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

Good day, and thank you for standing by. Welcome to Replimune RP1 Program Update Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to Philip Astley-Sparke, Chief Executive Officer. Please go ahead.

Good morning, and thank you for joining our investor conference call. We are pleased to have this opportunity to show everyone a comprehensive data update on the studies we are running with RP1 in multiple skin cancer settings. Before we begin, I need to highlight our forward-looking statements. On Slide 3, I'm Philip Astley-Sparke, CEO of Replimune, and I have with me today from management, Dr. Robert Coffin, our President and Chief R&D Officer. We're also very pleased to have with us several leading physicians in sites, all with considerable experience of using our products. Professor Mike Migden, Global PI and Co-Chair of the CERPASS Steering Committee, from the Departments of Dermatology and Head and Neck Surgery at MD Anderson Cancer Center; Professor Caroline Robert, Co-Chair of the CERPASS Steering Committee, Head of the Dermatology unit at Gustave Roussy, and Co-Director of the Melanoma Research Unit at INSERM Paris-Sud University, also at an investigating site on the IGNYTE study. Dr. Nikhil Khushalani, Vice Chair of the Department of Cutaneous Oncology at Moffitt Cancer Center and the leading investigator on the CERPASS study; and Professor Mike Wong, the Department of Melanoma Medical Oncology at MD Anderson Cancer Center, leading investigator on the IGNYTE study. Slide 4 shows the agenda. Following an overview section, the second section comes after CERPASS study, frontline cutaneous squamous cell carcinoma comparing RP1 plus cemiplimab against cemiplimab alone. The third section covers supporting non-melanoma skin cancer studies as well as for the first time, the full population from our study in anti-PD1-failed melanoma being run with registration intent before a wrap-up section. On Slide 6, the company has the ambition to establish with RP1 a full skin cancer franchise with the studies being run with registration intent in first-line cutaneous squamous cell carcinoma and anti-PD1-failed melanoma to the fore. We're also running studies in anti-PD1-failed non-melanoma skin cancers and the ASCO study in transplant patients with skin cancers, based from which we will also present today. As a reminder, we also plan to move our well-tolerated products early in disease courses and have a neoadjuvant study being planned with Incyte with cutaneous squamous cell carcinoma. On Slide 7. In summary, in our SURPASS study in frontline cutaneous squamous cell carcinoma, the primary study end points were missed with a p value of less than 0.025 [ in SURPASS two set ], at each of the 2 endpoints of overall response and complete response tested separately. However, we showed the addition of RP1 cemiplimab that has more robust and durable responses and an improvement in complete response with a p value of less than 0.05. We believe the data demonstrates a meaningful treatment effect combining RP1 with anti-PD1 therapy, both complete response rate and durability of response and confirms that RP1 provides additional benefit as compared to that which can be achieved with anti-PD1 alone. The improvement in durable complete responses we've seen in SURPASS also supports our study with Incyte in the neoadjuvant setting. The SURPASS study itself currently requires longer follow-up for all the time-based endpoints of durable response, PFS and OS to mature. Further data cuts will be made. In our ARTACUS study in solid organ transplant patients, clear monotherapy activity has been shown and its very difficult to treat population, with a 35% overall response rate. We are also reporting today a 30% response rate in anti-PD1-failed non-melanoma skin cancers, consistent with the signal we've seen in the larger anti-PD1-failed melanoma study. Last but not least, in our IGNYTE melanoma study in anti-PD1-failed melanoma being run with registration intent, we are on track to share approximately 1 in 3 patients benefiting from durable responses in this major unmet need setting. Pending completion of the study and independent central review, we plan to submit a BLA in the second half of next year under the accelerated approval pathway. A confirmatory study and concept has recently been agreed with the FDA. With a favorable safety profile, will be the breadth of our data post emergence of RP1 with a potential new treatment option for a variety of hard-to-treat skin cancer. I will now hand over to Dr. Khushalani, to describe the unmet need of cutaneous squamous cell carcinoma.

Good morning, and thank you for the kind invitation to be here and speak to you about this important topic. So what exactly is cutaneous squamous cell carcinoma? This is the second most common type of skin cancer that we see, second only to basal cell carcinoma, with a rising incidence over the last 2 to 2.5 decades. Previously, the ratio in terms of incidence of basal cell to squamous cell was approximately 4:1 and more recent data suggests that this is actually closer to 1:1. The vast majority of these patients presented with small localized disease and remain within the domain of the dermatologists. However, approximately 3% to 5% of tumors eventually develop what we refer to clinically as locally advanced or eventually metastatic disease that requires true multidisciplinary care between surgeons, dermatologists, radiation oncologists, medical oncologists and others. Most of our patients with this disease tend to be older, the median age is greater than 70 years. And many of these skin lesions or cutaneous squamous cell carcinoma develop from pre-existing lesions, typically actinic keratosis that are related to sun damage and ultraviolet life exposure. The vast majority as anticipated, developed on the scalp and the head and neck region. This is predominantly an external disease and outgrowing disease, as you can see on the photographs in this slide. Many of these tumors, when they reach this aspect are large, painful and can adversely impact quality of life, and eventually even contribute to psychosocial isolation. What we see in the clinic frequently are disfiguring tumors often with foul smelling drainage and bleeding, and patients will often unfortunately seek -- are delayed in seeking medical care. Another important aspect that we will discuss today is many of these patients have underlying immune deficiencies including solid organ transplant, rheumatoid arthritis, chronic lymphocytic leukemia and others that increased the risk significantly of developing cutaneous squamous cell carcinoma. An important aspect to highlight is that local regional progression occurs in many of these patients and therefore, intratumoral or intralesional approaches are of dedicated interest in our field. On the next slide, you will note that until recently, there were very limited options for the treatment of patients with locally advanced or metastatic disease for whom surgery or radiation are no longer options for curative treatment. We now have 2 FDA-approved agents, cemiplimab and pembrolizumab that are considered standard of care within this population. And as shown in this slide, each of these has an overall response rate of approximately 40% to 50% in previously untreated patients. Importantly, only about 12% to 20% of these patients achieved a complete response, i.e., complete resolution of evident clinical disease. And as seen in these studies above, attaining a complete response importantly, can lead to durable disease control. That's something that I'd like you all to keep in mind and eventually clinical benefit as well. Despite this, more than half of our patients unfortunately do not benefit, either from primary or secondary resistance to anti-PD1 agents and options for subsequent lines of therapy tend to be limited, for example, chemotherapy or anti-EGFR agents such as Erbitux, both of which have modest benefit and associated toxicity. Therefore, identifying novel treatments to increase efficacy in the frontline setting as well as in the second and beyond line setting is critically important and an unmet need in our field. And finally, as discussed previously, the high-risk populations, including the immunocompromised patients, such as transplant recipients, who have greater than 100-fold risk of developing cutaneous squamous cell carcinoma of the skin remains very challenging because anti-PD1 therapy has to be used with extreme caution in these patients due to the risk of organ rejection. I will now hand over to Dr. Midgen to further discuss the primary results for CERPASS.

