL therapy to date. The Iovance Cell Therapy Center, or ICTC, is our 136,000 square foot internal manufacturing facility in the Philadelphia Navy Yard.

We custom-designed ICTC and in just 2.5 years, constructed it from birth on the ground to an operational facility supplying Iovance's clinical studies. Manufacturing is critical for any commercial launch particularly for autologous cell therapies.

So our top priority is to prepare ICTC for BLA submission and commercial supply. Today, the ICTC is upgrading flood suites for clinical manufacturing and conducting BLA readiness activities in the core suites. In addition, we are on track in preparing the ICTC and our contract manufacturers facility for FDA pre-approval inspections.

The ICTC is expected to supply most of the commercial TIL therapies upon approval with flexibility to use contract manufacturing to optimally manage capacity and fully meet patient demand. As we look to establish TIL as the next paradigm shifting plus of cancer therapy, we are also planning for our future capacity needs.

As currently constructed, the ICTC includes 12 core suites and 4 Flex suites with projected capacity to treat more than 2,000 patients per year. Within the existing structure at ICTC, the available shelf space allows us to double the number of core suites and increase annual capacity to provide TIL for more than 5,000 patients annually. Longer term, to reach TIL manufacturing capacity for more than 10,000 patients annually.

Our technology plans include streamlining and automating manufacturing processes, while adding new facilities. These new facilities potentially include an adjacent wall in the Philadelphia Navy Yard, where we have an option to build on the similar terms at ICTC.

To support and protect our proprietary manufacturing processes and know-how and to further solidify our leadership in TIL therapy, we are growing our intellectual property or IP portfolio. We currently own more than 50 granted or allowed U.S. and international patents, including Gen 2 patent rights that are expected to provide exclusivity into 2038.

I would now like to hand the call to Jim Ziegler to highlight our commercial launch preparation.

Thank you, Igor. Leadership positions and key roles are currently in place for commercial and other important functions supporting the launch of lifileucel for metastatic melanoma patients. Our cross-functional team has built the foundation to scale rapidly and efficiently as we accelerate launch preparations based upon key regulatory milestones.

We continue to collaborate with our top targets to become authorized treatment centers or ATC. We are prioritizing leading cancer centers to treat patients as soon as possible after approval. Our goal is to onboard and train at least 40 ATCs within the first 90 days of launch.

From our analysis of CAR-T claims data, we anticipate a patient concentration for lifileucel similar to the CAR-T market, where approximately 50% of CAR-T patients are treated in the top 10 centers and approximately 80% of CAR-T patients are treated in the top 40 centers.

Through structured interactions with the ATCs, we are efficiently facilitating the development of new workflows and that are unique to TIL cell therapy while leveraging existing workloads within prevalent cell therapy service lines at the ATC.

We designed our customer-centric approach to meet ATC training needs and ensure just-in-time preparation for each center. In addition to onboarding the ATCs, we plan to target high-volume community practices to increase awareness and encourage referrals to the ATCs.

We foresee a strong collaboration between the ATCs and community medical oncologists because we expect preferred patients to receive onetime treatment with lifileucel at the ATCs and then transition back to the community for ongoing monitoring and care.

Moving to our reimbursement strategy, we are focused on securing coding, coverage and payment. Our market access team continues to engage the key national and regional payers to support appropriate and timely access to lifileucel upon approval. As a reminder, lifileucel will be administered on an inpatient basis with reimbursement from payers to hospitals generally falling under a case rate for commercial patients and the DRG or diagnostic-related group for Medicare patients.

This means all care, treatment, services and hospitalization are generally reimbursed under one bundled payment. Finally, our proprietary Iovance Cares program is on track to assist health care providers and patients through their TIL journey as a best-in-class cell ordering, chain of identity, chain of custody and patient support program for launch.

As we prepare for commercialization, I want to acknowledge the strong and sustained effort by our core cross-functional teams who have built the foundation for launch. I will now pass the call to Friedrich Finckenstein, our Chief Medical Officer, to highlight the clinical progress.

Thank you, Jim. Today, I would like to share recent clinical and research program update that reflects the evolution of our pipeline to incorporate additional treatment modalities and next-generation technologies to address more cancer patients in new tumor types at various stages of disease.

First, I will briefly summarize the positive top line clinical data from 153 patients across Cohorts 2 and 4 in the C-144-01 trial in metastatic melanoma. We previously reviewed these results in detail in our data press release and conference call in May.

