Replimune Group, Inc. (REPL) Earnings Call Transcript & Summary

Ladies and gentlemen, thank you for standing by. Welcome to Replimune's top line primary analysis data from the IGNYTE clinical trial conference call. [Operator Instructions] Please be advised that today's conference is being recorded. I would like now to turn the conference over to Sushil Patel, Chief Executive Officer. Please go ahead.

Good morning, and thank you for joining our investor call. Today, we are excited to share positive topline primary analysis of blinded independent central review of the IGNYTE study in anti-PD1 failed melanoma. But before we begin, I need to highlight our forward-looking statements. As a reminder, our actual results could differ from the materials being presented today. We encourage you to refer to our materials filed with the SEC for more information. From management, I have with me today Kostas Xynos, our Chief Medical Officer; as well as our Founder and Chief Scientist, Rob Coffin. We are also pleased to have with us 2 leading physicians and opinion leaders with considerable experience with RP1 and the emerging treatment landscape in melanoma. Firstly, Professor Mike Wong from the Department of Melanoma Medical Oncology at the University of Texas MD Anderson Cancer Center. We also have with us Professor Caroline Robert, Head of the Dermatology Unit at Gustave Roussy and Co-Director of the Melanoma Research Unit at INSERM, Paris-Sud University. Here is the agenda for the call, which will start with a brief summary and introduction from me, followed by 3 other sections. The first section will be a recap of our [ overall ] ASCO 2024 presentation of the IGNYTE investigator-assessed data on all 156 patients, which was presented by Dr. Wong this past Monday. The next section includes new data and is the first presentation of positive topline IGNYTE primary analysis by independent central review of the 140 patient registration-intended cohort. The third and final section will summarize our path to BLA with some concluding remarks. As mentioned, following the presentation, we'll be holding a live Q&A. The primary analysis by central review shows an overall response rate of 33.6% by mRECIST 1.1. This is the protocol specified endpoint. And 32.9% by RECIST 1.1, an additional analysis requested by the FDA. As you will hear today, this was in a hard-to-treat population using rigorously defined criteria that anti-PD1 failed melanoma. Both central reviewed ORR endpoints were improved versus the investigator-assessed ORR of 32.1% by mRECIST 1.1. By independent central review, the median duration of response was greater than 35 months with 100% of responses lasting more than 6 months from treatment baseline, which was consistent with investigator assessment. We expect to enroll our first patient in the confirmatory Phase III IGNYTE-3 study in Q3 with a BLA submission planned for the second half of 2024. With that, I will now hand over to Dr. Wong, who will recap the IGNYTE ASCO data and then share the new topline central review data.