Thank you, Dr. Khushalani. Good morning. Next slide. This is Slide 12. The CERPASS registration-directed Phase II study in CSCC enrolled 211 patients, randomized 2 to 1, received a combination with RP1 versus cemiplimab alone. And this is the largest randomized study in advanced CSCC to date. There was stratification of locally advanced or metastatic disease and prior CSCC-directed therapy. There were dual primary endpoints of objective response rate and complete response rate. To win on both, we needed a p of 0.05; to win on 1, we needed a p of less than 0.025, which is approximately 15% difference between the arms. Next slide, which is Slide 13. Unfortunately, neither primary endpoint was met. However, clear treatment effect was seen validating RP1 as to what anti-PD1 alone can achieve. While the ORR works very similar between the arms of around half and both arms responding, for reasons that we will -- possible reasons we will discuss the substantially improved with RP1 plus cemiplimab with a 38% complete response rate with the combination, as compared to 25% complete response rate with cemiplimab alone, which gave a p value of 0.04, just shy of the 0.025 needed. In fact, 0.025 was missed literally by just 1 or 2 patients. Among the 83 patients with locally-advanced disease, the complete response rate was increased to 48%. And in the combination group versus 22.6% in the monotherapy group, which is a greater than 2x higher rate, which has clinically impactful results as its complete responses, which provide long-term benefit to patients. RP1 plus cemiplimab substantially increased the portion of responders that were complete responses seen with 72.6% for the combination, versus 48.6% for cemiplimab alone with a p value of 0.013, although this wasn't a prespecified analysis. Immature data also shows that the duration responses improve with the combination with the hazard ratio of 0.45 currently as would be expected with an increased rate of CR. It was also seen that RP1 plus cemiplimab appear to give better results in difficult to treat patients with particularly disfiguring disease in a way that cemiplimab is less often to achieve, including with my own clinical experience. While overall survival and progression free survival are currently immature at this first data cut and while the primary endpoints weren't met, RP1 plus cemiplimab demonstrated an overall improvement in the quality of responses in terms of each for depth, durability and improvement in the quality of -- in the clinical meaningfulness for patients with challenging to treat disease, which speaks to the power of what the combination can achieve. It is important to remember that this is a first data cut from the study and that the patients will be further followed in particular, to show the time-based endpoints of duration of response, progression free survival and overall survival to mature upon which the totality of the benefit can then be assessed. Next slide, which is Slide 14. Demographics and baseline characteristics, these were generally well balanced with a slight imbalance in the metastatic versus locally advanced with around 10% more metastatic in the combination group, which means about 10% less of the locally advanced. However, there was a notable imbalance in baseline tumor burden between the arms with 32 patients with baseline tumor burden greater than 10 centimeters in the combination arm versus only 9 patients in the monotherapy arm, which is around twice as many based on 2:1 randomization. As tumor burden is an important prognostic factor in CSCC, this difference needs to be taken into account when analyzing the data. Next slide, safety. Safety was as expected from prior data with RP1 and RP1 combined with nivolumab with predominantly a spectrum of grade 1, 2 flu-like symptoms seen in addition to the underlying safety profile of cemiplimab. Next slide. This is the response confirmed [ objective ] response and complete response in [ attempt to ] treat population. The objective response is very similar, but clinically meaningful statistical increase and complete response, which just missed the level of the statistical significance was needed on the study due to the dual primary endpoints. It's notable how close this was with one patient with a CR, which wasn't confirmed for a protocol having the confirmation at 21 days rather than 28 days, and therefore, classified as a stable disease on the table. With just that one additional patient, we would have taken the p value to 0.031, getting very close to that 0.025. However, the increase in CR rates seen and the increase in the proportion of CR is highly-clinically meaningful, especially from my perspective, as it is CRs which I'm really trying to achieve and that are the harbinger of being able to get to a truly durable benefit. Next slide, which is Slide 17. If we look at the responses by disease presentation, we see consistent results with the full population with rather similar objective response rates, but an increase in CRC is seen. The more than doubling in the CR rate in the locally-advanced patient is particularly notable, but even in the metastatic patients, you'll see more modest increase that does translate into improved duration of response, and we'll see more of that. Next slide. Confirmed ORR and CR by baseline tumor burden. So when we move to disease burden, we'll again see a similar trend with the objective response rate, but increased -- with similar objective response rate but increased complete response rate in both patients, with less than or greater than 10 centimeters. Baseline disease, although for the greater than 10 centimeters due to the enrollment and balance, it should be noted that the control arm sample size is very small. You can also see that for less than 10 centimeters, there is an improvement in objective response rate, and it could be that the enrollment in balance of tumor burden was part of the reason why an overall response rate improvement wasn't seen. Next slide, Slide 19, duration of response. While early and the data is still immature, duration of response data is looking promising with a clear treatment benefit for RP1 plus cemiplimab, with a current hazard ratio of 0.45, which at this point is a p of approximately 0.1. This is very encouraging to see as the increased rate of CRs would be expected to translate into duration of benefit, too. Next slide, and this is Slide 20. When we split out by disease setting, we see that the data for the metastatic group is somewhat more mature than for the locally-advanced group as would be expected, as metastatic patients tend to progress more quickly and events would, therefore, be expected to accumulate more quickly with a clear separation and duration of response seen in the metastatic patients, but that separation is only just beginning to be seen for the locally-advanced patients at this point. Next slide, which is 21. Duration of response by baseline disease burden. Similarly, when broken down by disease burden, we see an improvement in duration of response that is provided in both groups. Although, once again, it should be pointed out that for the greater than 10-centimeter group, the control arm is very small due to the enrollment imbalance. Overall, it is very encouraging to see the duration of response has improved as that is what I'm peeking to achieve for my patients and where achieving a big response is key to being able to get to that long-term clinical benefit. As yet, as mentioned earlier, both progression free survival and overall survival are very immature, with insufficient events having accumulated by meaningful analysis to be done. This is a first cut of the data, and I also indicated earlier, all endpoints, in particular, in time-based endpoints will now be allowed to mature to allow the totality of the benefits to be better assessed once the data has fully matured. Okay. And I will pass on now to Dr. Khushalani, to look at some cases.

Thank you, Dr. Midgen. Next slide, please. As you can see on this particular slide, obviously, a picture is worth a thousand words. What we have done here in the next couple of slides is highlighting some of the most visually impactful complete responses seen on both treatment arms within this trial. In this slide, you see the 5 most visually impactful CRs on the cemiplimab arm, and this is out of a total of 8 patients who had visibly detectable disease that was identified by photographs that were meticulous and clinic in terms of their characterization as well as measurements. The rest of all of these within this trial are available in the appendix that will be available on the company's website. As you can see, for example, in the top left, the patient with a modest-sized tumor behind the left here and then treated with cemiplimab approximately 2 months into therapy, having a complete response. On the top right, you see someone with a large ugly tumor on the nose that again has visually a wonderful response to cemiplimab alone. Next slide, please. Similarly, what you can see here are 5 of the most visually impactful complete responses seen on the combination therapy arm with intralesional RP1 and intravenous cemiplimab. These 5 were selected from 45 complete responses that were seen in patients with visible disease. Again, all of those photographs will be available on the website and are also available on the appendix provided to you. What you can clearly see on the top left is an enormous tumor burden in an individual's left half of the face with complete resolution on treatment after approximately 3 months. On the top left or sort of middle of the slide, you see a tumor over the left, neck, again, a large disfiguring tumor with complete resolution. And what you see on the right-hand side is an example of a patient with a large tumor that is ulcerated on the scalp as well as 2 additional areas, one behind each year and on treatment with combination therapy with complete resolution. I think what's important to understand is this is extraordinarily important from a patient care perspective and from a quality of life issue, to go from a disfiguring tumor to essential resolution without the use of disfiguring surgery is indeed success in my book. To further characterize this, I will hand it back to Dr. Midgen, to talk a little bit about some of the unique responses and patterns of response that we see with these agents.