Patients in both Cohorts 2 and 4 met the same primary eligibility criteria at the same study assessment and receive the same treatment regimen in lifileucel that was produced using the same Gen 2 cryopreserved till manufacturing process.

Our pivotal Cohort 4 met the prespecified primary endpoint which was ORR assessed by IRC. ORR as well as various measures of durability for Cohorts 2 and 4 represent meaningful improvement over available care for our clinical trial population.

We look forward to announcing more detailed data from the C-144-01 trial at a medical meeting later this year. We also continue to develop TIL in combination with pembrolizumab in checkpoint inhibitor-naive patients with various tumor types to expand upon the initial opportunity for lifileucel monotherapy after anti-PD-1 therapy.

We are committed to starting a Phase III study in frontline melanoma later this year, which is also designed to serve as the confirmatory study. As Fred mentioned, during the second quarter, we also began site activation and patient recruitment for the IOV-GM1-201 first-in-human study of IOV-4001.

IOV-4001 is a PD-1 inactivated TIL therapy that recovers the talent gene editing technology licensed from Cellectis. IOV-4001 may leverage the combination of TIL and interruption of PD-1 signaling within a single therapy in a murine model of melanoma, the antitumor activity of IOV-4001 was superior to non-edited TIL product whether alone or in combination with an anti-PD-1 antibody.

The IOV-GM1-201 study includes 2 patient cohorts. The first cohort includes advanced melanoma patients who were previously treated with anti-PD-1 therapy similar to the patient population in our C-144-01 study. The second cohort in IOV-GM1-201 is recruiting metastatic non-small cell lung cancer patients whose disease has progressed after up to 3 lines of prior therapy, including anti-PD-1 therapy and will also include patients with tumors with EGFR ALK or ROC activating mutation.

Data from unmodified TIL clinical trials in comparable patient population provide appropriate benchmarks for potential differentiation of IOV-4001. We look forward to dosing the first patient in this study in the second half of this year.

Continuing on to our non-small cell lung cancer pipeline, we have multiple shots on goal with a total of 6 cohorts across 3 Iovance studies now enrolling patients in various stages of disease and using multiple treatment modalities. One cohort, which I just mentioned, will receive our genetically modified TIL therapy IOV-4001.

Three cohorts are being treated with TIL monotherapy LN-145 for metastatic non-small cell lung cancer after progression on chemo and anti-PD-1 in our IOV-LUN-202 clinical study. Two additional cohorts are receiving combination treatment in our basket study, IOV-COM-202, TIL plus pembrolizumab in anti-PD-1 naive patients and TIL plus ipilimumab, nivolumab in patients who progressed after anti-PD-1 monotherapy.

As Fred mentioned, we plan to enroll additional cervical cancer patients who has progressed on anti-PD-1 therapy into cohort 2 of our C-145-04 study. Existing active sites are expected to begin recruitment in the coming weeks. TIL therapy with lifileucel has the potential to offer an entirely new class of treatment to address a significant unmet need for service of cancer patients who progress after anti-PD-1 therapy.

Available care in the setting is chemotherapy with ORR ranging from 3.4% to 15% and median duration of response is 4.4 months. Cohort 2 is intended to be pivotal to support regulatory submissions for the treatment of cervical cancer after chemotherapy and immune checkpoint inhibitor therapy.

The prespecified primary endpoint for Cohort 2 is objective response rate or ORR, as assessed by independent review committee or IRC using RECIST 1.1. On the CMC side, we plan to leverage our know-how from the potency FA matrix for lifileucel and melanoma.

We also have a robust research pipeline investing towards the clinic. Following the success of IOV-4001, several targets for genetic modification are in preclinical studies using the gene editing talent technology licensed from selective, including double genetic knockout programs.

Using additional technologies, our research and preclinical side include approaches to increase TIL potency using CD39/69 double negative TIL and gene knock-in targets as well as IND-enabling studies of our novel interleukin 2 analog.

I am available to provide additional details during the question-and-answer session. For now, I will hand the call over to Jean-Marc to discuss our second quarter and first half 2022 financial results.

Thank you, Friedrich. My comments will reflect the high-level financial results of our second quarter and first half 2020. Additional details can be found in this afternoon's press release as well as in our SEC filings. I will begin with the strength of our cash position.

