Welcome to the Iovance Biotherapeutics Fourth Quarter and Full Year 2021 Financial Results. My name is Cherie, and I will be your operator for today's call. At this time, all participants are in a listen-only mode. Later, we will conduct a question-and-answer session. During the session, if you would like to ask a question, please press star then one on your touch-tone phone. Please note that this conference is being recorded. I will now turn the call over to Sara Pellegrino, Vice President, Investor, and Public Relations 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, Jim Ziegler, our Senior Vice President, Commercial, Dr. Friedrich Graf Finckenstein, our Chief Medical Officer, and Jean-Marc Bellemin, our Chief Financial Officer. Dr. Madan Jagasia, our Senior Vice President, Medical Affairs, is also on the call to participate in the Q&A. This afternoon, we issued a press release that can be found on our website at iovance.com, which includes the financial results for the three and 12 months ended on December 31, 2021, as well as 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 regulatory plans and results, research and pre-clinical activities, potential future applications of our technologies, manufacturing capabilities, regulatory feedback and guidance, payer interaction, collaboration, cash position, 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.
Thanks, Sara, and good afternoon, everyone. I'm pleased to highlight our fourth quarter and full year 2021 progress at Iovance during today's conference call. In 2021, we continued to advance toward our first BLA submission and expanded our TIL platform into new indications in earlier treatment settings. For our lead TIL therapy, lifileucel, our top priority remains our planned BLA submission in metastatic melanoma. We have continued ongoing work developing and validating our potency assays. We have also engaged discussions with the FDA during the second half of 2021, and we are confident in our current guidance for the anticipated BLA submission during the first half of 2022. Resolution of the potency assay in melanoma is also a key step towards regulatory plans and other indications. 2021 was our busiest year yet in terms of TIL data presentations.
Over the past 12 months, we presented data in 118 patients across five indications in four solid tumor types at multiple medical meetings, including the American Association for Cancer Research or AACR meeting, the American Society of Clinical Oncology or ASCO meeting, and the Society for Immunotherapy of Cancer or SITC meeting. We believe that this growing set of clinical data continue to demonstrate the potential power of Iovance TIL therapy to become the next paradigm-shifting treatment regimen for solid tumors. Last year, we also opened the Iovance Cell Therapy Center or ICTC in Philadelphia. We have made significant progress in our internal manufacturing capabilities at ICTC, which Igor will highlight further. We grow our organization to prepare for commercial manufacturing and launch.
Today, we have approximately 350 employees at the company who have, on average, more than four years of cell therapy experience. We believe that the breadth and depth of talent within our organization during this important time of growth is a testament to the potential of our Iovance TIL therapy in solid tumors and our ability to maintain leadership within the field. Looking towards 2022, our milestones include submitting our BLA for lifileucel in metastatic melanoma in the first half of the year, advancing TIL therapy in non-small cell lung cancer, which Friedrich will highlight, executing an updated registrational strategy in cervical cancer based on FDA dialogue and feedback in reflection of the evolving landscape of care in this indication, defining our strategy for TIL plus pembro combinations in early-line solid tumors, beginning with melanoma.
Finally, initiating the first Iovance clinical study for IOV-4001, a genetically modified TIL product in which PD-1 is inactivated, and further advancing our research in next-generation TIL programs to remain at the forefront of TIL therapy in solid tumors. Overall, we are confident in the strength of Iovance's position to be the global leader in developing, delivering, and innovating TIL therapies for patients with cancer. We are well on our way to becoming a fully integrated organization to launch the first one-time cell therapy in solid tumors. Owning our manufacturing capability is the key to our success, so I will hand the call to Igor now to talk more about our progress there.
Thank you, Fred. During 2021, we achieved several milestones at the Iovance Cell Therapy Center or ICTC, which is our 136,000 sq ft cell therapy manufacturing facility. We completed commissioning activities and initiated TIL clinical supply from the ICTC in the third quarter of 2021.
The first patient with cancer received TIL manufactured at ICTC in September 2021 as part of our ongoing clinical trial. In parallel with clinical manufacturing, we are on track in preparing the ICTC for the BLA submission and commercial manufacturing upon the potential BLA approval. Several important activities are now underway, such as validation activities and process performance qualification or PPQ runs. In addition, we are getting ready for FDA pre-approval inspections at both ICTC and our contract manufacturing partner's facility, which we expect to occur soon after the BLA filing. Turning to our intellectual property or IP portfolio, we continue to build our robust and growing IP portfolio to support our proprietary manufacturing processes as well as our know-how surrounding TIL therapy. We currently own more than 35 granted or allowed U.S. and international patents.
