Good day, and thank you for standing by. Welcome to Replimune RP1 up, Program Update conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there'll be a question and answer session. To ask a question, you'll need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. 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're running with RP1 in multiple skin cancer settings. Before we begin, I need to highlight our forward-looking statement. On slide three, 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 from sites all with considerable experience of using our products. Professor Michael Migden, Global PI and Co-Chair of the SURPASS Steering Committee, from the Departments of Dermatology and Head and Neck Surgery at MD Anderson Cancer Center.
Professor Caroline Robert, Co-Chair of the SURPASS Steering Committee, Head of the Dermatology Unit at Gustave Roussy, and Co-Director of the Melanoma Research Unit at INSERM Paris-Sud University, also an investigator site on the IGNITE study. Dr. Nikhil Khushalani, Vice Chair of the Department of Cutaneous Oncology at the Moffitt Cancer Center and the Leading Investigator on the SURPASS study, and Professor Michael Wong from the Department of Melanoma Medical Oncology at MD Anderson Cancer Center, Leading Investigator on the IGNITE study. Slide 4 shows the agenda. Following an overview section, the second section covers our SURPASS study, frontline cutaneous squamous cell carcinoma, comparing RP1 plus cemiplimab against cemiplimab alone. The first section covers supporting non-melanoma skin cancer studies, as well as for the first time, the full population from our study, anti-PD-1 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 broad skin cancer franchise, with the studies being run with registration intent in first-line cutaneous squamous cell carcinoma and anti-PD-1 failed melanoma to the fore. We are also running studies in anti-PD-1 failed non-melanoma skin cancers, and the ASKA study in transplant patients with skin cancers, data 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 RP1 in cutaneous squamous cell carcinoma. On slide 7, in summary, in our SURPASS study in first-line cutaneous squamous cell carcinoma, the primary study endpoints were missed with a p-value of less than 0.025 being the path of success for each of the 2 endpoints of overall response and complete response tested separately.
However, we showed the addition of RP1 to cemiplimab led to 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-PD-1 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-PD-1 alone. The improvement in durable complete responses we've seen in SURPASS also supports our study with Incyte in a 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 ASKA study in solid organ transplant patients, clear monotherapy activity has been shown in this very difficult to treat population, with a 35% overall response rate.
We are also reporting today a 30% response rate in anti-PD-1 failed non-melanoma skin cancers, consistent with the signal we've seen in the larger anti-PD-1 failed melanoma study. Last but not least, in our IGNITE melanoma study, in anti-PD-1 failed melanoma being run with registration intent, we're on track to show 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 in concept has recently been agreed with the FDA. With a favorable safety profile, we believe the breadth of our data points to the emergence of RP1 as a potential new treatment option for a variety of hard-to-treat skin cancers. I will now hand over to Dr.
Khushalani to describe the unmet need in 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-to-1, and more recent data suggests that this is actually closer to 1 is to 1. The vast majority of these patients present with small, localized disease and remain within the domain of the dermatologist. However, approximately 3%-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 keratoses, that are related to sun damage and ultraviolet light exposure. The vast majority, as anticipated, develop on the scalp and the head and neck region. This is predominantly an external disease, an 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 increase 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 two FDA-approved agents, cemiplimab and pembrolizumab, that are considered standard of care within this population. As shown in this slide, that each of these has an overall response rate of approximately 40%-50% in previously untreated patients.
Importantly, only about 12%-20% of these patients achieve a complete response, i.e., complete resolution of evident clinical disease. 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-PD-1 agents, and options for subsequent lines of therapy tend to be limited, for example, chemotherapy or anti-VEGFR 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 a hundredfold risk of developing squamous cell carcinoma of the skin, remains very challenging because anti-PD-1 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. Migden to further discuss the primary results for SURPASS.
Thank you, Dr. Khushalani. Good morning. Next slide. This is slide 12. The SURPASS registration-directed phase ll study in CSCC enrolled 211 patients, randomized 2 to 1 to receive the combination with RP1 versus cemiplimab alone. 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 one, we needed a P of less than 0.025. It was 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 the RP1 as to what anti-PD-1 alone can achieve.
While the ORR was very similar between the arms, with around half in both arms responding, for reasons that we will, possible reasons we will discuss, the CRR was substantially improved with RP1 plus cemiplimab, with a 38% complete response rate, with the combination as compared to a 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 one or two patients.