Thank you. Good morning. I'm Michael Wong. I'm a Medical Oncologist at the MD Anderson Cancer Center. I have over 30 years of experience in melanoma treatment in clinical trials. And it's my pleasure and privilege today to give you a recap of my ASCO presentation done just this past Monday, which includes data from all 156 anti-PD1 failed melanoma patients enrolled on study. I will then follow this up by the primary endpoint of the registrational-intended cohort of 140 patients, which has not yet been presented previously in any setting. Next slide. There are limited options for patients who have failed anti-PD1 therapy. Retrospective analysis of such patients using a much less rigorous [indiscernible] criteria as in this trial show a response rate of 6% to 7%. Other available therapies come with higher toxicities such as TIL for selected patients. This is a schema of the design of the IGNYTE study, which is a Phase I, II trial of RP1 and oncolytic intratumoral immunotherapy in combination with nivolumab in patients with anti-PD1 failed melanoma. This study was conducted globally with a primary endpoint as overall response rate by central review, all patients have had at least 12 months of follow-up. I would like to draw your attention to the eligibility criteria as these are, to my knowledge, the most stringent in this area of study. Eligible patients must have had confirmed progression after at least 8 weeks of PD-1 therapy. So as you can see, this is a very rigorous definition of anti-PD1 failure with improved progression while on PD-1 treatment. Next slide, please. This slide enrolled a real-world melanoma population, reflecting a difficult-to-treat population. There are 4 points that highlight this. Roughly half the patients have visceral disease. Approximately half of the patients have progressed on anti-PD1 and anti-CTLA-4 therapy. 2/3 of the patients had primary refractory disease as their last line of anti-PD1 therapy. These patients essentially [ blue passed ] available treatments within 6 months of PD-1 treatment start. And finally, 1/3 had high LDH at baseline in known characteristic of a high-risk difficult-to-treat population. Data presented at ASCO is the investigator-assessed data with all patients having had at least 12 months of follow-up. The overall response rate for these patients is 32.7%. And this response rate is consistent across all subgroups. However, there are 2 subgroups worthy of special mention. The completion of those individuals who had progressed on prior ipilimumab and nivolumab presented overall response rate at 27%. This is a subgroup with really no real standard of care. The overall response rate is 34% and patients have progressed within 6 months of anti-PD1 start. This is a population in which we [indiscernible] having primary resistance to immunotherapy from the get-go. Next slide, please. This is the waterfall plot, which looks at changes in the [ similar ] diameters of target lesions by RECIST criteria. As you can see, target lesions were reduced in over 50% of patients. And importantly, responses are seen across disease stages, including complete responses in Stage IVM1b and M1c disease, which are known difficult-to-treat populations with advanced disease. This slide is important as it shows the systemic effect of anti-PD1 therapy plus RP1. 70.4% of responding patients had non-injected lesions. Spider graph shows the first 28 responses within the injected lesions in red and the non-injected lesions in blue. Both injected and non-injected lesions responded with similar duration and kinetics. Deep responses were observed whether lesions were injected or not. This is important because non-injected -- response of non-injected lesions demonstrate the systemic benefits of RP1. Next slide. This slide is important because it reflects the durability of responses. And durability, as you know, is a first step on a way to a long-term outcome, which translates as a cure in patients. As you can see in this [indiscernible] curve, the median duration of response was 36.6 months with 100% of responses lasting for more than 6 months. This further demonstrates a prolonged benefit for the patient to ensure a systemic benefit observed in the non-injected lesions. These are treatment-related adverse events reported on a study related to either study treatment reflecting a favorable safety profile for this treatment. RP1 combined with nivolumab continues to be a generally well-tolerated regimen with predominantly grade 1 and 2 constitutional type side effects, a low incidence of grade 3 and 4 events and no grade 5 events. Next slide, please. In closing this part of the presentation, of the 156 patients with anti-PD1 failed melanoma, RP1 combined with nivolumab in melanoma patients who had confirmed progression on prior anti-PD1 continues to show deep and durable systemic responses with an overall response rate of 33%, a median duration of response of greater than 36 months and a favorable safety profile. This concludes a recap of the ASCO presentation. Now I want to transition to the presentation of the primary endpoint of the registrational-intended cohort of 140 patients, which has not yet been previously presented. On this slide, you'll see 3 numbers showing a primary analysis in this registrational-intended cohort. On the left is the investigator-assessed overall response rate of 140 patients, which is 32.1% by modified RECIST 1.1. On the extreme right, you'll see an additional analysis as requested by the FDA using RECIST 1.1. This centrally reviewed overall response rate is 32.9%. And finally, in the middle, highlighted, I'm very pleased to report the primary endpoint of the trial. This centrally reviewed overall response rate of 33.6% of modified RECIST 1.1 is similar to and slightly better than the investigator assessment that I presented previously. Next, I want to show you several examples of therapy -- of what you can get with therapy on this trial. This is a heavily pretreated patient who had 4 prior lines of therapy, including BRAF-directed target therapy, ipilimumab plus nivolumab combination therapy, and thus this patient has exhausted all known treatments possible in this patient. These are acknowledged to be one of the most difficult patient cohorts to treat. The red circles indicate injected lesions and the yellow circles indicate non-injected lesions. Importantly, you will see responses seen in the non-injected distant and visceral tumors within the abdomen, lung and include healing of lytic bone lesions, this is an extraordinary response of a distant effect from locally injected tumors and shows a systemic possibilities of this therapy. Next slide is actually my patient. This is a patient who had 3 prior lines of therapy, including BRAF-directed treatments and Opdualag, which is the FDA-approved treatment with a combination of anti-PD1 and anti-LAG3. This patient underwent 4 months of RP1 nivolumab therapy. And you'll see there's a large gap between 4 months and 15 months. And the reason for that is that this patient, subsequent to this, underwent repair of an aortic aneurysm. This was a life-threatening condition, which had to be delayed because of his active melanoma. But because of his response was able to undergo life-saving -- life continuation surgery. And I want to point out that the restrictive material from his aortic aneurysm was negative for any evidence of cancer. And importantly, after this patient returned from rehabilitation, his 15-month picture, as you can see here, shows lesions which are much less in number. However, we were distressed by the fact that there were still reasons visible. All target lesions in this patient were [indiscernible], including 3 distant lesions from the target site. I'm pleased to report that all lesions are negative for active cancer and show only melanosis, which are phagocytic inflammatory cells which have [indiscernible] and internalized pigment similar as you might get in a tattoo. This man is now completely free of cancer and is basically on a cruise. In conclusion, IGNYTE study shows clinical meaningful benefit in this challenging to treat population with limited treatment options. 1/3 of patients respond as assessed by central review with durable response over 35 months. RP-1 combined with nivolumab continues to be a generally well-tolerated regimen with predominant grades 1 and 2 constitutional type side effects, which are transient. Full data to be submitted for presentation at an upcoming major medical congress.