This IP covers TIL compositions and methods of treatment and manufacturing in a broad range of cancers, including Gen 2 patent rights that are expected to provide exclusivity into 2038. Our granted patents as well as our filed patent applications are directed towards Gen 3 manufacturing, selected TIL products, stable and transient genetic TIL modifications, tumor digest and fragment compositions and methods, including cryopreservation and combinations of checkpoint inhibitors and TIL products. I would now like to hand the call to Jim Ziegler to highlight our commercial launch preparations. Jim.
Thank you, Igor. Throughout 2021 and into 2022, the Iovance team has made steady progress in our commercial launch preparations while maintaining financial discipline. Our launch priorities include the onboarding of our authorized treatment centers or ATCs, payer engagement, and related operational readiness activities. Our cross-functional teams continue to partner with leading U.S. cancer centers to build their TIL service line capabilities. Our training program is designed to ensure cross-disciplinary teams can administer the lifileucel treatment regimen upon FDA approval. Our goal is to onboard at least 40 ATCs for launch. This number is informed by our assessment of the CAR-T market, where claims data indicate that the top 10 centers account for about 50% of the CAR-T treated patients, and the top 40 centers account for about 80% of the CAR-T treated patients.
We expect a similar concentration across our ATCs for the potential commercialization of lifileucel. Our longer-term goal is to have enough sites so that most patients in the U.S. can be within a few hours' drive to an ATC offering lifileucel TIL therapy. The plan, timing, and execution of key onboarding and training is aligned to BLA-related milestones to ensure just-in-time training and readiness at our ATCs. Although there is a significant amount of work that will occur between our BLA submission and launch, our core commercial team has built the foundation to scale rapidly and efficiently. Reimbursement is also a critical factor for patient access at launch. In the last year, our market access team engaged commercial and Medicare payers responsible for more than 90% of the covered lives, as well as Medicaid states responsible for approximately 50% of the covered lives.
Based on these interactions, we believe that payers appreciate the unmet need and the potential clinical value of lifileucel for patients with metastatic melanoma cancer. Our reimbursement strategies are designed to secure coding, coverage, and payment. In 2021, Medicare expanded DRG 018 to include CAR-T and other immunotherapies, including lifileucel. This is an important milestone achievement because upon lifileucel approval, hospitals will have more appropriate payment for Medicare beneficiaries. We continue to engage payers and CMS as we plan for BLA submission and prepare for commercialization. We are also pleased with the progress of our IovanceCares program, which remains on track for launch. Our goal is to deliver a best-in-class cell ordering and patient support system that assists the patients, physicians, and ATCs at every step of the process.
IovanceCares includes our proprietary chain of identity and chain of custody system, our patient management approach, and our integrated approach to quality. I will now pass the call to Friedrich Graf Finckenstein, our Chief Medical Officer, to highlight our clinical progress.
Thank you, Jim. I am pleased to share highlights from our TIL clinical programs across the various data presentations from 2021. In melanoma, we presented updated Cohort 2 data at ASCO 2021. We reported 36.4% overall response rate or ORR and a median duration of response or DOR that was not reached at 33.1 months of median study follow-up as assessed by investigators. These Cohort 2 data continue to demonstrate the durability of one-time treatment with lifileucel in metastatic melanoma patients after anti-PD-1 therapy. Looking ahead for this year, we plan to report data from the pivotal Cohort 4 in our melanoma study, as assessed by an independent review committee in connection with the BLA submission. We are also excited about the data for TIL in combination with pembrolizumab in checkpoint inhibitor naive melanoma patients.
The most recent results presented at SITC 2021 demonstrated a 60% ORR and 30% complete response, and support the potential for this combination as earlier treatment for melanoma. We look forward to enrolling additional patients and to further defining a strategy in front line melanoma during the coming year. We are also very excited about the proof of concept for TIL plus pembro as an early treatment option in cervical and head and neck cancer patients, which we also highlighted at SITC 2021. Overall response rates for TIL plus pembro were above the published response rates for pembro alone in melanoma, cervical and head and neck patients who are naive to anti-PD-1 therapies. In additional solid tumor indications, lung cancer patients continue to have an unmet need for new treatment options.