Among the 83 patients with locally advanced disease, the complete response rate was increased to 48% in the combination group, versus 22.6% in the monotherapy group, which is a greater than two times higher rate, which has clinically impactful results as it's 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, although this wasn't a pre-specified analysis. Immature data also shows that the duration of response was improved with the combination, with a hazard ratio of 0.45 currently, as would be expected with an increased rate of CR.
It was also seen that RP1 plus cemiplimab appeared 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 clinical meaningfulness for patients with challenging to treat disease, which speaks to the power of what the combination can achieve.
It's 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 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 cm in the combination arm, versus only 9 patients in the monotherapy arm, which is around twice as many based on 2-to-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 intent-to-treat population. The objective response was very similar, but a clinically meaningful statistical increase in complete response, which just missed the level of statistical significance needed on the study due to the dual primary endpoints.
It is notable how close this was with one patient with a CR, which wasn't confirmed per 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 0.035. However, the increase in CR rate seen and the increase in the proportion of CRs is highly clinical meaningful, meaningful, especially from my perspective, as it is CRs, which I'm really trying to achieve, and that are the harbingers 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 CR seen. The more than doubling in the CR rate in the locally advanced setting 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 if we move to disease burden, we'll again see a similar trend with objective response rate, but increase 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 imbalance, it should be noted that the control arm sample size is very small. We can also see that for less than 10 centimeters, there is an improvement in objective response rate, and it could be that the enrollment imbalance or 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 0.0, excuse me, 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 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 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 seeking for to achieve for my patients, and we're achieving a complete 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, and particularly the 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. Migden. Next slide, please. So 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 five most visually impactful CRs on the cemiplimab arm, and this is out of a total of eight patients who had visibly detectable disease that was identified by photographs that were meticulous in 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, a patient with a modest-sized tumor behind the left ear 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, 1 behind each ear, 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. Migden 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 three 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, you know, 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 had their complete resolution.
And then also, what about patients when they get to that kind of peak in terms of a very disturbing look, very frightening, and will they come off? And in fact, we did see patients that had 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 SURPASS summary and conclusions. The RP1 plus cemiplimab combo provided 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 is 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. This is now Robert Coffin, Chief R&D Officer at Replimune. And following from that presentation of the data, to which Mike indicates that while we've shown a very clear clinical benefit of RP1 combined with cemiplimab, the data, as Mike just said, really does require 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.
I'll now hand over to Dr. Mike Wong of MD Anderson to provide an update on our IGNITE study, first on the safety front, and then data in patients with non-melanoma skin cancer who have progressed on prior anti-PD-1 therapy, which also remains a significant unmet medical need. Over to you, Dr. Wong.
Thank you, Dr. Coffin. It is my honor and privilege to present to you the initial data on evaluable 30 patients who on the IGNITE data concerning patients with non-melanoma skin cancers. Dr. Robert, later on in the program, will speak to the patients who have melanoma. The next slide, please. This slide, number 31, talks about the treatment-related adverse events for skin cancer patients treated with RP1 combined with nivolumab. I note that this does not include patients who received RP1 monotherapy or RP1 plus nivolumab, only those with RP1 and nivolumab. And this table includes all the adverse events which were seen on 5% or more of these patients, whatever grade these were seen. I point to you the dearth of Grade 3, Grade 4 toxicities, with Grade 3s in the single digits.
The top line three most prevalent toxicities include fatigue, chills, and pyrexia. Next slide, please. RP1 combined with nivolumab in anti-PD-1 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, number 33, is the overall response rate of a subgroup of these 30 patients. 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 NCI designation, and all these patients failed while on the 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 caution. These, again, are small numbers, but our task here is to really look and see if there's a signal here of efficacy. 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. 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.
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. 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 the tumor burden in each individual patient is represented here. You will see that some patients respond as soon as 60 days. However, you'll see with some of these showing an increasingly downward slope of curve over time, that 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. You also see, and Dr.
Migden spoke to this, that some patients show an upward inflection followed by downward trend of the spider plot showing an initial pseudoprogression. So this is a response that we're seeing in this 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 patients. Again, these are for exploratory purposes, but 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 a complete response. And 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-PD-1 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.