Thank you, Dr. Wong. Before I conclude, I would like to offer the opportunity for Dr. Robert to maybe provide her thoughts on clinical perspectives on the data presented today.

Yes. I think as my colleague said, I would like to highlight who are not familiar that this is a population for whom we really don't have any treatment to propose. And not only we have a lot of primary resistance, but also all the patients will have on treatment and the anti-PD1 based treatment must have been the last treatment, meaning that we don't have a long interval and then rechallenge with the treatment because in this case, we know that sometimes we may have some responses. But if it's just after the treatment with a very, very short interval, we usually don't see any response with PD-1 [ single agent ]. So it really means that this combination brings something really important and more than 30% of response for us, it's really extremely meaningful. And I think this is an extremely important result.

Thank you, Dr. Robert. So now just probably talking about some of our progress to BLA. This is a topline summary of 2 key FDA interactions and the feedback received has been incorporated in the [indiscernible] program and which the results just presented also address. I would just like to highlight a few things which you've heard about today, mainly that the IGNYTE study adopted a strict definition of progressional anti-PD1 where literature, including by [indiscernible] based on reviewing a large FDA [ Board ] analysis suggests further anti-PD1 treatment would only expect to show an overall response around 6% to 7%. We also heard of the clinically meaningful benefit across many hard-to-treat patient subgroups, including those with primary disease, resistant disease [indiscernible] progressive on ipi-nivo. Our Phase III confirmatory study is moving towards first patient enrolled in Q3 and the scheme on the next slide shows the study in more detail. The IGNYTE-3 study will be conducted in advanced melanoma patients who have progressed on anti-PD1 and CTLA-4 or who were not candidates for anti-CTLA-4. The study design has a 1:1 randomization to receive either RP1 plus nivolumab or a limited dealers' choice of options highlighted here, including Opdualag, chemotherapy, all patients will be allowed rechallenge with monotherapy anti-PD1. The primary endpoint will be overall survival. Next slide, please. In April 2024, we conducted a productive Type C meeting with the FDA, which confirmed what's needed in terms of our CMC to support the RP1 BLA submission. We have a state-of-the-art manufacturing facility in Framingham, Massachusetts, which will -- from which we will aim to supply global demand for RP1 and RP2. As a reminder, and as opposed to many cell therapies, we have a highly attractive cost of goods and off-the-shelf product practicality. Given the data shared today, we believe RP1 plus nivolumab provides a potentially compelling risk-benefit profile that is able to address a broad range of anti-PD-1 failed melanoma, and is well suited to the first treatment option for patients who progress on an anti-PD1 based regimen from either adjuvant or first-line settings. The administration and safety profile to treatment regimen will allow adoption in the community not just academic centers. In summary, today, we share strong primary endpoint ORR data by independent central review of 33.6% with durable responses in a difficult-to-treat patient population. Our manufacturing is on track to support RP1 BLA and global commercialization. We expect the first patient to be enrolled in our confirmatory study in Q3 '24, with BLA submission planned for the second half of '24. Finally, we are excited by the attractive commercial opportunity in anti-PD1 failed melanoma where there is a significant patient population and remains a high unmet need. This concludes the presentation. I will now turn over for Q&A.