Thank you, Dr. Khushalani. So here, we're talking about pseudoprogression, and this is a particular area of interest for me. Pseudoprogression is, as you can see in these 3 patients, when you have the baseline size of the tumor, and then you get a substantial increase around somewhere in the midpoint of these photographs. And then only if you continue on the study in these cases, to get to complete response. And what's exceedingly important is to know about this and education about pseudoprogression, particularly in this study because the combination of RP1 plus cemiplimab had a much higher frequency of patients that got appearing to be worse before they have their complete resolution. And then also, what about patients when they get to that kind of peak in terms of the very disturbing look, very frightening and will they come off. And in fact, we did see patients that have that rapid increase which speaks to the potential for having a more robust immune response with the combination. So particularly important to be aware of that. And certainly, having patients come off at that midpoint could impact the data. Next slide. So CERPASS summary and conclusions. The RP1 plus cemiplimab combo provided a clinically meaningful benefit in terms of depth, durability and in terms of meeting a key unmet need in these particularly difficult-to-treat patients. RP1 plus cemiplimab is very well tolerated. There was a high rate of complete responses, also very promising for other settings such as neoadjuvant treatment of CSCC. It is also important to note that this is only a first data cut from the study, and the data will be allowed to further mature, particularly the time-based endpoints such that the totality of the benefit can be more fully assessed once that data has matured. Replimune will share this data with the FDA and further data as it matures in support of the overall filing strategy for RP1, which will be discussed later in the presentation today. Now I'll pass on to Rob.

Thanks very much, Mike. And this is now Robert Coffin, Chief R&D Officer of Replimune. And following from that presentation of the data to which [ me ] indicates while we've shown a very clear clinical benefit of RP1 combined with cemiplimab, the data, as Mike just said, really does require a further follow-up to mature, which is what the next steps really in the study will be. However, following from that presentation, I'd really like to thank on Replimune's behalf, all of the clinical trial investigators and clinical trial site staff and not least all of the patients who are participating and will continue to participate in this study, without which the conduct of the study would clearly not have been possible and for which Replimune would like to extend its very sincere gratitude. So I'll now hand over to Dr. Mike Wong of MD Anderson, to provide an update on our IGNYTE study, first, on the safety front and then data in patients with non-melanoma skin cancer who have progressed on prior anti-PD1 therapy, which also remains a significant unmet medical need. So over to you, Dr. Wong.

Thank you, Dr. Coffin. It's my honor and privilege to present to you the initial data on invaluable 30 patients on the IGNYTE data, concerning patients with non-melanoma skin cancers. Dr. Robert later on the program would speak to the patients who have melanoma. Next slide, please. This Slide #31 talks about the [ attributable ] adverse events with skin cancer patients treated with RP1 combined with nivolumab. I note that this does not include patients who received RP1 monotherapy or RP1 plus cemiplimab, only those with RP1 and nivolumab, and this table includes all the adverse events that are seen on 5% or more of these patients, whatever grade these were seeing. I'd point to you the dearth of grade 3, grade 4 toxicities, of grade 3s in the single digits. And the top line, 3 most prevalent toxicities include fatigue, chills and pyrexia. Next slide, please. RP1 combined with nivolumab in anti-PD1-failed non-melanoma skin cancers, this protocol will be discussed in greater detail in Dr. Robert's section of this presentation. Next slide, please. This slide #33, is the overall response rate of a subgroup of these 30 patients. And this is concerning patients who have cutaneous squamous cell carcinoma, CSCC, Merkel cell carcinoma, MCC, basal cell carcinoma, BCC and angiosarcoma. I note that these are tumors that are classified as rare tumors by traditional SCI designation. And for -- and all of these patients failed while on immunotherapy and are considered immunotherapy refractory patients using criteria consistent with and exceeds the consensus definitions of resistance. I also point out that these patients who have failed immunotherapy have no standard of care. And it is, therefore, meaningful to show that there are response rates, which are seen here [ in our KASHI ]. These again are small numbers, but our task here is to really look to see if there's a signal here of efficacy. And I show you response rates, which and complete response rates in this group which overall are 30% in conglomerate. Next slide, please. This is a swimmers plot of these patients and each line horizontally represents a patient on study. And a couple of things come to mind. First of all, you'll see on the horizontal axis, days on study that the numbers extend out into the 800 days. And what that gives you a sense of in this graph is the fact that these patients can have long-lasting survival on this and also long-lasting responses on this. And if you look very closely at a color coding showing responses, some of these can be major responses, which you'll see in the next slide, Slide 35, which is a spider plot where each -- where the tumor burden in each individual patient is represented here. And you will see that some patients respond as soon as 60 days. However, you'll see with each -- with some of these, are showing an increasingly downward slope of curve over time, as some of these responses can deepen over time, which is important. It's something we see here and in other parts of the presentation today. And you also see, and Dr. Midgen spoke to this, some patients show an upward inflection followed by a downward trend of the spider plot showing an initial pseudoprogression. So this is a response that we're seeing in the sort of novel therapy in this rare group of skin cancers. Next slide, please. Here, this is a depth of response in this 30-cohort patient. Again, this is for exploratory purposes that you will see that some of these approach 100% and importantly, some of the responses are in Merkel cell carcinoma, known to be a highly invasive, highly metastatic, extremely proliferative cancer. And just, for example, it's not uncommon in my practice to have patients come in with a mitotic rate of 40, 50, 60 and even 100% in these patients. So it's meaningful in the context of this rare tumor to see that some of them can have major responses, including complete response. That's for me, a signal deserving of further investigation. Next slide, please. Duration of response is shown in this graph here and really what you're trying to take away visually is the fact that these responses can be durable. And you'll see the horizontal axis showing months up to 12, which is a year and showing that these responses in this refractory cohort can be long lasting and meaningful. Again, an early signal deserving of further investigation. I want to talk about some examples of anti-PD1-failed melanoma and we can begin with the next slide, in Slide 39, which shows a patient who has a scalp cutaneous squamous cell carcinoma. And what you're seeing here is an individual who has a major disfiguring erosive tumor on the vertex of the scalp. He had received a cemiplimab therapy, and his best response to cemiplimab therapy was progressive disease. And he also met a strict criteria for PD-1 refractory disease. And you'll see over time that this lesion flattened out and was considered to be a complete clinical response in this patient. Next slide, please. This is Slide 40 showing patient 2029, left-hand side are a series of CT scans and the right-hand side, upper-right shows what this looks visually. And I will echo Dr. Khushalani's statement that these are erosive, destructive tumors. And in the context of skin cancer, the concept of locally advanced is extremely important, because left untended, these will result late -- physically in erosion. You'll see this on the CT scan, into bone of the scalp. These are disfiguring, will leave holes in people and highly sort of deforming and mutating. And therefore, response is extremely meaningful. And you'll see what happened here, visually, upper right-hand corner at 6 months, this lady who had received 6 previous lines of therapy, including failure of intratumoral experimental clinical trial drug and also failed anti-PD1 immunotherapy, achieved a meaningful response -- complete response in this particular case. Next slide, please. Slide 41 shows you what Merkel cell carcinoma can do. It is a highly-metastatic disease. And you'll see this man -- this lady, unfortunately, had disease, which resulted in a series of across -- we would say, of in-transit skin lesions, palpable, growing. In my personal practice, it's not uncommon for patients to call me up every 3 days with the new nodules because they're incredibly metastatic. This patient had failed pembrolizumab therapy previously, best response was progressive disease, and so this was primary PD-1 resistant disease. And you will see that this patient had a partial response at 3.5 months after the first dose of RP1 and nivolumab and treatment is still ongoing in this patient with a wonderful, complete cutaneous response. Next slide, please. So RP1 and nivolumab provides clinically meaningful and durable benefit in patients anti-PD1-failed immunotherapy. And I'll point out, as in the previous cases, the clinical pictures will be available both online and with the appendix of the document you receive as well, for your perusal. As I said to you before, this is a signal in a population of patients who have very limited treatment options and more importantly, gives hope to people with these rare tumors. And as I've said previously, I'll end with this line, RP1 plus nivolumab is well tolerated in these patients. And on that, next slide, please. I will hand off to Dr. Midgen, who will speak about the ARTACUS trial. Thank you.