What you're seeing here is an individual who has a major disfiguring, erosive tumor on the vertex of his scalp. He had received a cemiplimab therapy, and his best response to cemiplimab therapy was progressive disease. And therefore, and he also met 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.
In the context of skin cancer, the concept of locally advanced is extremely important because left unattended, these will result late, basically 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 mutilating, 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-PD-1 immunotherapy, achieved a, a meaningful response, a 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 see this man, this lady unfortunately had a disease which resulted in a series of a crop, we'll say, of in-transit skin lesions, palpable, growing. In my own personal practice, it's not uncommon for patients to call me up every three days with a new nodule 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 2.5 months after their 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 nivolumab provides clinically meaningful and durable benefit in patients with anti-PD-1 failed immunotherapy.
I point out, as in the previous cases, these clinical pictures will be available both online and with the appendix of the document you received 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 said previously, and I'll end with this line, RP1 nivolumab is well tolerated in these patients. And on that, next slide, please. I will hand off to Dr. Migden, who will speak about the ARTACUS trial. Thank you.
Thank you, Dr. Wong. Next slide. So, the ARTICUS 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 100 times the incidence of skin cancer in these transplant patients, and that greater than 90% are a 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 ca-Kaposi's, but these are less frequent. Management of locally advanced and metastatic disease has spread to the skin and soft tissues, and solid organ transplant is not well established... You know, there's no real easy way to give a sync-- to give a immunotherapy, such as an anti-PD-1, because it puts at risk loss of the graft. Next slide. Patient demographics. This was a male-predominance older population. The allograft type 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 not 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 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, 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. We really don't have anything much at all to offer them except for very ineffective alternatives. Looking at the responders, tumor type, three-quarters CSCC, one-quarter Merkel cell, and then stage at study baseline, three-quarters locally advanced, one-quarter 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 patient who had a CSCC primary at baseline subsequently formed while on treatment of basal cell. But they both, the baseline target lesion 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 of a post-radiotherapy baseline and a complete response at 13 months. The middle panel is paraspinal muscle lesion at the C1, C2 vertebrae, 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 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 palpated the photograph at the bottom, you could feel his teeth clearly through that skin graft. There was no more indurated, bulging tumor. Next slide. 3 additional examples: a submental lesion at baseline and complete response at 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 had 3 invasive squamous cell carcinomas at baseline, and then 3 months, complete response. And not only was there, you know, nothing palpable on that scalp, but it was very hard to find where the tumor had ever been. Next slide. So in conclusion, summary, this is the first clinical trial assessing single-agent RP1 in organ/hematopoietic cell transplant patients, and this was up to 2-week treatment for up to 2 years. This is in patients having advanced skin cancer. RP1 monotherapy showed a clear anti-tumor activity with objective response rate of almost 35%, and that confirmed complete response rate around 22%.
No evidence of allograft rejection was observed, including kidney 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, 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 IGNITE study in patients with anti-PD-1 failed melanoma. We are on slide 53 now. Let me remind you the context, the medical context. In spite of the huge progresses that have been made in the field of metastatic melanoma with immunotherapy and targeted therapy, as you know, unfortunately, not all patients respond to immunotherapy when they have failed anti-PD-1 therapy. In case they have melanoma, that is BRAF mutant, which is about 50% of the patients, they can receive an BRAF/MEK therapy. But this treatment gives high level of response, but the responses are transient, and patients eventually develop resistance. They can also receive anti-PD-1 plus anti-CTLA-4. That's the regimen IPI/NIVO, which gives about 30% of response in these patients.
But you know that this is at the price 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 ll trial with TIL therapy, like lymphocytes that are re-injected 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 the standard treatment. On this slide 54, you see the design. So this is a combination of RP1. The first dose of RP1 is injected alone, and then the seven 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 RECIST criteria. What is also noteworthy is to look at the criteria for CP, well, CPI failure. We require that the patient had received at least 8 weeks of anti-PD-1. The progression must have been confirmed by 2 subsequent CT scan, and the patient must be on PD-1 when they develop resistance. This is even more strict, stricter than the recently edited criteria by the CT, where a patient with PD-1 failure, but after they stop PD-1 and they develop their resistance, can be enrolled in the trial. We know that in this situation, you can when you re-challenge with anti-PD-1 as a single agent, you may have responses.