Last year, we presented our first clinical data set for Iovance TIL as treatment for non-small cell lung cancer at SITC. We were very encouraged by the observed responses in heavily pre-treated non-small cell lung cancer patients who received one or more prior systemic therapies, including anti-PD-1 therapy. This data set was an important proof of concept for TIL in non-small cell lung cancer, and provided valuable learnings to enroll earlier line patients in our ongoing IOV-LUN-202 study. We are enrolling second line metastatic non-small cell lung cancer patients in the IOV-LUN-202 study at 30 sites, while engaging with the FDA about parameters for further registration. In cervical cancer, as Fred mentioned, we are actively engaged in regulatory discussions.
Lastly, I am excited by the growth of our research pipeline as we look to enter the clinic this year with our first genetically modified TIL therapy candidate, IOV-4001. IOV-4001 is a TIL product with inactivated PD-1 using the TALEN technology licensed from Cellectis, and has the potential to deliver TIL and PD-1 inhibition within a single therapy. I will now hand the call over to Jean-Marc to discuss our fourth quarter 2021 financial results.
Thank you, Friedrich. My comments will reflect the high-level financial results from our fourth quarter and full year of 2021. Additional details can be found on this afternoon's press release, as well as our, in our SEC filings. I will begin with our cash position. As of December 31, 2021, Iovance held $602.1 million in cash equivalents, investments, and restricted cash, compared to $635 million on December 31, 2020. A strong cash position is expected to be sufficient into 2024 to advance our operating plan, including pipeline development, commercial manufacturing readiness, and launch preparation. Moving on to the income statement.
Our net loss for the fourth quarter ended December 31, 2021, was $99.3 million, or $0.63 per share, of which approximately $6.3 million, or more than $0.04 per share, were one-time expenses. This compared to a net loss of $68.4 million or $0.47 per share for the fourth quarter ended December 31, 2020. Net loss for the full year period ended December 31, 2021, was $342.3 million or $2.23 per share, compared to a net loss of $259.6 million or $1.88 per share for the full year period ended December 31, 2020.
Research and development expenses were $75.6 million for the fourth quarter ended December 31, 2021, an increase of $23.1 million compared to $52.5 million for the fourth quarter ended December 31, 2020. Research and development expenses were $259 million for the full year period ended December 31, 2021, an increase of $57.3 million compared to $201.7 million for the full year ended December 31, 2020. The increase in research and development expenses in the fourth quarter 2021 over the prior year period was primarily attributable to an increase in cost associated with growth of the internal research and development team, including stock-based compensation expenses and increase in clinical trial costs and facility-related costs associated with ICTC.
The increase in research and development expenses in the full year of 2021 over the prior full year period was primarily attributable to growth of the internal research and development team and an increase in the clinical trial cost and facility-related costs associated with ICTC. General and administrative expenses were $23.8 million for the fourth quarter ended December 31, 2021, an increase of $7.7 million compared to $16.1 million for the fourth quarter ended December 31, 2020. General and administrative expenses were $83.7 million for the full year period ended December 31, 2021, an increase of $23.5 million compared to $60.2 million for the full year ended December 31, 2020.
The increases in general and administrative expenses in the fourth quarter and full year 2021 compared to the period, to the prior year periods were primarily attributable to an increase in costs associated with growth of the internal general and administrative team, including stock-based compensation expenses and an increase in intellectual property filing related costs. As of December 31, 2021, there were approximately 157 million common shares outstanding. We continue to focus on investment in four key areas as outlined previously to ensure the growth and strength of our value creation. This includes advancement and expansion of our clinical pipeline, launch readiness, a strong cash position, and manufacturing at ICTC, which will provide new cost efficiencies as we are able to shift work currently being done through contract manufacturers to ICTC.
I remain confident that by managing our investments across these priorities, we will continue to stay focused and align our spending with our corporate priorities. With late-stage clinical assets in our pipeline, as well as a strong balance sheet and focused investment on launch preparation, we are also well positioned to execute our operating plan. I will now hand the call back to the operator to kick off the Q&A session.
Thank you. As a reminder, to ask a question, you will need to press star one on your telephone. We ask that you please limit yourself to one question and one follow-up question. You may then return to the queue. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. Our first question will come from Tyler Van Buren with Cowen. Please go ahead.
Hey, guys. Congrats on the progress. Thanks very much for taking the question. Don't you have to have resolution on the potency assay front in the next month or two in order to be able to run the assay or assays with the Cohort 4 patient samples and generate the data to submit the BLA by the end of the first half? I guess my follow-up to that would be, is it possible that you've already started testing the Cohort 4 patient samples with the latest iteration of the potency assay or assays in anticipation of the filing?