[Operator Instructions] Our first question comes from Anupam Rama with JPM.

Question for the company as well as the KOLs. So for the company, would these centrally reviewed data in hand plus the guidance of the first patient being enrolled in IGNYTE-3 in 3Q, what are the final gating factors to kind of finishing the BLA package as well as the filing. And then for the KOLs on the line, perhaps for both of you, with the emerging clinical profile of RP1 here, how do you think about incorporating this product into your treatment paradigm? And any considerations on the logistical side?

Thank you, Anupam, for your question. I appreciate that. Just in terms of next steps, we, as you may have seen in the press release, have already submitted the topline data to the agency. We'll be requesting a pre-BLA meeting in the coming months, where we will then discuss the data in more detail. We will be providing a more detailed briefing package with additional analysis from the study. And then following that, we will then be submitting an understanding what's required for our pre-BLA package, as we mentioned in the second half of 2024. With that, maybe I'll hand over to the KOLs for your other question.

So 2 questions. Number one, incorporating the practice. The thing that's most amazing about the situation is this low toxicity rate with really single-digit grade 3s and 0 grade 4, grade 5 toxicities, extremely safe. And so basically, for us, our consideration is that once you fail anti-PD1, the options we have are limited, especially if you fail a combination of anti-PD1 and anti-CTL4 ipi/nivo or Opdualag, which you saw in the case here. So this is not just a hard-to-treat population, but one in which there's no standard of care. So having something which is safe and efficacious makes this sort of an easy plug in to our normal everyday practice. Logistically, this is intratumoral therapy. This is something we're familiar with in our institution. We have all the sort of local practitioners around us in Texas are familiar with this as well, this is a specific growing -- I'd say part of the growing repertoire where they can offer patients. So we see this as an opportunity, which will continue to grow as people realize this as a viable option in their patient population.

Yes, I echo what you say. In France also, it was very rapidly -- all the hospitals were very rapidly familiar and there was an extremely rapid learning curve to educate the colleagues and the interventional radiology to do this injection. And I think there was quite a lot of excitement in doing that. So there is no issue with the logistics. And also we are so desperate to give something to this patient for whom we have new things that we sometimes compromise on the safety and we sometimes consider treatment that may be very toxic. And here, what is really incredible is we have the best results that we can have today without toxicity. So we don't compromise either on the efficacy nor on the safety, which is quite excellent.

The next question comes from [ Alexander Bolis ] with Barclays.

This is Alex on for Peter Lawson. I just have 2. So the first one for the KOLs. Wondering if you could speak to the responses you saw in injected versus uninjected lesions and how consistent are these response rates? And then the second question, just for the IGNYTE Phase III study -- IGNYTE-3 trial. What is your expectation for the median overall survival in the control arm?

So I'll speak to the first question. So I've always said that response in injected -- within the injected lesions is not surprising. I've been at this for 30 years. I've injected all manners of things, [ phenol ], [indiscernible] alcohol, BCG, you name it. I've done it in desperation to get a response. However, what is remarkable here, our responses within distant uninjected lesions. So we see things within the liver, which is particularly difficult, to inject not -- by the way, [indiscernible] as M1c disease. So you see there's a large sum of those patients on trial. And in fact, we saw a case of response in bone, which is exceedingly -- it's wonderful to see exceedingly difficult to get. So these are very encouraging findings. Now it's preliminary, you have to go through almost like a lesion by lesion by lesion assessment. What we've certainly seen and I personally seen responses in the distant uninjected lesions. And for me, that's indicative of a systemic response, which is exactly what you hope to get in order to get to long-term survival. And you're seeing that within the duration of response graph and the Kaplan-Meier of 36 months. And you don't get that unless you have some sort of systemic response globally.

As for the median overall survival in the control arm, I would expect around 10 months.

Yes. Thank you, Caroline. I can add a little bit more flavor to that as well because it's obviously a dealer's choice and some of the treatments may be a little higher than others. So we have Opdualag, chemotherapy and single-agent PD-1. But yes, we're sort of estimating per sort of some of the statistics for 12 to 12 months or so -- 12 to 14 months.

I think you're...

Alex, hope we have addressed your question?

Yes. Great. That was it.

The next question comes from Evan Seigerman with BMO Capital.