But in our situation, patients were still on anti-PD-1, so if you give just anti-PD-1, you, you cannot see any. Next slide, 55. The demographics of the patients. What's very important to look at in this slide is the proportion of patients with really advanced disease, stage 4 M1c/d, which means that they have systemic metastasis, internal organ metastasis, more challenging, more than half of the patients. We also see that patients have received anti-CTLA-4 plus anti-PD-1 for 46% of them, which is really the most difficult situation to rescue. And although very important to note the percentage of patients with high LDH 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 166 patients, and you see the first 16 patients, 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 population, subpopulation. It's very consistent. The most challenging situation, secondary resistance, where the patients have a primary resistance, but where the patients have not demonstrated any response to PD-1. It's just on the right, you see 27% of patients. In the patients who have received previously anti-PD-1, anti-CTLA-4 plus anti-PD-1, 26%, so very close to 30%. Very consistent, close to 30% of response rate in all these patients subpopulation. On the slide 57, we see what you 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 metastasis. And we also see that responses and even deep responses can be seen in patients with very adverse stage four M1c. Next slide. This is the swim 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, where you have a sort of integration of the post-treatment graphs.
You see the duration of response, and you see the evolution of the target lesions over time. And you see that for some patients, unfortunately, it doesn't work like a 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 goes up a 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 metastasis. 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 lesions.
That's very important because you see that the lesions that have not been injected also have a very favorable outcome, decreasing the size in the responders, meaning that we have a distant effect... we don't see the response only in the injected lesions. Next slide. Duration of response. So after more than two years, you see that close to 80% of the patients are still responding, so very durable responses. Next slide. PFS and OS for all patients with a nice plateau in progression-free survival and with the overall survival on the right. On the next slide, slide 63, you see that we can break down the overall survival by response, response or non-response. We include the patients who have any response type.
You see that the survival curve is remarkably flat and high, and of course, it will be less positive in the patients who do not respond. Next slide. We see that this highly promising OS response can be seen across the disease, the various subsets, 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 one-third of the patients who experience a response. We see that, about, 26.4% exactly of patients respond when they have received ipilimumab plus nivolumab. So this is very important information. It is highly challenging population.
We see that 100% of the response lasts more than six months, and a median duration of response of more than two years. We see response across all the groups enrolled, 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 a very, very attractive, safety- I mean, ratio between the safety and the efficacy. If you compare to the very few treatments that have shown some efficacy and not higher in the same population of patients. So now I'm going to hand, over to, 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-PD-1 failed melanoma. So on the current SURPASS 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 for 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-PD-1, sorry, prior anti-CTLA-4, was one of unmet need. Secondarily, the FDA agreed with our proposed confirmatory trial concept in support of a potential submission for accelerated approval based on the IGNITE data. This study will be a two-arm study comparing RP1 to RP1 plus nivolumab with investigator's 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 central review data by RECIST 1.1.
That all patients should be followed for at least 12 months, which is the same, same as the primary analysis to this trigger for the study. And finally, that responders should be followed for 6 months following response initiation. On slide 68, this is the schematic of the confirmatory trial design, which I just described. As I said, this will enroll anti-PD-1 progressed melanoma patients with investigator's choice of control therapy, from a top-defined list of control therapies, with 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 SURPASS 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 enhanced treat settings such as solid organ transplant recipients and anti-PD-1 failed melanoma and non-melanoma skin cancers, demonstrated compelling efficacy with an attractive safety profile. Initial snapshot data from all 156 anti-PD-1 failed melanoma patients demonstrate that RP1 plus nivolumab maintains transformative potential in this high unmet need setting with limited treatment options. A BLA submission and the accelerated approval pathway is intentionally made in the second half of 2024, based on the primary analysis data, which is triggered in March 2024.
The framework for confirmatory study to be underway at the time of the filing has been agreed with the FDA.
... Turning to the pipeline, with strong data with RP2 in uveal melanoma presented at a plenary presentation at SMR in November, we are planning for a randomized control study in second-line uveal melanoma. This provides a relatively rapid path to result in a randomized controlled trial, as well as a 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 and RP2 registrational 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 provide value for multiple meaningful data and regulatory catalysts. With that, I would like to turn the call back to the operator for questions.