As of June 30, 2022, Iovance held $430.9 million in cash, cash equivalents, investment and restricted cash compared to $602.1 million on December 31, 2021. Our cash usage from operations during the second quarter included significant onetime retention-related payments.

As a late-stage oncology company approaching potential commercialization, we continue to make prudent investments in commercial launch preparation, internal manufacturing and pipeline expansion. We maintained prior guidance that our cash position is sufficient to advance these activities and our overall operating plan into 2024.

Moving to the income statement. Our net loss for the second quarter ended June 30, 2022, was $99.3 million or $0.63 per share. This compares to a net loss of $81.4 million or $0.53 per share for the second quarter ended June 30, 2021.

Net loss for the 6 months ended June 30, 2020, was $191 million or $1.21 per share compared to a net loss of $156.8 million or $1.04 per share for the first half of 2021.

Research and Development expenses were $73.4 million for the second quarter ended June 30, 2022, an increase of $11.3 million compared to $62.1 million for the second quarter ended June 30, 2021. Research and Development expenses were $141.7 million for the 6 months ended June 30, 2022, an increase of $23.6 million compared to $118.1 million for the first half of 2021.

The increase in research and development expenses over the prior 3- and 6-month periods was primarily attributable to the growth of the internal research and development team, including stock-based compensation expense, to support our ongoing and plan pipeline activity as well as increased facility-related and internal research program costs.

These higher costs were partially offset by lower clinical and manufacturing costs in the first half of 2022, driven by completion of enrollment in pivotal clinical trials. General and administrative expenses were $26.3 million for the second quarter ended June 30, 2022. An increase of $7 million compared to $19.3 million for the second quarter ended June 30, 2021.

General and administrative expenses were $49.7 million for the 6 months ended June 30, 2022, an increase of $10.8 million compared to $38.9 million for the first half of 2021. The increase in general and administrative expenses compared to the prior 3 and 6 months period was primarily attributable to the growth of the internal general and administrative and commercial teams including stock-based compensation expense as well as costs associated with the build-out of the new corporate headquarter and precommercial and launch readiness activity as well as our overall growth.

As of June 30, 2022, there were approximately 157.8 million common shares outstanding. With the strength of our balance sheet and by continuing to align our spending with our corporate priorities, we are well positioned to execute our operating plan into commercial launch and beyond. I will now hand the call back to the operator to kick off the Q&A session.

(Operator Instructions) And our first question comes from the line of Peter Lawson with Barclays.

Great. I guess during the pre-BLA meeting, was there any discussion around the confirmation trial that's required? And then any commentary around alignment around the potency assay would be great.

Yes. Thanks, Peter. Yes, as part of the pre-BLA meeting confirmatory trials did come up, and we did get some favorable commentary on what we're currently planning, we don't have any updates on the street just yet on that. But there is -- as you know, we're planning a frontline melanoma study later this year, and the FDA did provide at least some commentary that we read as being favorable towards what we're proposing in that trial.

And to your second question on the potency assay matrix situation, that really wasn't a major topic of the meetings. And so we really don't see any change in our prior discussions of that topic come out of the meeting.

Got you. And then I guess a final question around the pre-BLA on my final question would just be around the read-through from that meeting and how it could help inform filings for also cervical cancer and lung cancer.

Peter, it's interesting question. I think, look, we learned a lot at that meeting about what it's going to take right now with FDA to get cell therapies approved. So I think in general, it gave us some insight. We're not going to share all that publicly because I think it's competitively valuable but we do know quite a bit now having gone to a pre-BLA meeting over this that I think is going to be helpful.

There's nothing specific that I think we've learned there that we didn't already know that would impact cervical or long right now. but there is general some general information that we got out of the meeting that we think is helpful as to how you get these drugs approved. So we'll certainly take advantage of that.

And our next question comes from the line of Michael Yee with Jefferies.

This is Dennis on for Mike. Two questions from us, please. One, can you please talk about what were the issues discussed at the pre-BLA meeting? Was there anything the FDA asked that may have been unexpected? And I guess, what were their comments on durability after seeing the Cohort 4 data?

And then my second question is around what specific gating factors do you guys work through to actually submit the BLA. It's a rolling BLA now too apparently, which wasn't a scenario for most investors, I think. So talk about the decision to do that as well.

Sure. So on the first point, there was -- FDA commented very favorably about the clinical data and that includes the durability. They saw all the data. They sold the data that effectively we'll be talking about in medical conference later this year and there was a favorable commentary we have mentioned in our press release.