Thank you, Dr. Wong. Next slide. So the ARTACUS study is a single agent RP1 treatment of solid organ transplants, including those of liver, kidney, lung, heart and hematopoietic stem cell. The background is that you hope if you get a transplant in one of those groups that your transplant surgeon tells you that your transplant may not become your biggest problem, your skin cancer that's going to come from the immunosuppression can become your biggest problem and could potentially kill you. Very important to recognize that, as Dr. Khushalani said, it could be greater than 100x the incidence of skin cancer in these transplant patients and that 90% -- greater than 90%, are combination of CSCC and BCC. But as you can see on the plot on the right, it's a lot more CSCC than BCC and then also some risk for Merkel-cell and Kaposi's, but these are less frequent. Management of locally advanced and metastatic disease as present in skin and soft tissues and solid organ transplants is not well established. There's no real easy way to give an immunotherapy, such as an anti-PD1 because it puts at risk loss of the graph. Next slide. Patient demographics. This was a male predominance, older population. The allograft pipe is 82% kidney, 14.8% liver, lung 3.7%. And in the data cutoff, there were no heart. But since that time, we have enrolled heart. In terms of the cutaneous malignancies, around 89%, CSCC, the rest, 11%. Merkel-cell stage at baseline, locally advanced and metastatic similar, slightly more locally advanced and a primary location skin is the majority at 96%. Next slide, which is 46. Safety profile is -- basically, the flu-like symptoms, primarily grade 1, grade 2 that we would expect from an oncolytic virus generating an immune response. Next slide. In terms of efficacy, what we saw was an objective response rate of almost 35% with complete response rate almost 22%; importantly, the disease control, which is the responders plus stable disease around 40%. We have to remember that it's so important and independent of other types of patients, these transplant patients alone as a single agent therapy. This is something we can offer patients that really don't have anything much at all to offer them except for very ineffective alternatives. Looking at the responders, tumor type, 3/4 CSCC, 1/4 Merkel-cell and then stage at study baseline, 3/4 locally advanced, 1/4 metastatic. Next slide. Looking at the characteristics of response over time. You see that there's a wide range in terms of the duration of response and that top patients who have a CSCC primary at baseline subsequently formed while on treatment of basal cell but they both -- the baseline target, at least in CSCC as well as the newly formed BCC, both had a complete response as indicated by the triangle. Next slide. Here, we see 3 patients example, the postauricular baseline and complete response at 13 months. The middle panel is paraspinal muscle lesion at the C1, C2 vertebra baseline and at 6 months, partial response. And then -- and by the way, the first panel was complete response. And then this is my patient on the far right, he had skin cancer surgery, that's the site of a skin graft placement. But when I first met him, he had tumor bulging from under his skin graft, very indurated. And then a complete response as quickly as 2 months, whereas when you [ palm faded ] the photograph at the bottom, you could feel his teeth clearly through that skin graft. There was no more indurated bulging tumor. Next slide. Three additional examples of submental lesions at baseline and complete response of 3 months, in fact, these are all complete responses. And then the middle case, the scalp case, 6 months and then complete response. And then my patient on the far right, who have 3 invasive squamous carcinomas at baseline and then 3 months complete response. And not only was there nothing palpable on that scalp, but it was very hard to find where the tumor had ever [ been ]. Next slide. So in conclusion, in summary, this is the first clinical trial assessing single-agent RP1 in organ/hematopoietic cell transplant patients, and this was acute 2-week treatment for up to 2 years, and some patients having advanced skin cancer. RP1 monotherapy showed clear antitumor activity, with objective response rate of almost 35%, and that confirmed complete response rate around 22%. No evidence of allograft rejection was observed, including hepatic and lung transplant patients. RP1 monotherapy was well tolerated with a safety profile similar to what you'd expect with just a single-agent oncolytic virus. Next slide. Okay. And I will pass on now to Dr. Robert.

Thank you very much, Dr. Migden. It's my pleasure to present the updated results of the IGNYTE study in patients with anti-PD1-failed melanoma. We are on Slide 53 now. Let me remind you the context, the medical context in spite of the huge progress that has been made in the field of metastatic melanoma with immunotherapy and targeted therapy. As you know, unfortunately, not all patients respond with immunotherapy when they have failed anti-PD1 therapy. In case they have the melanoma landscape BRAF resistance, which is about 50% of the patients, they can receive anti-BRAF/MEK therapy, but this treatment is high level of response, but the responses are transient and patients eventually develop resistance. They can also receive anti-PD1 plus anti-CTLA-4, this regiment ipi/nivo, which is about 30% of response in these patients, but you know that this is comprised of a high toxicity, when they have already received ipi/nivo, then there is really nothing that has been really -- that has proven any significant efficacy. And there is a Phase II trial with [ steel ] therapy like lymphocytes that are reinjected to the patient, very, very toxic treatment that we can only provide to a highly selected population of patients, with about 30% of response also in this situation. So this is a high medical need, and we really do not have any standard option for these patients after they develop resistance to this [ tumor ] treatment. On this Slide 54, you see the design. So this is a combination of RP1, the first of dose of RP1 is injected alone. And then the 7 following cycles are together with nivolumab. Nivolumab can be given up to 2 years. The primary objective of the study was to assess the safety and the response rate based on the modified resistance criteria. What is also noteworthy is to look at the criteria for CPI failure, we required that the patient had received at least 8 weeks of anti-PD1. The progression has been confirmed by 2 subsequent CT scans and the patient must be on PD-1 when we [ develop it ]. And this is even more strict -- stricter than the recently exited criteria by the CT. Where the patients with -- PD1 failure after the [ sub ] PD-1 and the [ immunotherapy ] can be enrolled in the trial. We know that in this situation, you can -- when you rechallenge with anti-PD1, at the [ sake of a chance ], you may have resistance. But in our situation, patients were still on anti-PD1, so you keep just on [ PD1 ] you're going to see [ it there ]. Next Slide 55, the demographics of the patient. What's very important to look at in this slide is the proportion of patients with really advanced disease, Stage 4 N1b/c/d, which means that they have [ a systematic ] internal organ that are more challenging, more than half of the patients. We also see that patients have received anti-CTLA-4 PD-1, for 46% of them, which is really the most difficult situation with cure. And although very important to note, the percentage of patients with [ INDH ] is 32% of the patients. So this is really a population of patients, very similar to our metastatic patients in the most difficult situation. Next slide. So you see the response rate. We have a total of 156 patients. And you see the first 15 patients, they are they are in the same situation that they were from the prior cohort. But altogether, the response rate, 31.4%. You see it has been broken down in the different populations, subpopulation. It's very consistent. The most challenging situation, secondary resistance, where the patients have not demonstrated any response to PD1, it's just on the right, you see 27 patients. In the patients who have received previously anti-CTLA-4, anti-CTLA-4 was 26%. So very close to 30%. Very consistent, close to 30% of response rate in all this patient subpopulation. On the Slide 57, we see what we call the waterfall graph. This is the depth of the response. And you see on the right, patients who have a decrease in the size of the target lesion. You see that for more than 50% of the patients, we see a decrease of the size of the [ lesions ]. And we also see that responses and even complete responses be seen in patients with very advanced, stage 4 and [ 1c/d ]. Next slide, this is the swing graph where you see in the X-axis, the duration of response. And here again, you see that we have very long responses, very durable responses as of today. 88 weeks of median follow-up, 78% of responses are ongoing. On the next slide, we see what we call the spider graph, very, very informative graph, which is the result of integration of the post [ precedent ] graph, you see the duration of response, and you see the evolution of the target lesion over time. And you see that for some patients unfortunately it doesn't work like the target lesion size goes up, but you see for the majority of the patients, it goes down. And we also can see that sometimes it go up a little bit before going down, which means that the responses are evolving over time, but you also see that for a proportion of the patients, quite high proportion, you see a very rapid decrease in the size of the lesions. On the next slide, it's not the totality of the population. It's not the complete population of patients. It's only 75 patients, where we show here the spider graph, the evolution of the injected and non-injected patients. And that's very important because you see that the lesions that have not been elected also has a very favorable outcome, increasing the size in the responders, meaning that we have a different effect, that we don't see the response only in the injected group. Next slide, durational response. So after more than 2 years, you see that close to 80% of the patients are still responding, so very durable responses. Next slide. PFS and OS were all patients with a nice plateau in progression free survival and we did overall survival on the right. And on the next slide, Slide 63. You see that we can break down the overall survival by the response, response or nonresponse, we grew the patient to have any response that we could see that their survival growth is remarkably flat and high and of course, a little bit less positive in the patients who to not respond. Next slide. We see that this highly promising OS response can be seen across -- that this is the values of success by stage, by prior treatment. Next slide. So in summary, this combination appears as a very attractive treatment in this population of patients. We see that we have 1/3 of the patients who experienced a response. We see that about 26.4% exactly of patient response when they have received ipilimumab plus nivolumab. So this is a very important information. It is highly challenging population. You see that 100% of the response last more than 6 months and the majority of response of more than 2 years. And we see response across all the groups involved, even the most difficult to treat patients. In fact, when we are reminded of the toxicity profile that Dr. Wong presented earlier, this is really very attractive safety. I mean, the ratio between the safety and the efficacy, if you compare the very few treatments that have shown some efficacy and not higher in the same population of patients. So I'm going to hand over for Dr. Coffin.