Yeah, thanks, Tyler. I can answer some of that. We haven't disclosed the detail of how those interactions are going with the FDA and what, whether we've commenced testing or that, at that level. In general, yes, we have to get some. We have to be moving towards the BLA filing. I should note that it's important to understand that we could be holding conversations with the FDA in parallel while we do work. We could be staging it so that we manage the risk really well. It can come right down relatively late in the game for us to really feel comfortable.
Regardless, right now what we've been saying publicly and clearly again here on this earnings call is that we're comfortable filing a BLA in the first half of this year. That should give you some indication of where we think we are with the FDA.
That's great. Thank you very much.
Thank you. Our next question will come from Michael Yee with Jefferies. Please go ahead.
Hi. Thank you, and thanks for the update, guys. I have one question and a follow-up. My question is, in relation to the filing, is there a scenario where you file and meet your guidance and go ahead and do that and that you have to tell the Street or will tell the Street that the final agreement or the final sign-off or the final validation is obviously an ongoing process and ultimately everything gets filed and finalized at the PDUFA date? Can you maybe just talk about that scenario? I think like Wall Street just thinks you have this green light on a piece of paper, and then you just file. Maybe talk to that a bit, that scenario.
Yeah.
My follow-up. One quick follow-up. You did say clearly that you'll announce the Cohort 4 melanoma data. Can you just, when that gets done, can you just remind me, you had previously had an interim, and can you just tell me where Cohort 4 is? When you do it will be an independent review when you present it, and that's supposed to be similar response rate data as Cohort 2. Just remind us about that status. Thank you. Thank you.
Sure, Michael. Let me take the last one first, actually. The Cohort 4 data is part of the BLA submission. It's IRC-read data, and as part of the BLA submission, in conjunction with that, we would talk more about that Cohort 4 data. That's timed to go in with the BLA, and obviously it's important information to put that out. Cohort 2 is already out there. We've been talking about it for a while. You can see that data. We don't know Cohort 4 yet. It's something we're still working on. But you know, the Cohort 2 data is a very similar study in many respects, so it can give you know, some guidance as to what we expect in these populations, although of course they can differ.
On the assay part, let me try to answer the whole question there. Going all the way through to the PDUFA date, which, you know, could be in early 2023, potentially or very late 2022, depending on when we submit the BLA this year, there can be conversations with the FDA during the entire pendency of the BLA after it gets accepted as to sort of the specifications and some aspects of your potency assay or assays that you're proposing for your product. Things can change during that period. I think that's what you might be asking. Of course, they can comment on validation. You could present additional data.
You could, you know, provide them with more information about the specifications that you're proposing, and they could ask questions about any aspect of the validation package during that period, and you could go back and forth with them on that. You're absolutely right in thinking that you don't really know for sure until the BLA is approved that all this is done, and that's the way it just is in drug development. Earlier in the process, though, when we submit the BLA, when we have the pre-BLA meeting prior to that, we're trying to get as much clarity as we can from the FDA so we can make sure we're successful on the PDUFA date, and getting that approval.
We're not submitting something that has gaps in it that we could have filled had we listened to the FDA. That's our big goal leading up to the BLA submission itself. Of course, some of that includes successfully completing validations and doing a lot of the work that eventually gets reviewed during pendency of the BLA. That was a long-winded answer, but I hope I got what you were trying to get there, Michael.
I think that makes sense, and I can see that. Thank you.
Okay.
Thank you. Our next question will come from Peter Lawson with Barclays. Please go ahead.
Great. Thanks for taking the questions. Just on cervical cancer, wonder if you could walk through kind of timelines and kind of what's changing around the potential for filing for cervical cancer that we should be thinking about.
Yeah. Friedrich, do you wanna answer that one?
Sure, happy to. Good question. Obviously, we are acknowledging that the treatment landscape in cervical cancer has changed quite a bit. The approval of checkpoint inhibition as part of first-line standard of care was a paradigm shift, and it's great to see immunotherapy to enter that field for the patients. That's good news. That obviously now changed the landscape in opportunities after first-line chemo, and we saw that with how this impacted some of the additional checkpoint inhibitors that were going after that second line after chemotherapy-only space. TIL therapy is differentiated from checkpoint inhibitors. We know that we see activity in patients that have received checkpoint inhibitor therapy from our melanoma data, and that's really based on a differentiated mechanism of action.