We think they're supporters of the product from a clinical perspective based on what they commented at the meeting. So I don't think there was anything specific there. Nor would I say there was anything unexpected at the meeting in terms of things that came out of left field that we were not planning for one way or another.

Now going into your -- the second part of your question, the second mid part of your question, rolling BLA is something that we are obviously announcing here. The rolling BLA is something that gives us some advantages.

It allows FDA to start looking at our following first and start to potentially get comfortable and work through some of the models while we finish up on a few secondary tasks and get those submitted. So that's really the story behind the rolling BLA submission.

And our next question comes from the line of Tyler Van Buren with Cowen.

Guys. Good afternoon. Just had a follow-up on the pre-BLA meeting, of course, specifically what feedback do they give you regarding the potential for Cohort 2 data to get into the label?

And that second question is just a point of clarification for the C-144-01 data being presented at a medical meeting by year-end. Will it include the pooled analysis of Cohort 2 and 4? Any additional color there will be helpful.

Yes. Let me take a reverse order. On the second part, yes. We'll definitely be talking about the full analysis of Cohort 2 and 4. We think that's the most relevant to the medical community. As we said before, we cannot.

I can have other members of the team follow up and tell you more about that. We haven't announced the conference yet, but that is our intention is to focus on that data because that's really the same patient population with the same unmet medical need that beats the same thing for the investigators out there.

After Cohort 2 being supported, the FDA has reiterated the supportiveness of Cohort 2. They did mention that, in fact, pulled cohort 2 and 4 could be supported as well. So we don't know anything more beyond the fact that they've set that many times now, and we think that's what they're thinking. They didn't have anything negative to say about Cohort 2 in the meeting.

And our next question comes from the line of Reni Benjamin with JMP Securities.

Maybe just starting off again with the pre-BLA meeting, the total package, Fred, how many patients' worth of safety data will be included. Is it just those from the C-144-01 study? Or can you pull others together -- and when -- in your discussions with them, were there any review issues? Or do you think there might be a potential for an ODAC panel?

Let me take the second part of that first, Reni now and then I'll ask Friedrich to answer the first part because I actually don't know the exact number of the full size of the safety set and he can explain it to you.

We didn't hear anything at the meeting on an ODAC panel that changes what we said previously. We think -- we don't think it's something that's going to happen here, but we're preparing in case there is a deal, and you always have to prepare.

So we're going to be well prepared if that does happen but there was nothing in the meeting on that topic that gave us any indication if that would be the case. Friedrich, do you want to answer Reni's question about the total size of the safety data set.

Yes. I don't think that we share the exact number of the patients that are going in the safety set what we have shared is the full analysis set with this 153 patients from 66 patients from Cohort 2 and 87 patients from Cohort 4.

So those are the patients that will drive the efficacy. There are some additional patients that could be considered as part of the review of safety data and FDA will certainly do that.

Got it. And then just as a follow-up, just based on your FDA discussions regarding the cervical study, can you maybe just provide some color as to how those discussions went. How many patients actually remain on the study because you're going to be reexpanding or reopening cohort 2.

I'm just wondering if there's a chance for let's say, a data update for people who had remained on the study versus the new patients that you plan on enrolling? And about how many patients are you planning on enrolling for the new expanded cohort 2?

Yes. So we haven't disclosed any patients to remain on study, and we look -- we have what we think is a sufficient amount of data as always, we would put out some data potential on that. It is a pivotal study that we have to be careful about doing that.

We're not, at this point, fully finalized on the total patient number here, but you should think of the sample size here as being similar to what we looked at for melanoma. And we're taking feedback to account. So could be slightly higher, we'll have to figure that out as we go here. But the sample size, I would broadly say it's consistent with what we did with melanoma.

The next question is from the line of Mark Breidenbach with Oppenheimer.

Glad to hear the pre-BLA meeting went relatively smoothly. Just one for Fred. I was wondering if you can kind of offer any more granularity around the steps of the rolling BLA submission and kind of like what's giving you the confidence that the process will be completed in the fourth quarter.

And then kind of an addendum on the previous question with regard to the cervical cancer cohort that's reopening for enrollment. I know you can't tell me how many patients you're planning to enroll. But does the FDA kind of indicate why they want more patients? Is it more to satisfy safety database requirement? Or where is this request for more patients coming from?