Thank you very much, Dr. Robert. So on Slide 67, I'm going to now give a brief update on next steps our recent regulatory interactions with the FDA and also the RP1 confirmatory study we have planned or are planning in anti-PD1-failed melanoma. So on the current CERPASS data, we'll share this with the FDA in the near term and continue to gather data from the clinical trial, in particular, for the time-based endpoints of duration of response, PFS and OS which are all currently rather immature. The more mature data will then also be shared with the FDA and what that data shows will determine the next steps with the potential pathway forward in CSCC. On melanoma, we recently held a Type C meeting with the FDA where we got confirmation on a number of aspects of the program. First, the FDA confirmed that the study population including each of the subsets of melanoma patients, including those who both had and hadn't received prior anti-PD1 -- sorry, prior anti-CTLA-4 was one of unmet need. Secondarily, the FDA agreed with our proposed complementary trial concept in support of the potential submission for accelerated approval based on the IGNYTE data. This study will be a 2-arm study comparing RP1 to RP1 plus nivolumab with investigators' choice of other therapy, with OS and/or PFS as a primary endpoint and is as is described on the next slide, not yet. The FDA also indicated this study should be underway at the time of the BLA submission. Finally, the FDA confirmed what should be in the actual filing package, which will include centrally reviewed data by RECIST 1.1, that all patients should be followed for at least 12 months, which is the sign is the same as the primary analysis to this trigger for the study. And finally, that responders should be followed for 6 months following response initiation. Onto Slide 68. This is the schematic of the confirmatory trial design, which I just described. As I said, this will enroll anti-PD1 progressed melanoma patients with investigators' choice of control therapy from a top of a defined list of control therapies that would likely -- actually OS as the primary endpoint. Full protocol development is currently underway, following which the full details of the study design will be able to be shared. And with that, I'll hand back to Philip to provide some concluding remarks.

Thanks, Rob. So on the final slide, Slide 70. Wrapping up, although CERPASS did not meet its primary endpoints, meaningful clinical benefit in cutaneous squamous cell carcinoma was shown. We will wait for the data to further mature before deciding the path forward. Other skin cancer data sets, including hard-to-free settings such as solid organ transplant recipients and anti-PD1-failed melanoma and non-melanoma skin cancers demonstrated a compelling efficacy with an attractive safety profile. Initial snapshot data from 156 anti-PD1-failed melanoma patients demonstrate that RP1 plus nivolumab maintains transformative potential, its high unmet need setting with limited treatment options. A BLA submission and the accelerated approval pathway is intently made in the second half of '24 based on the primary analysis data which is attributed in March 2024, the framework for confirmatory study to be underway at the time of the filing as it agreed with the FDA. Turning to the pipeline. The strong data with RP2 in uveal melanoma presented at a plenary presentation of SMR in November. We are planning for a randomized controlled study in second-line UBL melanoma. This provides a relatively rapid path to result in a randomized controlled trial as well as the potential label for RP2. We also plan to further investigate with RP2, other rare disease indications where we've seen activity, which, in aggregate, represent a sizable market opportunity. In a capital-constrained environment, we've deemed it prudent to extend our cash runway into 2026 and have made some portfolio prioritization decisions. While we believe RP2 continues to show evidence it is more potent than RP1, RP3 has not shown evidence it is more potent than RP2 in our Phase I expansion study. To focus on our near-term priority studies, our RP1 confirmatory study in melanoma, our RP2 restorational study in uveal melanoma, RP3 development in head and neck cancer and CRC has been discontinued. Second line HCC development will continue with RP2. Finally, we have a strong cash position to drive value through multiple meaningful data and regulatory [ catalysts ]. With that, I would like to turn the call back to the operator for questions.

[Operator Instructions] Our first question will come from the line of Jonathan Chang with Leerink Partners.

I have two. One, is there a path forward for RP1 in CSCC? And what would that look like? And two, how should we be thinking about whether and how CERPASS results implicate the opportunity in melanoma for both the clinical and regulatory perspective?

So on the first point of what the potential path forward is in CSCC. I do think that the current data already does show a strong clinical benefit even though the primary endpoints were not already met. However, as multiple [indiscernible] have said, really, we need more mature data before we can formally decide what the path forward might be and have provided that more mature data to the FDA, in particular, that relates to the time-based endpoints of duration of response, PFS and OS, although the response-based endpoints also have a potential for improvement as well. If you remember, it has always been the case that the FDA has indicated that the totality of the data will be important for any potential approval decision. And that totality of data is just not yet fully mature. CSCC is a longer-term disease than some other cancers and therefore, it's not surprising that it takes quite some time for that data to fully mature. This is very much a first look at the data, the study will continue and we will gather that data over time. So with respect to potential impact on melanoma, our view is that our RP1 plus cemiplimab has demonstrated contribution of components with clear benefit of RP1 combined with anti-PD1 compared with anti-PD1 alone. And on that basis, we believe, is supportive of the program in melanoma, which is a single-arm study. They are also rather different settings. There are different diseases, and you can't over cross-compare data from those different settings. But we certainly think that overall, the CERPASS data is supportive of, as I said, contribution of components which should also be supportive of a contribution of components in melanoma, too.