Because we knew that and because we were foreseeing the changes in the first-line landscape and acceptance of checkpoint inhibition as standard of care, we started a post-checkpoint inhibitor cohort early in 2019 already. We do think that that is an area of unmet need that we would be able to address with data in that setting. We are planning to execute a registrational strategy addressing feedback from the FDA and addressing this changed landscape, and we do think that we do have some headway in that post-checkpoint inhibitor setting.
Perfect. Thank you. Just with the addition of Raj Puri, does that change the process in any way for filing? Is there any chance you'll file at risk?
No, I don't. That's not really the plan there, Peter. He's essentially a you know great addition to our team. That's not really tied to the BLA or how we would handle the BLA. Of course, having him join us is gonna be very helpful in doing anything from a regulatory perspective, but that's not really something we're thinking about.
Gotcha. Okay. Thank you so much. Thanks for taking the questions.
Thank you. Our next question will come from Nick Abbott with Wells Fargo. Please go ahead.
Good afternoon. Thanks for taking my questions, and appreciate the clarity, Fred, as always. First one, just going back, following up on Mike's question from earlier. Have you closed the Cohort 4 database that's being cleaned, ready for analysis?
We haven't announced that yet, Nick. Without getting into the details there, obviously, we're very late in the game, so that's something we would need to do in a relatively short time period here, but we haven't spoken directly about that yet.
You know, maybe thinking forward, you know, the potential approval of nivolumab and relatlimab, do you think you need to show benefit in these patients that's in a similar magnitude to what you've shown currently from Cohort 2 and presumably what you're showing Cohort 4?
It could be important in the future landscape, of course, 'cause there'll be patients coming off that line of therapy that would potentially be candidates for lifileucel. But don't assume that we haven't seen some of those patients already because, you know, those patients are out there right now in the clinical trials getting them. So that's something we're looking at closely. I can tell you there's. You know, that's something we've considered closely, and we'll try to provide updates at medical meetings on how we might address those patients.
Perfect. Thank you.
You're welcome.
Fred, can I chime in here? I think one thing to keep in mind is that the data that we have presented are clearly indicating benefit that's comparable between patients who have failed PD-1 monotherapy and patients who have failed PD-1 and CTLA-4 blockade combination. I think that might be indicative of what we might be seeing in patients who have failed other combinations as well. Obviously, we don't have data on that yet in a controlled fashion, but I think that's something to keep in mind for that setting.
Yeah, that's a good point, Friedrich.
Thank you. Our next question will come from Mara Goldstein with Mizuho. Please go ahead.
Thanks for taking that question. Just on the initiation of the trial for IOV-4001 in this year that you've indicated, can you talk about the clinical plan for that and what indications you might look at? Then I just wanted to ask about the sequential R&D spend and what that run rate looks like going forward, given the different, you know, the delta in the fourth quarter versus the prior quarters.
Yeah, maybe I can take the first one and have Jean-Marc follow up on the second one. We haven't disclosed that yet, Mara, but that's something we'll obviously talk about the clinical plan for that asset, as soon as we can, because that's tied. You know, once we get the regulatory filing through, I think you'll hear a lot more from us on that. We're obviously interested in indications that we know and can benchmark against, as well as potentially new indications that might benefit from the combined effects of a checkpoint inhibition mechanism built into the TIL cell itself, which can theoretically infiltrate better into the tumor than the antibody, as well as our polyclonal T-cell platform combined in the same asset.
We're looking for indications that would benefit from that approach, and hopefully we'll be able to talk about that pretty soon. Jean-Marc, do you wanna talk a little bit about the R&D spend?
Yeah, sure. Thanks for the question. Look, honestly, of course, we are focusing spending on the building of pipeline and, you know, the research will be part of it. IOV-4001 is only one aspect of the program that we are building. From a spending perspective, I mean, we are definitely looking at reallocation of expenses in a way that if you think about what we spent for building ICTC, for example, in 2021 and will be reallocated to research for 2022. We have an increase in research and development spending in Q4. I've mentioned during the script that we have this one time $6.3 million.
Mm-hmm.
That's why you have a little bit more of expenses there. Honestly, there is no real concern. We'll keep steady on the research and development spending for 2022.
Okay. You know, if I could just also ask the question around the CEO permanency and what that looks like from this, at this point in time, from a timing perspective?
Basically, our board is conducting a search, and we're still looking for candidates. It continues to be ongoing, a top priority for our board, and we'll announce the outcome as soon as we can.
Okay.
I don't really have anything else.
Thank you.