Thank you. As a reminder, to ask a question, you'll need to press star one one on your telephone. To withdraw your question, please press star one one again. Please wait for your name to be announced. Please stand by while we compile the Q&A roster. One moment for our first question. Our first question will come from the line of Jonathan Chang with Leerink Partners. Your line is now open.
Hi, guys. Thanks for taking my questions. I have two. One, is there a path forward for RP1 and CSCC, and what would that look like? And two, how should we be thinking about whether and how SURPASS results implicate the opportunity in melanoma from both a clinical and regulatory perspective? Thank you.
So on the first point of what the potential path forward is in CSCC, I do think that the current data already does show strong clinical benefit, even though the primary endpoints were not formally met. However, as multiple others 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 all have also have the 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 the 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 RP1 plus cemiplimab has demonstrated contribution of components, with clear benefit of RP1, combined with anti-PD-1, compared with anti-PD-1 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. They're different diseases, and you can't over cross-compare data from those different settings. But we certainly think that, on overall, the SURPASS data is supportive of, as I said, contribution of components, which should also be supportive of a contribution of components in melanoma, too.
Got it. Thanks for taking the questions.
Thank you. One moment for our next question, please. Our next question comes from the line of Anupam Rama with J.P. Morgan. Your line is now open.
Hey, guys. Thanks so much for taking the question. Can you outline how you think about the timelines for additional data cuts for SURPASS 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, you know, durability, PFS, these types of data would be accepted by regulators, given these were secondary endpoints?
So we can't formally comment yet on the exact timing of when the next data cut will be. Beyond that, we would intend it 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, 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 SURPASS, IGNITE, and in fact, ARTICUS, too.
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. 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. The last point related to regulators' acceptance of the secondary endpoint data as part of a 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.
Thank you. One moment for our next question, please. Our next question comes from the line of Evan Segerman with BMO. Your line is now open.
Hi, guys. Thank you so much for taking the question. So I would love for you to just talk about the quality of responses you saw in CSCC, any abscopal effect 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, you know, in the, you know, in prior experience, CRs usually translate into OS. How are you thinking about it, and what do you hope to see, you know, as this data continues to, return progress? Thank you.
Right. So the first part of that question, let's turn that to our KOLs who've been treating the patients. Start with Dr. Middleton.
Yes, in regards to the quality of the response, as you saw in those cases that were, you know, very overwhelming, large, fungating lesions with discharge that would cause patients to, you know, be isolated and so on, to have them, in a more consistent fashion on the combination, get to a complete resolution, you know, has a tremendous impact. And the reliability of seeing that occur more frequently, is, you know, is of great value to these patients.
And then in terms of, you know, this is in a context where, as I alluded in pseudoprogression, because it appears that there's a more vigorous response with the combination of these therapies, you know, you have to be educated and, talk to your patients and have the confidence that, you know, 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 it's progression. And I think that definitely impacted or has potential to impact the objective response rate.
This is Nikhil Khushalani . I could add to that as well. I think, you know, at 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 develop 9-12 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.
Another part of that question was to do with the abscopal effects. Obviously, CSCC is very much a local regional dominant disease. This is in a front-line setting, so it may not be the best setting to demonstrate the 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 evidence of systemic benefit coming through in the durability of response.
It's so, it's so important to recognize that the sound of a 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 local 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 would 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 two drugs together, because 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 that, 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.
Yeah, and just very briefly back to abscopal effect, as Philip said, this disease is not the optimal setting in which to demonstrate clear, abscopal effect. And it's also a first-line setting where cemiplimab alone is an effective drug, even though we do think we've shown improvements over cemiplimab alone. But if obviously, one refers to the melanoma data, particularly the spider plot which Dr. Robert showed of injected, uninjected lesions, we see 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 clearest separation of this relatively early time point. For the whole population, as stated by Dr. Migden, 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 and response over time. With regard to OS and PFS, those endpoints would tend to mature more slowly and behind duration of response.
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 curves would have extraordinarily small numbers of events to contribute to those. So it's just too early as yet.
However, as duration of response is already showing a good benefit, we do anticipate that with much more mature data, when it is appropriate to do a, an analysis of a PFS and OS, that we may also see good separation there, supportive of the totality of the benefit, and a true durable clinical benefit is indeed being achieved on the combo arm as compared to the monotherapy.