Our next question comes from the line of Anupam Rama with JPMorgan.

Can you outline how you think about the time lines for additional data cuts for CERPASS and how you ensure sort of patient retention in the study? And then following up on the prior question, do you have regulator feedback that durability PFS, these types of data would be accepted by regulators given these were secondary end points?

So we can't formally comment yet on the exact timing of when the next data cut will be beyond that we would intended to have more mature data available to include in the BLA submission for melanoma, and that BLA submission is planned for the second half of next year. So as I said, we would intend to do a further data cut at a time point which would allow that to be included in that BLA submission. The FDA has always indicated to us that when we file a BLA for RP1 or be it for melanoma or CSCC, that they would wish to see the data from all of the different clinical trials with RP1 in skin cancers, including CERPASS, IGNYTE and in fact, ARTACUS-2, so the data is intended to come together at that now slightly revised timing. With regard to retention of patients on the study, obviously, all the patients are enrolled. The study is continuing and the patients will be followed, not only on the study for continued response and survival, but also as part of their standard clinical care in any case. So we do believe that with this actually supportive data that we're having a treatment effect, that the clinical trial sites and patients will be motivated to continue to allow us to collect the data necessary to determine the totality of the data. So the last point related to regulatory acceptance of the secondary endpoint data as part of the filing package, I believe, and as I've already referred to, the FDA since the beginning of this program has always indicated that the primary endpoint data in isolation would not be sufficient. One would always need to demonstrate based on the totality of the data, particularly time-based endpoint data, you are really having clinical benefit. Response is really only a surrogate for long-term clinical benefit, and the FDA always made it clear that they would wish to see a secondary endpoint time-based endpoint data in support of whatever one saw in the primary endpoint. And while we did just miss the CRR primary endpoint by literally 1 or 2 patients, I still believe myself that over time the totality of the data will become compelling and may, depending on what that data shows, provide us a path forward.

Our next question comes from the line of Evan Seigerman with BMO.

I would love for you to just talk about the quality of responses you saw in CSCC. Any abscopal effects here? And really maybe walk us through what we could expect from kind of duration of response, PFS and OS. I know it's early, but in prior experience, CRs usually translates into OS. I guess how are you thinking about it? And what do you hope to see as this data continues to return progress?

For the first part of that question, let's turn that to our KOLs who have been treating the patients to start with Dr. Midgen.

Yes, in regards to the quality of the response, as you saw in those cases that were very overwhelming, large, fungating lesions with discharge that would cause patients to be isolated and so on, to have them a more consistent fashion on the combination, get to a complete resolution has a tremendous impact. And the reliability of seeing that occur more frequently is a great value to these patients. And then in terms of -- this is in the context where as I alluded in pseudoprogression. Because it appears that there's -- it appears that there's a more vigorous response with the combination of these therapies, you have to be educated and talk to your patients and have the confidence that you can continue as long as the patient is tolerating and they feel okay otherwise. Because without that, you could be tempted to take patients off because the response looks so vigorous that people wonder if its progression, and I think that definitely impacted or has potential to impact the objective response rate.

This is Nikhil Khushalani, I can add to that as well. I think first, look, the question that you asked regarding quality of the response. I think the quality was very impressive, particularly with regards to the complete response rate, more so in the locally advanced disease where we see the combination increasing the complete response rate. I think it's important to address quality from the standpoint of how the study was conducted and the fact that there was very stringent central review that assessed the response. I think that's really important. And therefore, the data that has been generated is certainly irrefutable from that standpoint. When we follow these patients clinically, what we have seen from prior studies, particularly the EMPOWER study with cemiplimab, is with every subsequent data cut, we have seen stable disease convert to partial response and partial responses also converting to complete responses over time. So it is not entirely surprising to me as a physician to keep treating these patients and eventually seeing a complete response developed 9 to 12 months after we had started therapy. So obviously, this is the first look at the data. And I think patients will certainly be encouraged to continue their participation. And those who have benefited from the treatment regardless of what arm they got randomized to, will certainly be motivated to continue their participation and contribution towards this data set.

And I'll [ part ] that question with the due abscopal effects. Obviously, CSCC is very much a loco-regional dominant disease that is in the front line setting. So it may not be the best setting to demonstrate abscopal effect as opposed to PD-1-failed melanoma. Would you like to comment any further on that part of the question? Obviously, we are seeing a systemic benefit coming through the durability of response.

So it's important to recognize that the sound of the metastatic case, a metastatic disease sounds like this is going to be worse, but it's really the locally advanced plus some neck nodes, or loco-regional disease that is by far and away the biggest need in these patients. That's the part that results in high morbidity and mortality more so than the metastatic patients.

I think specifically with regards to the abscopal effect question, it will be really hard to discern whether there is truly abscopal effect related to RP1, given the fact that this is a combination therapy arm. I think more appropriately, one would say if there is benefit to the combination it is likely a synergistic effect from the 2 drugs together and not specific -- could an abscopal effect have contributed to that? Certainly a possibility, certainly hypothesis generating. But I don't think one can clearly dissect this being an abscopal effect from combination therapy, unless one had a much larger runway of just monotherapy and assessing both the injected as well as the uninjected lesions and then adding a second drug at a later point in time.

So I think the final part of the question was related to the PFS and OS.

And just very briefly back to abscopal effect. As Philip said, this disease is not the optimal setting in which to demonstrate clear abscopal effects. There's also a first-line setting when cemiplimab alone is an effective drug, even though we do think we've shown improvements over cemiplimab alone. But if obviously want first the melanoma data, particularly despite of what -- with Dr. Robert showed us with injected/uninjected lesions, we've seen very clear abscopal effects in that disease, which tends to be a lot more widespread than CSCC. The other part of the question related to duration of response, et cetera, and what we hope to see. I think we are already seeing a very clear separation of the curves for duration of response, with the types of patients for whom that would be expected to mature most quickly, i.e., metastatic patients showing the clearer separation of this relatively early time point. For the whole population, as stated by Dr. Midgen, the hazard ratio is already 0.45, which is a clear signal. It's not yet statistically significant, the p value currently is 0.1, but it clearly has the potential to develop into a statistically significant improvement of duration of response over time. With regard to OS and PFS, those endpoints would tend to mature more slowly and behind duration of response. And as a result, bearing in mind the duration of response is still pretty immature, the PFS and OS data has not yet accumulated sufficient events to do a viable analysis, which would be anything other than potentially misleading. The tails of the curve have -- the curves would have extraordinarily small numbers of events to contribute to those. So it's just too early as yet. However, as durative response is already showing a good benefit, we do anticipate that with much more mature data when it is appropriate to do an analysis of a PFS and OS, that we may also see good separation there, supportive of the totality of benefit and that true durable clinical benefit is indeed being achieved on the combo arm as compared to the monotherapy.

Our next question comes from the line of Roger Song with Jefferies.

Great. A couple of questions from us. Maybe first is the past. Understanding you're still waiting for the mature data to inform the filing strategy, but just curious, given you do see the statistical significance in [ your research of ] the population like the locally advanced and low tumor burden, how likely you can file the CSCC in those -- the groups? Kind of that's number one. And number two, for the IGNYTE, understanding you're combining the early IGNYTE cohort versus the registrational IGNYTE cohort, 16 plus 140. Is that the intent for you to file based on that 156 patients or versus the 140 patients in the later cohort? Have you got the FDA agreement on this? And I have a quick follow-up after those two.