Sure. I'll take them on a reverse order. On cervical, it's not really so much -- I'm sure safety is part of what they're thinking, but it's just we need the size of a patient. We need a size similar to what's been accepted a statistically meaningful for other cell therapies, including our own.

So with 20-plus patients in that study, it's not going to do it in the patient population we're interested in. So they're just asking us for the efficacy set first and foremost, to increase the size. And of course, that will form safety as well, although we've got well long in the 500 patients with the safety data across the cohort programs.

On the rolling BLA and a little bit more granularity. We're primarily going to be submitting supportive information during the rolling period such as manufacturing capacity demonstration information and things like that. These things are not super complicated.

They are the things that we can we think we can get done fairly quickly, which is why we've got confidence in that fourth quarter and hopefully as early as possible on completion of the rolling BLA.

And our next question comes from the line of Mara Goldstein with Mizuho.

I have a question on manufacturing. And at the time of launch, I know you have annualized capacity of about 2,000 patients. But what should we think about for sort of steady state, if you will, for those initial few months of launch?

And how much capacity do you need to lead back to fulfill clinical trial requirements and I'm just curious about the possibility of improvement on a margin basis from where you will be at launch to where you will be when you get to a steady state.

Igor, would you be able to answer that one?

Happy to. Mara, thanks for your question. So I guess it's a twofold question. So it's launch we have very detailed plans. We're not disclosing the exact numbers, but we're planning obviously for meeting the commercial demand that we anticipate and in parallel, of course, we continue clinical trials.

And all of that's included in the capacity that we're planning to have at ICTC at the Advance Cell Therapy Center in the Navy Yard and also supplemented by additional capacity as needed at our contract manufacturer. The cost of goods, there's a lot of focus on the margins, obviously, and that's the team is working on that.

And yes, we're anticipating as we scale up, we -- the cost of goods, we have more control over that by having our own facility, and we expect that to improve over time.

Okay. And just on the rolling BLA, sort of what's the statutory, if you will, time frame for FDA decision time from completion of that rolling BLA? Like how should we think about that?

So from the completion of the rolling BLA, they calculate 8 months to the PDUFA date. However, because you're submitting a rolling BLA, the benefit is they get to look at it early so you can -- you have a higher chance of early approval for PDUFA date.

Okay. But at the output, it's 8 months, that's what you're thinking?

Yes, that's the way they calculate it. But again, the benefit of rolling BLA is to get in front of the to get them releases that they can beat that date.

And our next question comes from the line of James Chen with Wells Fargo.

For the frontline melanoma study in PD-1 naive patients, can you disclose if you will take into account the number of baseline tumor lesions and LDH levels what NASH Cohort 4?

It's a different patient population, we're talking about there. Friedrich, do you want to maybe talk about how we think about the patient population from that perspective.

Yes, good question. No, I don't think that we would try to match Cohort 4 because again, as Fred just said, it's a different patient population. It's a much earlier treatment setting. Remember, median number of prior lines of therapy on Cohort 2 and Cohort 4 with 3, many patients had more lines of therapy.

These are checkpoint inhibitors, so frontline therapy naive patients. So the distribution of numbers other prognostic factors is very likely to be different, and we will certainly not match -- try to match the late-line population.

There are although some steps that you need to take when in population. There are though some steps that you need to take when you run around this trial, and that means you need to stratify for non prognostic factors. We're certainly going to do all the standard measures that you usually do in a study design like that.

And our next question comes from the line of Asthika Goonewardene with Truist.

This is Bill on for Asthika. We had a couple of questions for you guys. We were wondering how much would it cost for you to increase your capacity from 2,000 to 5,000. And then how much more additional to increase to 10,000 patients per year.

It's a complicated question, but let me give you some yard and then Igor, feel free to chime in. So the total capital investment we had in Philadelphia to get us to where we are right now is about $85 million of tenant improvement that belt shelf space.

Now that includes a lot of support services as well and what the building is built, so we can just expand the shelf space for manufacturing. So it would not be anywhere near $85 million to expand that space, and that will get us up to the approximately 5,000 patients a year.

To go to higher than 5,000 a year to the next level, we're talking about another building, and that's something you could -- again, you could do a comparison to what we've done in Philadelphia, but it depends on where you do that, we do have a very favorable -- financially favorable option on land here in Philadelphia to expand on to, but we could also do it elsewhere, not -- and it would be something like the investment that we made in this facility in terms of the lease plus $85 million just adjusted for inflation and the things that have changed in the real estate market. Igor, do you want to add anything to add?