First on the confirmatory trial, has FDA given you guidance as to how much of enrollment they want to see before they would approve RP1 in this setting? And then my second question is looking in the real world, maybe for the KOLs, do you see -- how would this -- kind of a follow-up to Anupam's, how this fit into your treatment paradigm for these patients? Would you consider using this? Would you consider using other novel technologies that have been recently approved? Where does this sit in given that data that we saw at ASCO and now kind of seeing again here in the central review set.

Thank you for your question, Evan. I'll take the first piece and then hand over to the KOLs for the second piece. So in terms of the guidance and information we've had around how much enrollment we need on the confirmatory trial, we've just been told that [ this is ] underway and which is why we are moving at pace to enroll as many patients as we can by the BLA filing. As I mentioned, we have now changed guidance a little tighter on first patient enrolled in Q3. So we would hope to have a handful of patients who enroll before BLA. On the other question around other novel treatments, I'll hand over to Caroline and Mike.

No, there are novel treatments experiments, but today, the position -- with the results that we have, I think this combination will become as a first choice after [indiscernible] PD-1 before trying other toxic experiment of treatments. And I don't see anything that has a benefit-risk ratio as good as this one.

So in perspective at ASCO, the excitement really surrounded a lot around TIL therapy. And we happen to be a major TIL site. I first [indiscernible] for over decade and IL-2 for longer than that. And the reality is that's a very small subset population. And just to be granular about it, you have to have these patients come in, they have to pass cardiovascular and pulmonary testing. They come in to get the 5 days of ablative chemotherapy, which drives blood count to 0, then you get your cells. Then you get IL-2, and then you wait for your cells to recover and then you let that patient comes out and then you know the response rate from all the ASCO presentations. This approach is devoid of any high-grade toxicities and really is -- makes it incredibly favorable to a more global population of patients in [indiscernible]. The second thing is more scientific, which is you now have response in patients who have failed anti-PD1 and anti-CTL4, and what does that mean? It means that you've given them best checkpoint inhibitor that we have available, yet they did not respond. And there are tumors who [ blue passed ]. And if you had a response in that population, it means you perhaps have done something to the immune system, which is unique and allows that immune system now respond with adding PD-1 to it. So that means that every subsequent patient -- thing that patient gets after RP1 plus nivolumab is working on an immune system, which is altered in a way favorable for response. So that tells me that there is incredible opportunity for this at all settings of oncology, including sort of more upfront setting. That's, of course, looking forward. But today, the encouraging thing is response and it's difficult to treat population with very, very favorable toxicity. So it makes it universally applicable in that failure population.

Plus, it is -- I mean, it's extraordinarily complicated to set up. In Europe today, there is one single center to -- that is able to do TIL currently. So it's just not available. And as you said, it's for a very selected population of patients, it has nothing to see.

The next question comes from Jonathan Chang with Leerink Partners.

Two questions. First, were the efficacy data by central review consistent across subgroups like in the investigator-assessed data? And two, can you discuss reasons for confidence in the accelerated approval path ahead?

Thanks for your question, Jonathan. I'm going to hand the first question over to Robert, and Kostas, feel free to comment as well.

Thanks, Jonathan. This is Rob here. So we are deliberately saving the majority of the topline data or the central review data for presentation at a future medical conference. However, in summary, we can say that all the data we have seen, including the subgroups is consistent with what we saw in the investigator-assessed data, which really bearing in mind that the response rates were very different, marginally higher by central review. It would be rather impossible that they weren't, in fact, so we're very pleased across the breadth of the data with the majority being safe as it were for presentation later in the year at a Medical Congress. Kostas?

Nothing to add. I think the data would speak in the future.

So you did also ask about confidence with regard to the accelerated approval pathway. Clearly, there's never a 100% guarantee in any regulatory process. Over the last years, we have had quite a number of different interactions with the FDA, as summarized by Sush in the relevant slide. The most recent in September last year, where we did take the FDA through the data, which we had at that time. And we discussed with the FDA what would be needed to include in the BLA filing using data as provided to the FDA, but by central review. So if you look at the slide, you'll see the things which we particularly discussed, but in high-level summary, we do believe that each of the things we discussed with the FDA, we have indeed done. And therefore, we should be in a good position to file the BLA later in the year and have a BLA accepted and hopefully accelerated approval to results in the fullness of time. But of course, there are no guarantees, but we think we're in a good place.