Thank you. Our next question will come from Mark Breidenbach with Oppenheimer. Please go ahead.
Hey, guys. Good afternoon. Thanks for taking our question. Just one from me, maybe directed at Friedrich. I was hoping he could provide a little more color on the nature of these parameter changes to the IOV-LUN-202 trial that you've been discussing with the FDA. Maybe a little bit more detail on that would be appreciated.
I don't think that we have spoken about the exact details of our discussions with the FDA in regards to LUN-202. I'm not sure I can really comment on that. Just as a reminder, what we're doing with LUN-202 is we are enrolling specifically patients that have failed the single line of checkpoint inhibitor plus standard of care chemotherapy. This is an earlier line population than the population that was enrolled to this proof of concept Cohort 3B from our basket study. That is, if that's the parameter changes that you're referring to. That's really the main point is focus on an earlier line population with this prior therapy.
Okay, that wasn't already part of the protocol as it was originally designed?
No, that was the design of the study as we opened it. We have not changed the design since then.
Okay. Thank you.
Thank you. Our next question will come from Colleen Kusy with Baird. Please go ahead.
Great. Thanks so much for taking our questions. Are there any characterizations you're able to provide as to how the latest conversations with the FDA have progressed regarding the potency assay?
Yeah, sure, Colleen. They've given us a lot of good advice, a lot of detailed advice, and we feel like we really understand what they're looking for, and we think we're gonna be able to address that. At the technical level, the details of that are still confidential, and that's not something we're quite ready to talk about. As a general matter, it's at the level where really productive discussions can be had, and we can respond to what we think their concerns are, and we can provide them with data and, you know, assays and sets of assays that we think address their concerns in detail. It's advanced quite a bit over the past nine months in that respect.
Understood. Thank you. That's helpful. Any comments on how the PD-1 combo in lung cancer is advancing and when we might see data from that combination?
Sure. That study is Cohort 3A in our IOV-COM-202 study. That study has been enrolling for a while now. We haven't guided to specific conferences or anything where we would present, but it is one of those studies where obviously we'd like to present some data at some point soon. We presented as much data as we possibly could last year, and, you know, I look forward to 2022 where we'll try to keep that up. I just can't say exactly when we'll be able to do that.
Great. Thanks for taking my question.
Thank you. Our next question will come from Ben Burnett with Stifel. Please go ahead.
Hey, thank you very much. I had a question regarding the melanoma BLA in the new manufacturing center, ICTC. I guess how much patient experience have you accrued from product manufactured here for late-line melanoma specifically? And I guess can you provide just a little more color just regarding your expectations for what's likely needed in terms of validation data, just numbers of samples or anything like that?
Yeah, Igor, do you wanna talk about at least the first part of that? I can maybe cover on the last part.
Happy to. Thanks for the question. We the facility is focused on two things right now. One is clinical manufacturing for ongoing clinical trials, and that's primarily the Gen 2 process that's a part of the Cohort 4 that we intend to file to the BLA. The other part is preparation for commercialization and BLA filing, including well including the filing and the subsequent inspection that we expect to take place soon after the filing. Following that, getting the capacity ready to meet the commercial demand after the potential BLA approval. That's where we're well on track along all of those activities. Fred will-
Oh, go ahead, Igor, if you wanna go, you wanna get the part about the retains. I think that's what you were asking about, Ben, right?
Yeah. If there's anything you can say about just the number of samples, kind of ballpark in terms of validation data that's needed.
I mean, it's a good number of samples. Igor, go ahead if you wanna answer it.
Actually, Fred, go ahead. I'm not sure I understood the question fully, so.
I think what you're saying, Ben, is the number of samples needed to perform validation exercises both for the assays and for anything we need to do with the facility. Is that right?
Yeah. Sorry for not being more clear. I think to validate that the product that's manufactured at the new site is similar to what's been manufactured elsewhere.
Yeah. That's what we call comparability and it's part of comparability and what we call PPQs or Process Performance Qualification. We have, you know, it's a good number of samples. I don't have the exact numbers, Igor probably doesn't either. But you know, there's obviously a lot of work done to make sure it's statistically well justified with the FDA, and so that's what really drives the number of samples. You know, we're well set in that area, we think.
Okay. Thank you very much.
Thank you. Our next question will come from Asthika Goonewardene with Truist Securities. Please go ahead.