Fred, I think you covered it again. And it's important to understand that the first expansion would be within the existing buildings, so it's within the existing shell, we can add additional, looking at 12 core suites, to double the core suite capacity.

That's -- beyond that, as Fred mentioned, it depends on the options we are considering several where to expand likely to be greenfield, but there are several location options that could be on the table. And we'll talk about that in due time, it's premature to comment on that today.

Great. And I guess when is the soonest do you think you get a green light for LUN-202 as a registrational study? And we noted that you had a distinct populations within that study namely PD-L1 1% to 49% and PD-L1 0%. Do you feel confident that one of those subpopulations would have a lower benchmark for viability?

Let me take the first part, and give -- ask Friedrich to speak to the PL-1 stats. We're still in the -- we've been seeking up the feedback on LUN-202 as a registrational study, we don't have anything to update you on right now.

We're always says we're continuing to enroll as fast as we can add study to see how the earlier line of treatment works for with cell therapy for those patients. Friedrich, do you want to comment on the PD-L1 status in those 2 cohorts, what the expectations.

Happy to. I think that deserves discussion. So remember, the PD-L1 status that we're defining for these scores is the PDL-1 status prior to first-line therapy. So that is the PD-L1 status before they start the chemo checkpoint inhibitor therapy.

We have separated these cohorts like that because we thought that there is a chance that the treatment course under first line -- on first-line therapy might be different. And because of that, these patients might go into cell therapy slightly differently, not because we think that the PD-L1 status at start of cell therapy necessarily would be driving treatment outcomes.

So that is obviously something that we will have to explore and demonstrate if we are not seeing differences, there is a very good chance that we would simply collapse and be able to look at this as a single population. I hope that makes sense.

And our next question comes from the line of Ben Burnett with Stifel.

I have a question around the release criteria for lifileucel. Understanding that the assays themselves have been established and agreed upon, I guess can you talk about the release margins or release criteria. To what extent are the lease margins established and agreed upon with the FDA?

Or is this something that could potentially get ironed out during the review?

This is something that can get ironed out there in the review. And we would that's pretty sensitive stuff for us to release our product specifications, but it's basically a big topic during the review.

We think we have a pretty good idea of where we stand in that area right now. But probably, we're going to stay very little even after we get it agreed as to what those are unless we have to.

Okay. Okay. Understood. And then if I could ask one other question. I think previously, you had mentioned that cohorts -- so the melanoma cohorts 2 and 4 when they were combined have a median DOR that hasn't yet been reached. And I guess can you comment is that still the case today?

We will -- all I can say there is stay tuned for our presentation in a medical conference later on this year.

And our next question comes from the line of Colleen Kusy with Baird.

I know you said previously, you're targeting 40 centers at launch. Can you remind us roughly how that compares to what the CAR-Ts had at launch? And then within those 40 centers, what do you expect the average capacity will be?

Do you think about that as patients per month, their beds at a time or just understanding how many patient might fed into that 40 launch?

Colleen, it's Jim here. Thanks for that. So we've done a lot of benchmarking of the CAR-T market, and we look specifically at claims data over about a 4-year period. And what we found is the top 10 centers drive about 50% of all the CAR-T-treated patients and the top 40 centers account for 80% of so based upon those insights and the centers of excellence that have been established in the CAR T market, that's how we are targeting the 40 centers, the top 40 centers within the first 90 days after approval.

And anything on kind of capacity within those?

Yes. So I think the way we think about capacity with them is what is their bed capacity, where are they conducting the cell therapy treatment and follow-up. And so it's going to vary site-by-site, but we have an idea of how many beds they are in the ICU, how many beds they are on the general oncology award, and we'll be working with each site specifically to ensure that we really understand their capacity, our capacity and make sure that we're able to treat patients appropriately.

Got it. And then just wondering if there's any guidance that we could expect any updates for the lung programs, either PD-1 combo or additional to monotherapy data this year?

Not right now, but as something as I mentioned earlier during the early earnings point there, one is really important to us. So that's something that we will be looking to do as soon as we can. With that many cohorts open, we hope to be able to get some more data out to.

And our next question comes from the line of Joe Catanzaro with Piper Sandler.