Thank you. One moment for our next question, please. Our next question comes from the line of Roger Song with Jefferies. Your line is now open.
Great. Thanks for taking the question. A couple questions from us. Maybe first is the path, understanding you are still waiting for the mature data to inform the filing strategy. But just curious, given you do see the statistical significance in certain subpopulation, like the locally advanced and the high, low tumor burden, how likely you can file the, the CSCC in those subgroups? Kind of that's number one. And number two, for the IGNITE, understanding you are combining the early IGNITE cohort versus the registrational IGNITE cohort, 16 + 140, is that the intent for you to file based on, based on that 156 patient or, versus the 140 patient in the later cohort? Have you got the FDA agreement on this? And I have a quick follow-up after those two. Thank you.
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 a third of patients responding, however you cut the data. 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 SURPASS 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.
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. But 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, one sees 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 of the path forward. But time will tell. It is immature data, and we've just got to wait until it properly matures without speculating too much at this point.
Excellent. Thanks, Rob. Maybe just last question regarding the confirmatory study for the PD-1 failed melanoma. Understanding you will need to start the 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 take into account the potential new therapy like a TIL will be part of the physician choice? Thank you.
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 it is underway and that we have enrolled some reasonable number of patients at that point without defining exactly what that is. On the complementary 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 or 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 investigator's choice list.
Great. Thanks for all the comments. That's it from us. Thank you.
Thank you. One moment for our next question. Our next question will come from the line of Peter Lawson with Barclays. Your line is now open.
Great, thanks for taking my question. Just, I guess I got a question around the imbalance that you saw with the baseline tumor burden, if that's a kind of an issue of CSCC, or if that wasn't something you were thinking about controlling for. And then, just the percentage of patients that would fall under the kind of the classification of locally advanced disease in CSCC, and then the CR rate, whether you think that over time will mature and deepen and you'll kind of get a potential of having a statistically significant CR rate. Thank you.
So the first part of the question, Dr. Macon, relates to the imbalance in the study as it relates to tumor burden and whether or not you felt that stratification is a relevant one in this disease and whether or not it could have ameliorated the result.
Absolutely. Larger than 10 cm tumor burden, whether it's a combination of lesions or just a single or double, very large lesion, I think widely known with my colleagues to be more challenging to treat. And unfortunately, a stratification into locally advanced and metastatic and prior line of therapy didn't prevent this imbalance. But the fact that we ended up with so much more tumor burden in the group that we would have liked to have, you know, just the equal amount, certainly when you're, you know, 1-2 patients shy of getting to an endpoint can make a huge difference. And I expect that it definitely contributed to that.
I think with further time, because they are more difficult to treat, that we hopefully will overcome that derogatory effect of the imbalance.
Dr. Kishida, any further comments on that topic? 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. You know, in my practice, we've seen 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 effect in melanoma as well, I would probably say that the effect that we saw 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 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, 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 this 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 pseudoprogression over some years with immunotherapy, but I don't know if you looked at all of the sites worldwide, whether and it may vary by site, that the alarming appearance of that crescendo of the immune response couldn't have resulted. It appears that there were a number of patients taken off study because of this. 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. Middleton, 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, and obviously a dogma that patients die of metastatic disease, but could you speak to also the importance of treating locally advanced disease?
Right, and that's actually a misconception. You know, again, hearing metastatic tumor is scary sounding and implies that, you know, this is the worst-case scenario, but very large percentage of these patients, you know, are the locally advanced patients. And if you combine the locally advanced with just some small amount of, like, lymph node in 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, you know, before you become metastatic, in a lion's share of these cases, you become locally advanced. It's much less common to have a...
It does occur, but a very small primary, and then end up with metastatic disease. The numbers are actually quite large.
I would agree. I think, roughly speaking, 75% of tumors tend to be in this disease category, tend to be locally advanced. And then the remaining 20%-25% would be what we would refer to as, metastatic, and that would include regional nodal disease based on definitions both within IMpower as well as SURPASS, and of course, distant metastatic disease, where it's primarily lung, liver, and bone metastatic involvement.
Thank you. As a reminder, to ask a question, you'll need to press star one one on your telephone. Please wait for your name to be announced. One moment for our next question. This question comes from the line of Allison Bratzel with Piper Sandler. Your line is now open.