Hi, guys. Thanks for taking my question. Just to maybe set a logistical one here. If I understand your answer to Tyler's question, and you might be doing some of these potential potency assay work to include in the filing, you know, prior to you getting the official okay from the FDA, is that a scenario that the FDA comes back to you and says, "Well, we want you to do a couple more things," and you run out of samples? I have a follow-up question about lung cancer after that.
All right. Let me take the first one. They could always come back and ask for stuff, and you could always just run out of reagents at some point, but we don't expect that to be the case. We think we've got the reagents we need to answer their questions right now. We're comfortable, you know, performing the assays that we've developed and that we think are responsive to what the FDA wants. I think maybe sort of the core of your question is the timing of the whole thing and these, 'cause you mentioned the concept of the FDA giving us the go.
What I was saying earlier to both Michael and to Tyler in their questions was, you don't really know it's done until the PDUFA date and they approve your BLA. That's when they truly say go. What you're trying to do is be responsive to their feedback during the process and of course preserve your rights and, you know, provide them with information as they ask for it and not burn bridges unnecessarily during the process. That's something we're doing very carefully here.
Got it. Okay, thanks. A question for Friedrich if I may. Friedrich, I mean, given what we've seen with the non-small cell lung data that you presented earlier, I want to just get your thoughts on the confidence that you have that LUN-202 by going it at maybe a potentially earlier stage than the previous data that was presented, that you could have better durability of the responses that you have there. Then related to that, is there a...
Do you think that it could be an option for you to consider giving maybe adding another arm to IOV-LUN-202, where you're combining the TIL with PD-1 with the goal to help for the PD-1 to give the TILs a little bit more kick to continue them persisting?
Yeah. Those are two good questions. Obviously, about the durability and our confidence that going at an earlier line will improve the durability. Number one, that is to some extent just clinical experience and knowing how sick late-line non-small cell lung cancer patients often are.
In regards to organ function and performance status. Going into an earlier line will somewhat get you into a little better starting point. Really, the confidence comes from the data that were presented by Dr. Creelan and published by Dr. Creelan from the Moffitt. This was obviously a slightly different design and a single-institution experience in what was overall an earlier line population with patients that had either received a single prior line or were even treatment-naive, long-term and durable responses were observed. That was informing this step to frontline to at least partially. We obviously have to now run this clinical experiment and generate the data supporting that, but that's the rationale.
About your question of adding PD-1 blockade to TIL for better durability, that's something that we are actively exploring in Cohort 3A of the basket study in a checkpoint inhibitor-naive population, albeit we are generating data in our non-small-cell lung cancer with that combination. So we are interested in that. Whether that is something that one would want to translate into a checkpoint inhibitor-pretreated population is a question that we can ask once we understand what we're seeing in the checkpoint inhibitor-naive population. Keep in mind, lung cancer docs do not tend to reuse checkpoint inhibitors after failure of checkpoint inhibitors. This is slightly different from melanoma. There is not a lot of confidence in checkpoint inhibitors, at least not by themselves in reusing them after failure.
That's slight difference to the situation in melanoma.
Got it. Thanks, guys.
Well, thank you.
Thank you. Our next question will come from Reni Benjamin with JMP Securities. Please go ahead.
Hey, good afternoon, guys. Thanks for taking the questions. I apologize, I jumped on the call a little late, so I apologize if you guys have already answered this. Can you just tell us how you are thinking about ex-US or, you know, specifically European filing, especially if this BLA, you know, you are able to pull off this BLA submission on time here in the U.S. What are the kind of gating steps going forward? Also just to clarify, you know, we typically see, you know, clinical data more as a review issue.
Is there any reason to think or ever to consider that, you know, the potency assay or any part of the CMC could be part of a review issue if there is one? Thanks.
Sure. I can take those. Our European strategy really hinges on the FDA outcome, so really we're focused on the FDA right now. Since we have European patients in the trials we've talked about before, if things go well with FDA, we think we can turn around the EMA and hopefully move pretty quickly there. We haven't announced any details on that yet, so you're just gonna have to stay tuned on some of this. You know, we did prepare for that eventuality, and we do think we can do something there fairly quickly after we resolve the issues with the FDA. Your second question, yes. I mean, look, there can be review issues on everything with the FDA. The FDA can always say that.
They sometimes use that language in every single question that you ask them at a type B or type C meeting. Our goal is to try and get it to whatever is left that's a review issue is so minor that we feel very comfortable that we'll get a successful approval when the PDUFA date hits. That's really the way we look at it. The fact that they could say that, they could say that for the clinical side, they can say it for the CMC side, they can say it for non-clinical side.
you know, we try to close that window as tightly or as close to completely closed as we can with pre-BLA filing interactions to make sure that we're not caught in a situation where during the review something becomes a real problem.