Wondering first, if you could clarify whether the decision to move to a rolling BLA submission was driven by any of the feedback you received during the pre-BLA meeting or was that decision wholly independent of that. And then second question, maybe perhaps a bit speculative, but wondering if the impact of duration of prior PD-1 that you've observed in melanoma is something you expect to extrapolate into other settings. And I guess I'm asking that in the context of post PD-1 cervical now being the emphasis in that indication.

Let me take the first one and, Friedrich, maybe you can take the second question. During the pre-BLA think, provided us with some context for our submission as a whole. And I think as a result of that, we just basically came to the conclusion that rolling BLA submission was the best approach here. And really, I don't want to say any more about how that went down, but it's basically a full picture of what happens to the conclusion of the rolling BLA was the best approach to the success of the product, and we think FDA is very supportive but not understand that. Friedrich do you want to answer the second part of the question?

Yes, sure. Good question. So I don't think that we have sufficient information at this point yet either based on clinical data that we generated more on really fully understanding what the mechanism of action is that PD -- prior PD-1 therapy might drive that explains some of the differences that have been observed mainly in melanoma really between patients that were previously treated with check inhibitors such as the patients in Cohort 2 and 4 in our C-144-01 study versus patients that are checkpoint inhibitor naive.

There are a couple of hypotheses out there, and there are some recent publications coming out of the Rosenberg group that are elucidating some of that. Whether that translates into other indications or tumor types, I think that needs to be shown clinically. We have presented initial data on combinations of lifileucel with pembrolizumab in checkpoint naive patients, namely in patients with head and neck cancer with cervical cancer.

We are seeing encouragingly high response rates that are clearly higher than what you would be expecting with temporal loss. So we might be seeing that difference as well, but I think we need to generate more data.

For cervical cancer, however, the unmet medical need certainly is in the post-PD-1 setting. There is really nothing good out there for the patient this is an underserved population of patients. Chemotherapy is terribly inefficient after failure of frontline doublet chemo and TIL therapy is a real opportunity for these patients, and that's what we are focusing on currently.

And our next question comes from the line of Madhu Kumar with Goldman Sachs.

This is Omar for Madhu. So we have 2 questions. First, how should we think about the objective response rate that will be necessary for expiry approval of lifileucel post-PD-1 cervical cancer. And then two, on post-PD-1 melanoma, beyond cohort can we expect any additional data disclosures from the pipeline in 2022?

We can say the for which -- your second question, I missed for which study?

And the second question beyond Cohort core from closing or expect any additional data disclosures from the pipeline.

Got it. Okay. Well, the first question, there is no -- right now, there's no approved therapy in post-CD1 cervical patients. There's available care out there that the FDA would look at is chemotherapy with very poor results. And maybe, Friedrich, if you want to add a little bit to add, but these are things that we don't view as huge barriers to a successful study. Friedrich if you want to add anything with available care for surplus few on several patients.

Yes. There is limited data on late-line outcomes of cervical cancer patients with chemotherapy, which is really the main therapeutic options that these patients have Rs are ranging somewhere between 3% and 15% with chemo. That includes additional doublets is quite toxic.

So that's and the duration of responses last time I looked in this historical quarter, it's been 4 and 5 months. So that bar is relatively low. There is no experience with chemo after failure of PD-1 checkpoint inhibitors. The FDA usually, when you're looking at what would be required for an approval says that they are going to look at the totality of the data at the time of approval in the context of available care. There is not much activity in that field. So maybe these initial numbers, could you -- give you a rough idea.

And to answer the second part of your question, you want to think about data flow beyond melanoma Cohort 2 core 4 data flow that we already talked about. The way we're thinking about it at least is one has not all so long as one of our priority areas. That's the one we'd like to get some data out soon. We haven't given any specific guidance on that, that's high on our list and then after that the other indications.

I'm showing no further questions. So with that, I'll hand the call back over to Interim President and CEO, Fred Vogt, for any closing remarks.

Thank you, operator. Thank you again for joining the Iovance Biotherapeutics Second Quarter and First Half Financial Results Conference Call. It's an exciting time to be part of Iovance. I would like to recognize the patients, physicians and regulators who have collaborated with us throughout the journey to develop TIL therapy as well as our employees and cross-functional teams for their hard work and arriving at this point.

I would also like to thank our shareholders and covering analysts for their support. Please feel free to reach out investor relations team if you wish to follow up. Thank you.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating, and you may now disconnect.