Hi, good morning, and thank you for taking the questions. So first, just a follow-up question, kind of a clarification, just to make sure I understand that the timeline 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 SURPASS data in the melanoma filing in second half 2024. 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, you know, did I hear that correctly? And then just secondly, can you help us understand the typical delta for investigator-assessed responses versus central assessments in melanoma?
And just, you know, how we should be thinking about that, heading into, to the IGNITE data next year, and what gives you confidence you'll be able to complete those central assessments, along the timelines you outlined? Thanks.
So with regard to the first part, as I stated, the FDA has always indicated that they would wish us to include all the data with RP1 in skin cancer in 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 a 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 centrally reviewed. However, at a high level, the number of responses by central review are, I think, very similar to independent assessment. And if anything, the number of CRs may be a little bit higher, not worrying about split between arms, by central rather than local review.
And I think that is because the central reviewers fully take into account the totality of the data, including biopsy and other data, along with just scans, and photographs in coming to a central determination. And so the central 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 central reviews will proceed efficiently, effectively, and in good time for the intended BLA filing in the second half of next year.
Thank you. One moment for our next question. Our next question comes from the line of Kaveri Poleman with BTIG. Your line is now open.
Yes, good morning, and thanks for taking my questions. Two for me. For SURPASS, you know, besides tumor burden, can you tell us anything about patients with visceral disease and how RP1 performed in those patients? And, you know, do these updates change anything for the ARTACUS trial, especially in terms of enrollment criteria for tumor burden and the overall development path? Thank you.
Okay. So we haven't, we have only had the data from SURPASS 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 local regional disease, with much more rarely, visceral, more distant tumors. There are certainly patients who had visceral, lung in particular, and bone, as Dr. Khushalani mentioned, in the study, and patients with responses in patients with said visceral disease. However, as Dr. Khushalani also said, this is in the backdrop of an effective underlying therapy, and so it's hard to dissociate the exact contribution of RP1 to those effects.
But overall, and 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 local regional, disease. And sorry, I can't remember the second part of the question. Or maybe there was one more.
ARTICUS.
Oh, ARTACUS. So 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 really give to these patients. These are patients who have generally progressed after surgery and radiation, and as a result, tend to have less disease than in the SURPASS population. But Dr. Meakins 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, you know, even having multiple one centimeter lesions, you know that 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. You know, 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 SURPASS data does show that RP1 plus cemiplimab can treat higher tumor burden patients, but those higher 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, the key takeaways from all the data we presented today, as it relates 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, you know, obviously with the primary endpoints not being met, you have to try and understand, you know, additional contributing factors. 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. 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 IMpower study. And, you know, how does that affect, impact our assessment of the benefit of combination, if we truly, truly do understand that?
Again, I applaud the sponsors for, you know, 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. Migden?
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, the patient's in really bad shape, mentally and physically. Looking at this data in locally advanced, especially with a greater two time-- greater than two times 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 single agent cemiplimab.
When you talk to a patient, when I talk to a patient, if I can tell them, "You're gonna 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, "You know, I'll take just the single agent and I'll, you know, less than half the likelihood of the response." So the impact on our care of these patients is likely to be substantial. And I, again, I can't imagine too many patients turning down the proposition of combination therapy because of such a, you know, a great difference between the two.
Wong?
Thanks very much for inviting me. It's an honor and pleasure to be here. RP1 cemiplimab is safe, it is efficacious in subgroups, which are extremely difficult. And speaking to Dr. Robert's presentation on the IPI and NIVO refractory patient, IPI/NIVO was found a top line, most efficacious for whole immunotherapy, and yet in that group, you show efficacy. I applaud the Replimune for working in an extremely difficult area of rare skin cancers, Merkel, cutaneous squamous, angiosarcoma, who are refractory to 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, but in fact, Dr. Robert's institution is involved in both the SURPASS and the melanoma studies. So please feel free to comment on both.
Yes, I think this combination really appears as a highly and uniquely promising ratio between the toxicity and the efficacy in these two contexts. And I think Replimune is the only company who dare to be compared with IPI/NIVO or to propose something uniquely to patients who have failed IPI/NIVO, 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 do this combination today, I would prescribe it to several patients every week. So I think it's really going to continue.
Thank you very much. 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.