So on the last point first, the FDA has said that they wish to see all. However, they do want to look at them separately also. The 140 patients alone is pretty consistent with the full 156. We are ending up with roughly 1/3 of patients responding. However, [ you counted ] data and there are also still patients in the 140 with the opportunity for response. So yes, the FDA has clearly said they want to see both, but we'll also look at them separately. With regard to CERPASS and subsets of data, it's certainly the case that some of the data is maturing more quickly than other parts of the data based on sort of risk, et cetera. And we will -- once we have the more mature data, certainly look at it in aggregate and separately to determine whether the path forward is in a subset or for all of the patients. However, I do think different aspects of the data are strongly supportive that we're having benefit across each of the different groups. So while we've got an extremely strong increase in complete response rate for locally-advanced patients, to an unheard of level in CSCC at nearly 50% complete response rate in locally advanced patients compared to 22% complete response rate in the monotherapy arm, if one looks at the durability of response data which is expected or would be expected to mature more quickly than the locally advanced durability data on [ CEASAR ], an emerging strong signal in metastatic patients also. So we'll certainly look at subsets and see whether the pathway is a subset pathway. But we'll also not in any way give up on the totality of the data for all patients being supportive with the path forward. But time will tell. If it is immature data, and we just got to wait until it properly matures without speculating too much at this point.

Excellent, Rob. Maybe just last question regarding the confirmatory study for the PD1-failed melanoma, understanding you will need to start enrollment at the time of the BLA filing, just curious how much enrollment you needed before the BLA decision or review? And also in terms of the physician choice, what is the current thinking about this physician choice? Have you considered -- would you design the study, taking into account the potential new therapy like a TIL will be part of the physician choice?

On the first part of the question, the FDA has simply stated that the study needs to be underway with no formal requirement for how many patients need to have been recruited by the time of the BLA submission, and we intend to have met that requirement that is underway and that we have enrolled some reasonable number of patients at that point without defining exactly what that is. On the confirmatory study design, that's still in the process of being developed. The concept of the setting has been agreed with the FDA, and the exact details of the protocol, including whether we include patients who both have and haven't had prior anti-CTLA-4 or focus on patients who have all have had anti-CTLA-4 will define what the investigator's choice of drugs can be. It would intend to be -- include, however, only things which are standard of care currently or approved currently and therefore, would not be expected to include TIL therapy, which does have a very different overall profile to RP1, including probably to what type of patients are most appropriate for it and its side-effect profile. So the plan is not at the moment to include TIL therapy in the investigators' choice list.

Our next question will come from the line of Peter Lawson with Barclays.

Great. Just -- I guess I got a question around the imbalance that you saw with the baseline tumor burden, if that's kind of an issue of CCC or that wasn't something you were thinking about controlling for. And then just the percentage of patients that would fall under that kind of the classification of locally advanced disease in CSCC. And then the CR rate, whether if you think that over time will mature and deepen and you'll kind of get a potential of having a statistically significant CR rate.

The first part of the question, Dr. Midgen related to the impacts of the study as it relates to tumor burden and whether or not development at that classification is relevant in one of this disease and whether or not it could have ameliorated the result.

Absolutely. Larger than 10-centimeter tumor burden, whether it's a combination of lesions or just a single or double, very large lesion, is widely known with my colleagues to be more challenging to treat. And unfortunately, the stratification into locally-advanced metastatic and prior line of therapy didn't prevent this an ounce, but the fact that we ended up with so much more tumor burden in the group that we would have liked to have just the equal amount. Certainly, when you're 1 to 2 patients shy of getting to an endpoint could make a huge difference. And I expect that it definitely contributed to that. And I think with further time because they are more difficult to treat that we hopefully will overcome that derogatory effect of the imbalance.

And Dr. Khushalani, any further comments on that topic? And also, could you also explain what gave you actual confidence in your practice to treat through pseudoprogression?

Absolutely. So I'll take the pseudoprogression first. In my practice, we've said this in patients that received the combination therapy where RP1 was given first and then 3 weeks later, the combination was added. And even in that short time span of 3 weeks, we saw in at least a couple of patients treated at our site, noticeable increase in tumor burden. Now having done this for a while and seeing this defect in melanoma as well, I would probably say that the effect that we saw from pseudoprogression clearly appeared to be more robust or more pronounced would be a better term in CSCC. Now whether that is related to RP1 as a drug or that related to the unique tumor microenvironment for cutaneous squamous cell carcinoma, I think, deserves further investigation. But we stood the course and these patients then had a significant response once the combination came in. So there was certainly a worsening of tumor burden and then marked improvement. So I think the phenomenon is real. And that's something that we, as clinicians, should not only provide education about but always be aware of that, particularly in this disease with certain agents. I think in terms of disease burden, I think that's an important consideration. That's certainly something that we have learned from this trial. And we didn't go into the study thinking that, that necessarily should have been a stratification factor. But certainly, I think it gives us room for thought that in designing future trials, this should be a consideration.

Dr. Khushalani and I have a lot of experience in pseudoprogression over some years with immunotherapy, but I don't know if you looked at all of the sites worldwide, whether it may vary by site, that the alarming appearance of that crescendo of the immune response couldn't have the result. It appears that there were a number of patients taken off study because of this. And I would say that it doesn't take a whole lot of patients being taken off at that point to significantly impact especially objective response rate, but also the complete response rate.

So the second part of Peter's question was Dr. Midgen, what percentage of the CSCC population are locally advanced and again, maybe recap on the importance of being able to treat that population. There is obviously a [ document ] of patient's who die of metastatic disease, but could you speak to also the importance of treating locally-advanced disease?

Right. And that's actually a misconception. Again, hearing metastatic tumor is a scary sounding and implies that this is the worst-case scenario, but a very large percentage of these patients are the locally advanced patients. And if you combine the locally advance with just some small amount of like lymph node and the neck involvement, you're talking about the greatest percentage of morbidity and mortality because you can get direct tumor extension intracranially, and that's a very common scenario to cause death. So it's very much a misconception that the metastatic disease is worse. And in terms of numbers, I mean, before you become metastatic, a lion's share of these cases, you become locally advanced. It's much less common to have a -- and does occur but a very small primary and then end up with metastatic disease. So the numbers are actually quite large.

No, I would agree. I think roughly speaking, 75% of tumors sent to me in this disease category tend to be locally advanced. And then the remaining 20% to 25% would be what we would refer to as metastatic and that would include regional nodal disease based on definitions both within EMPOWER as well as CERPASS, and of course, [ disinmetastatic ] disease, where it's primarily lung, liver and bone metastatic involvement.

[Operator Instructions] This question comes from the line of Allison Bratzel with Piper Sandler.

So first, just a follow-up question, kind of a clarification, just to make sure I understand that the time lines for communication around a BLA path and CSCC. I think from the response to a prior question, it sounds like the plan is to include more mature CERPASS data in the melanoma filing in second half '24. So presumably, we could expect to see more mature durability data before then. But that's an important point. So I just wanted to make sure, did I hear that correctly? And then just secondly, can you help us understand the typical delta for investigators as responses versus central assessments in melanoma? And just how we should be thinking about that heading into the IGNYTE data next year? And what gives you confidence you'll be able to complete those central assessments along with time lines you outlined?