Got it. Okay. Just as a quick follow-up regarding the European filing, is that something you do, you know, kind of right after submitting the BLA, you know, 'cause you've worked everything out or waiting for the BLA to be accepted? Or is it something that you do after an approval here in the U.S.? How should we think about that?
It'd probably be more like the latter, but we haven't determined that fully yet.
Sure.
Again, our focus is on the U.S. market for melanoma first and foremost, 'cause that's the market we wanna be in. You know, we would look at the European opportunity as much as we possibly could with the resources that we have.
Terrific. Thanks for taking the questions.
Thank you. Our next question will come from Madhu Kumar with Goldman Sachs. Please go ahead.
Hey, everyone. Thanks for taking our questions. I apologize that I'm gonna beat this dead horse. How should we think about news flow through June 30th with regards to lifileucel and post PD-1 melanoma? Like, we will have the BLA submission, they'll have Cohort 4 data analyzed. Like, how should we think about kind of like what information is gonna come between now and June 30th?
Yeah, it's a good question. All that information comes out in that period basically, or should come out in that period, we expect it will come out in that period. How it comes out and the order it comes out in is still something that needs to be determined, but those are the critical elements which you mentioned there. Basically, the Cohort 4 data is the clinical data that will be, or at least the top line Cohort 4 data, the clinical data that will be in the BLA package. Where we stand with respect to the CMC issues as much as we know, the actual occurrence of a pre-BLA meeting, and you know, the actual occurrence of a filing, all that stuff has to happen.
We'll try to time. You know, we don't know the details yet. We can't predict exactly where all this is gonna happen, but we'll try to time the news flow and then keep the news flow coming as that process continues.
Okay. Following up on the last question, kind of a bigger picture question about accelerated approval in this context. What does a confirmatory trial look like to you with lifileucel as monotherapy in kind of advanced solid cancers?
In melanoma or just in general?
Well, I mean, as a confirmatory trial for the melanoma BLA. I mean, previously it has been discussed, the idea that a confirmatory trial does not necessarily need to be in the same indication. Like, is that this, the current view, or is there a notion that there needs to be a confirmatory trial specifically in post PD-1 melanoma? Like, how should we think about-
No.
What a confirmatory trial looks like?
A couple things there. FDA generally discourages you from having a confirmatory trial in the same indication you just got approval for. They're more interested in a different, yeah, like going to an earlier line of therapy. Another thing I need to point out is that with the RMAT designation, we don't know for sure whether we'd be required to have a confirmatory trial. That's very important to make clear. You know, we will be submitting, as we said many times, Cohort 2 data, IRC read data for Cohort 2 to the FDA as part of this as well, which FDA has said can be supporting. All that kind of goes into the same blender. From that, you will find out whether you need a confirmatory trial in the first place.
If you do, it's not likely to be in the same indication that you just ran your pivotal data in. Does that help?
To that end, is there kind of like a natural data set you guys have in-hand that serves that function? I mean, kind of one would logically think something like the cervical cancer data set that you have developed over the last few years. Is that kind of like a natural kind of confirmatory population to submit as a confirmatory group?
No, that would be for a separate label on cervical. What they'd be looking for a confirmatory trial, should they require one in melanoma, would be in melanoma. You know, maybe the natural one that you could think of would be in an earlier line of therapy in melanoma, like our Cohort 1A IOV-COM-202 or something similar to that. FDA's current thinking on this matter, as they talk about publicly, is that the sponsor should have that trial up and running at the time of approval or earlier.
Okay.
Is what they.
Cool. Thank you.
Ladies and gentlemen, thank you for participating in today's question and answer session. I would now like to turn the call back over to Dr. Fred Vogt for any closing remarks.
Thank you, operator. Thank you again for joining the Iovance Biotherapeutics Fourth Quarter and Full Year 2021 Financial Results Conference Call. We are really grateful for the patients and physicians who are participating in our clinical studies and moving the field of cancer forward. I wanna acknowledge our employees and cross-functional teams who are working tirelessly to prepare for our BLA filing to bring lifileucel to patients. I would also like to thank our shareholders and the covering analysts for their collaboration and support of Iovance. All of you are key contributors in advancing our mission to be the global leader in developing, delivering and innovating TIL therapy. Please feel free to reach out to our investor relations team if you wish to follow up. Thank you.
Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.