Just to add to that, Jonathan, I would say, it starts with strong data and -- the FDA requested central review data in RECIST 1.1, and we believe those have held up really, really well. So I think that certainly gives us confidence in addition to addressing a number of their other comments. So obviously, as I mentioned, we'll be submitting the data and requesting a meeting and providing more information in due course.

[Operator Instructions] The next question comes from Allison Bratzel with Piper Sandler.

Maybe first on the Phase III melanoma trial. Could you just talk to anticipated enrollment dynamics there, a number of sites, pace of enrollment and just overall willingness for docs and patients to participate. I just think the ASCO presentation has generated a decent amount of excitement there. And then maybe just a quick one on CSCC. Could you just clarify how much of the SURPASS data will be submitted in conjunction with the melanoma filing. And I know -- I think you're waiting for time-based endpoints to mature on CSCC before explicitly going to FDA on that. Is that being driven by FDA feedback?

Thank you for your questions. So maybe I'll start with -- maybe Kostas, you could take the IGNYTE-3 interest. And obviously, we just had ASCO and I'll let Kostas talk about IGNYTE [indiscernible].

This is Kostas here. The IGNYTE-3 study is planned. The plan for us is to enroll the first patient in Q3 relatively soon, and we have selected sites in the U.S. Our plan is to start with the U.S. sites initially and eventually expand to a global trial. Anything else about IGNYTE-3?

The interest.

The interest. The interest has been very high, especially after the data presented at ASCO. Just to give you an example, many of the investigators -- a few of the investigators who [indiscernible] the study down initially after seeing the data at ASCO, they approached us to participate as a site in the IGNYTE-3 study. So I think the data speaks of itself how potent this treatment is and how safe this treatment is, and therefore, it has ignited a lot of excitement for IGNYTE.

And in Europe, you have had several requests [indiscernible] to try to activate quickly in Europe.

I guess to point out, Mike Wong here, at the ASCO presentation, they were -- in addition to my own talk, there was the uveal melanoma talk. And for someone who walked in that room and didn't know anything about oncolytic therapy, they left a room firmly convinced that this was an [indiscernible] oncology, which is emerging. It's opening, it's safe and it works in some of the most difficult situations in oncology, uveal melanoma metastatic, which has no standard of care and the resistant populations, including ipi/nivo failures in melanoma. So if you knew nothing about oncolytic therapy walking into a room, you've left with a distinct feeling that this is an area which is very much deserving of attention.

Allison, you asked about SURPASS and just -- we submitted that data, as you're probably aware, to the FDA. We will be submitting updated safety data as part of the BLA for RP1. And we haven't had any further conversations with FDA around SURPASS. But Rob, I'll maybe let you comment on time-based endpoints.

Sure. Just a little further comment on the Phase III. So it's a globe of large Phase III study and will be conducted on a global basis as a result. And as a result, we'll also take several years to enroll and complete. We have not said how many sites or how many countries, but it would be a sort of standard in a [indiscernible] number for the purpose, and you can watch the evolution of the sites who are activated on clinicaltrials.gov as that occurs. With respect to SURPASS, the BLA filing is -- it will be focused entirely on melanoma. That's the indication we will be seeking but with supportive data from other activities with RP1, including the data from the ARTACUS study, which is monotherapy RP1 and including particularly safety data from the SURPASS study. But the efficacy data will be predominantly that from the melanoma cohort seeking a label in melanoma. We did believe at the time of the primary analysis of SURPASS that the secondary endpoints were beginning to show promise, and the plan remains to do a further analysis of those time-based secondary endpoints next year sometime when we will review what the data then shows. And then based on that data decide what we might do with it. But the melanoma BLA is no way dependent or connected to that.

The next question comes from Tony Butler with Rodman & Renshaw.

Dr. Wong, Dr. Robert, a couple of questions, if I may. To what degree do you think patients need to be treated at an academic center when given RP1 pembro versus a community setting center. That's question one, if I may. And then question two is, while the systemic effects, I think, have been demonstrated to be incredibly impressive, but would you actually treat a patient who present with brain mets with RP1? And then the final question would be again for both of you, would you recommend or advise the company, and I think Dr. Wong, you sort of alluded to this, on the potential of using RP1 pembro in a study in front-line melanoma?