So with regard to the first part, we were -- as I stated, the FDA has always indicated that they would wish us to include all the data with RP1 in skin cancer and a BLA filing in whatever setting we were seeking or trying to seek approval, and that remains the case. And we will include the most mature data available in that filing. The FDA will certainly not want to see data, which is by that point, over a year out of date. So we will provide more updated data from SURPASS in support of the melanoma filing. And once we have that more updated data we will determine what we think the pathway might be forward in CSCC specifically. But as I said, until we have the data, we can't speculate about exactly what it might show other than it by definition, will be more mature than the data we currently have, and the time-based endpoints do take considerable time to mature. With regard to the second part of the question in relation to central versus independent review, we do not yet have and haven't analyzed the investigator [ assessed ] response data, the primary endpoint was center reviewed. However, at high level, the number of responses by central review are, I think, very similar to independent assessment. And if anything, the number of CRs maybe a little bit higher, not wondering about a split between arms by center rather than local review. And I think that is because the center review is fully taking into account the totality of the data, including biopsy and other data along with just scans and photographs in coming to a central determination. So we -- the center review process for melanoma is a little bit more straightforward in CSCC. We followed from Regeneron and used WHO criteria for clinically assessed lesions from photographs and RECIST criteria for radiologically assessed lesions on CT, which is a little bit complicated. For melanoma, it's all just RECIST, which makes it more straightforward. And we have every confidence that the center reviews will proceed efficiently, effectively and in good time for the intended BLA filing in the second half of next year.

Our next question comes from the line of Kaveri Pohlman with BTIG.

Two for me. Of course, CERPASS, besides tumor burden, can you tell us anything about patients with visceral disease and how RP1 performed in those patients? And do these updates change anything for the ARTACUS trial, especially in terms of enrollment criteria for tumor burden and the overall development path?

So we haven't -- we only had the data from CERPASS for a very short period and haven't delved into it in huge amounts of detail as yet because we just haven't had the time to do so. However, as the various KOLs indicated, CSCC is a largely loco-regional disease, with much more rarely visceral or distant tumors. There are certainly patients who had visceral lung in particular, and bone as Dr. Khushalani mentioned in the study, and those -- and patients with responses in patients with said visceral disease. However, as Dr. Khushalani also said, this is in the backdrop of effective underlying therapy. And so it's hard to dissociate the exact contribution of RP1 to those effects. But overall, we haven't done that analysis as yet in line with how the disease presents. There's a relatively small number of patients with visceral disease unlike in melanoma, which is a much more widespread disease and where patients tend to die from that widespread rather than loco-regional disease. I'm sorry, I don't remember the second part of the question articles. Oh, ARTACUS. Thank you very much, Dr. Wong for reminding me. So the ARTACUS presentation is a little bit different. These are generally patients who have not had systemic therapy because there isn't any systemic therapy to already give to these patients. And these are patients that generally progressed after surgery and radiation. And as a result, they have less disease than in the CERPASS population. But Dr. Midgen also would like to comment, I think, on that, too.

Yes. The transplant patients that are immunosuppressed are such a challenge because that immunosuppression will just drive them to become very frequent formers of these cancers. And in terms of even having multiple 1-centimeter lesions, you know that when -- if you try to remove those surgically, they're going to pop additional ones and so on, it's just going to be eventually, for some of the transplant patients, an overwhelming process and can lead to their death in a good percentage. As I said earlier, you get a transplant. Hopefully, your transplant surgeon says that your skin cancer that you're going to get is likely to become your biggest problem and could kill you.

I would make one very quick further comment on higher tumor burden patients. The CERPASS data does show that RP1 plus cemiplimab can treat high tumor burden patients. But those high tumor burden patients are at just higher risk than the lower tumor burden patients and therefore, probably respond a little less frequently. And the problem was not having high tumor burden patients in the study per se, but there was a big imbalance between the arms due to statistical sort of bad luck and there was not room to also have that as a stratification factor in a relatively small study. But I do think, as Dr. Khushalani said, it is a key finding from the study, that in future randomized studies in CSCC probably it would be sensible to stratify for tumor burden as much as possible.

Absolutely.

Thank you. At this time, I'd like to hand the conference back over to Mr. Philip Astley-Sparke, for closing remarks.

Thank you. I'd actually like to end the call today by asking our key opinion leaders to provide a key summary and the key takeaways from all the data we presented today, if we relate it to real-world application in the clinical setting in their practices. So let's start with Dr. Khushalani?

Sure. I think I've already highlighted some of the comments that I made earlier. I think one of the takeaways obviously, with -- the primary endpoints not being met, you have to try and understand additional contributing factors. So what can we actually take away from a really important trial like this? I think the complete response rate is very impressive, particularly in the locally-advanced setting. I think that to me was one important takeaway with the stringent criteria that the study had outlined at the onset itself. And at least I believe that achieving a deeper response in this disease will likely translate into longer-term durable disease control. And I think that's what we are trying to achieve for our patients. So obviously, I can't predict what the future is going to be, and therefore, seeing these patients and following them out becomes critically important for all investigators to stay the course. That would be certainly one very important takeaway. The other thing that we probably didn't talk much about, but certainly deserves further scrutiny and investigation and thought, is that even on the control arm of cemiplimab, the complete response rate appears to be higher than what was previously reported on the EMPOWER study. And how does that impact our assessment of the benefit of combination if we are truly to understand that. Again, I want the sponsors for, again, the stringency and the encouraging of investigators to do biopsies for patients wherever feasible to actually prove or disprove whether this was a complete response or not. So that was one of the most important takeaways that I took from the study. Thank you.

Thank you very much. Dr. Midgen?

Thank you. So imagine a time from a physician's perspective that a patient comes in with a very large, locally-advanced lesion, it's fungating and the patients in really bad shape mentally and physically. And looking at this data in locally advanced, especially with a greater than 2x likelihood of complete response in the combination and you're having a discussion with the patient and you know that cemiplimab is already approved and they can get it the same way as with cemiplimab. When you talk to a patient, when I talk to a patient, if I can tell them, you're going to have greater than twice the likelihood of a complete response by coming in for the intratumoral injection, I just can't imagine based on my long experience with this, having many patients saying, I'll take just a single agent, and I'll less than half the likelihood of response. So the impact on our care of these patients is likely to be substantial. And again, I can't imagine too many patients turning down the proposition of combination therapy because of such a great difference between the two.

Dr. Wong?

Thank you very much for inviting me, and it's a pleasure to be here. RP1 plus cemiplimab is safe. It is efficacious and subgroups, which are extremely difficult. And I'll speak to Dr. Robert's presentation on the ipi and nivo refractory patient. Ipi/nivo was down the top line, most efficacious for potent immunotherapy and yet in that group to show efficacy. I applaud Replimune for working in an extremely difficult area of rare skin cancers, Merkel, cutaneous squamous, angiosarcoma, who are refractory to a top line, first-line immunotherapy and definitely showing a signal. I believe this strategy has legs and I look forward to what the future will hold for us.

Thank you, Dr. Wong. And lastly, Dr. Robert, we haven't had many questions on melanoma. I remember in fact, Dr. Robert's institution involved in both part and the melanoma study. So please feel free to comment on both.

Yes. I think this combination really appeared as a highly and uniquely promising ratio between the [ CCT ] and the efficacy in these 2 contexts. And I think Replimune is the only company who care to see comparisons if we go out to propose something uniquely to patients who are fairly [ vulnerable ] and this is -- I think it means something. And I can tell you, I won't repeat what I already said, but I can tell you that if I had the possibility to use this combination today, I would prescribe it to several patients every week. So I think it's really going to [ prosper ] and to continue.

Thank you very much. And with that, we'll close out this call. Thank you, everybody, for listening in, and enjoy the rest of your day.

This concludes today's conference call. Thank you for your participation. You may now disconnect. Everyone, have a wonderful day.