So for the community centers, I think I don't know if it's the same in Europe and in the U.S. In France, today, the trials were done in University [indiscernible]. But we have a lot of hospitals that now like private hospitals, private clinics that are very well equipped with the intervention radiology, and I am sure there would be no problem because it's not technically difficult. So I would not expect any issue if it continues to show this positive and very encouraging results that other private institute could use these projects. As for using this treatment in patients with active brain metastasis, today, we do not have any data. If the drug were available and my patient had metastases in the grade that I could treat with radiotherapy and the patients have already failed ipi/nivo, which is the [ base ] treatment for brain metastases. If I could control the brain with radiotherapy, I would definitely use ipilimumab plus nivolumab. And -- but today, we don't have any data so we cannot tell you.

So let me just speak to you those first 2 points as well. So I've been in this long enough that I remember 11 years ago, people in the community setting me patients to give ipilimumab, that was the [ concept ]. Dear Dr. Wong, give me ipi. There was a direct fear about immune toxicities, you can see from what's happened -- the evolution of immunotherapy, this has now given as routinely [indiscernible] almost. So what is driving that? It's toxicity. Toxicity drives community oncologist's decision for a couple of reasons. One is that you don't have the resources [indiscernible] academic center to handle toxicity. You don't have fellows at night, you don't have coverage, you don't have ICU, so on and so forth. Number two is, you don't have the sort of academic follow-up that help you understand the toxicity. So this is a treatment in which, again, to repeat the data as single-digit grade 3 toxicity and 0 grade 4, grade 5 toxicity -- no grade 5 toxicity, let's put it that way. So in the community setting, it makes it easy. There is now interventional radiology is a growing field, no doubt about it, and they cut their teeth while doing biopsies. If you can do a biopsy, you can do an injection. So basically, this is technically not a leap and bound type of situation and more of sort of changing your workflow. So I don't see an impediment to its more global use within oncology after a reset, obviously, your workflow to allow for intratumoral injection. You can do that easily by sort of scheduling, by getting the patients in a certain days, and it's a workflow [indiscernible] now. So -- but the driver of uptake in [indiscernible] is toxicity, which you don't really see with this. As for brain mets, as you know, patients in this study who have to have a controlled brain mets, it's just not enough data to help you understand. But I see no mechanistic reason why this cannot be applicable. Of course, this has to be done in a rigorous way. And I think this will come at some point in time in its development. I want to answer the last question, which is RP1 in a front-line setting. And there's a lot of -- one of the big [indiscernible] at this sort of Residential Symposia was the data on ipi/nivo and its use in the new adjuvant setting. And I have to remind you that when I treat these patients in neoadjuvant setting, my task is not just to treat a patient with immunotherapy, but to deliver to the surgeon the best possible patient. Because if you create a toxicity, and that patient cannot get surgery, you have converted a curable situation into one which is no longer curable. And it will have [indiscernible] and it's a very bad thing to do. So the safer the drug, the safer the approach, the better off you are in that setting. So I believe that there's an opportunity there, although we are very early in the discussion. But again, mechanistically, all the sort of attributes that you see here today, safety, efficacy, so on and so forth, line up to a possibility in the front line even in the very front-line setting. So there are multiple sort of pathways to that, but of course, driven by data. And -- but as it stands right now, there's nothing I can see that will impede sort of progress into that setting.

And maybe just to add, Tony, from a community perspective, obviously, all community site's not created equal. Within the U.S., it's kind of big group, you've got community hospitals, a large integrated delivery networks that have IR within the facility or close by, so that's more like an academic site in many ways. You've got a large oncology network like Florida Cancer, U.S. Oncology that work closely with IR as Mike just mentioned. And so we do think this is something that can be done in the community. There's also a nice incentive for the community to keep their patients versus having to refer these tough patients for something like TIL therapy, which would require treatment in academic center. So I do think there are positive incentives for community oncologists to keep and treat these patients locally.

The next question comes from Kaveri Pohlman with BTIG.

Congrats on the results. Maybe just one clarifying question first for the management team. Can you provide any additional color on modified RECIST 1.1, why it was chosen and how it is different from RECIST 1.1. And maybe a question for KOLs. Can you tell us what types of patients will be eligible for this therapy versus TILs? And also, if you can tell us if there were any patients with liver metastases and how the efficacy looks like in those patients?

Thank you for your questions, Kaveri. I'll hand over to maybe Rob to talk about the RECIST versus mRECIST, and then we can hand over to our KOLs on your other question.

So modified RECIST was the primary endpoint of the study when the study was designed, and the modification is a relatively simple modification compared to standard RECIST and it was to allow for the possibility for extended pseudoprogression in our patients. We expect there to be some level of increase frequently or inflammation prior to response with our modality of therapy and to allow for that, we require the progressive disease are needed to be confirmed by additional increase on a first scan following -- on a second scan, sorry, following the first scan, which showed PD. And that was allowed for the possibility of extended pseudoprogression, which might take a bit of time to resolve before the patient went into a response. On the study, we certainly did see increase before response. However, that increase was generally more transient than it might have been. It resolved within one scan interval and therefore, the modification we incorporated wasn't really required. And as you can see, the analysis by modified RECIST and standard RECIST, which the FDA asked us to also do was very similar with both being around 33%. And really, the difference was only one patient. So it was incorporated in the study in case we saw extended pseudoprogression, but what we actually saw was more transient pseudoprogression. So in hindsight, it was only needed in a very small number of cases, in fact, only 1. Before I hand over to the KOLs, I'll just comment a little bit on liver mets. We certainly have enrolled quite a few patients with M1c liver mets and have injected some and seen responses in those and inject it elsewhere and also seeing response in liver following injection to places not in the liver. As you would have seen in some of the examples we've seen -- shown today and frequently before. I'll hand over to Caroline and/or Mike to further comment on that.

Yes. The patient that will be eligible for TILs, they would represent maybe 20% -- 15%, 20% of the patients in this situation. And they have to be able to remain for 6 weeks to 2 months without treatment, so that's not anybody. They have to access and to be able to withstand the very difficult lymphodepletive chemotherapy that is necessary before infusion of the TILs and then to also be able to return the very high dose of IL-2. So -- and they have to accept this toxicity because 100% of them will have grade 3 or more toxicity, so it's very selective population of patients and whereas for this current treatment ipilimumab plus nivolumab, almost no limitation in the exclusion criteria as long as the patients have performance status that allows them to receive a treatment and not to have only [indiscernible].

So coming from a center that has done TIL for decades, I want to just emphasize a couple of points that Dr. Robert pointed out. The TIL is not universally available to people, you have other -- there are multiple gateways to get into TIL, including the fact you had to have tumor, which is harvestable. So typically, you have to either operatively do it or you have to have a place where you can have several passes of a need -- of a core needle biopsy to get enough tissue. So that's not everyone. The next is that you have to have these cells grow. So in the past 6 months, I've had 2 patients where there are tumors that there the TIL didn't grow. And we know that's a possibility as a percent of not growth, right? So then you don't have growth, then you [indiscernible] get into TIL. You have to control brain mets or no brain mets and then you have to pass a cardiovascular and respiratory testing because of the fact that you are going to go through something which will really be stressful to your body. And lastly, I defined grade 4 toxicities as toxicities that are potentially life threatening. You will have 100% grade 4 toxicity, why? Because your blood count will be down to 0, 0, 0 white count, 0 lymphocytes, sometimes 0 platelets in order -- before you get your TIL therapy. So -- and then you get [indiscernible] too, which is known to cause a syndrome similar to septic shock. So you are now comparing a strategy with a guaranteed grade 4 toxicity, life-threatening things going through and without any guarantee of getting on to one in which you can university treat patients with very low toxicity, 0 grade 5, 0 grade 4 -- or I should say, low grade 4s or low grade 3 toxicities. So TIL has its place. But one of the things that is not universal.

I show no further questions at this time. I would now like to turn the call back to Sushil Patel for closing remarks.

Thank you, Michelle. Thank you, everyone. We very much look forward to sharing additional details of the central review data. Obviously, very excited about the data we showed today, and we'll also look forward to updating you on progress towards BLA in the coming months and that concludes the call. Thank you for your time, everyone.

This concludes today's conference call. Thank you for participating. You may now disconnect.