Good morning, and thank you for joining our R&D investor event. We are excited to have this opportunity to share with everyone a number of important data and strategic program updates. Before we begin, I need to highlight our forward-looking statement. On slide three, I'm Philip Astley-Sparke, Chief Executive Officer of Replimune, and I have with me today from management, Robert Coffin, our President and Chief R&D Officer, and Sushil Patel, our Chief Commercial Officer. We're also very pleased to have with us today several leading physicians to present data and provide their insights on our development plan. These include Dr. Kevin Harrington, Professor of Biological Cancer Therapies at The Institute of Cancer Research, London, and Consultant Clinical Oncologist at The Royal Marsden. Dr. Nikhil Khushalani, Chief of Medical Oncology at the Moffitt Cancer Center.
Dr. Muneeb Ahmed, Interventional Radiology Division Chief at the Beth Israel Deaconess Medical Center, Associate Professor of Radiology at Harvard Medical School, and president-elect at Society of Interventional Radiology. Dr. Tony Saab, leader of Gastrointestinal Cancer Program at the Mayo Clinic. Slide four shows the agenda, which will start with a brief further introduction from me, followed by three content sections. The first section will cover our plans to establish a major RP1 skin cancer franchise, starting with cutaneous squamous cell carcinoma, where we will provide a detailed overview of the indication and our thoughts in relation to commercialization. We will also be presenting updated data from the completed cohorts from the phase II IGNYTE trial that continue to support our registrational studies in anti-PD-1 naive cutaneous squamous cell carcinoma and anti-PD-1 failed melanoma.
Additionally, we're presenting today new RP1 data from the cohort being enrolled in anti-PD-1 failed non-melanoma skin cancer, and from the ARTACUS clinical trial with RP1 as monotherapy in solid organ transplant recipients with skin cancer. In the second section, we'll present on the feasibility of deep injections with a focus on injections into the liver as we look to establish franchises beyond predominantly superficial tumor types before presenting on the indications we intend to pursue with RP2/3 in the final segment. Moving to RP2/3, we have seen strong initial data with RP2, which supports the advancement of RP2/3 into mid-stage development in new and difficult to treat tumor types. As a result, we're announcing today a broad RP2/3 phase II development plan, including new clinical trials in squamous cell carcinoma of the head and neck, hepatocellular carcinoma, and colorectal cancer. Following the presentation, we'll be holding a live Q&A.
To ask a question, you'll note there's a question submission bar on your screen that will be open throughout the presentation this morning and during the Q&A session. We will collect those questions throughout the morning and take as many as time allows. All questions will be held until the Q&A portion of the event. Moving to slide five, we are continuing to make great progress towards our ambition of making our products a cornerstone of immuno-oncology treatment regimens as the most practical and effective way to initiate a systemic anti-tumor immune response. Our mission is to deliver transformational results for patients across cancers using tumor-directed oncolytic immunotherapy to induce a powerful and durable systemic anti-tumor immune response, resulting in quality survival and a chance for cure. Moving to slide six, we are the leader in tumor-directed oncolytic immunotherapy with three wholly owned programs.
As aforementioned, we plan to establish a broad-based RP1 skin cancer franchise and look forward to revealing data from two skin cancer registration studies in late 2022, early 2023. With a broad-based mid-stage development plan now in place for RP2/3 beyond skin cancers, the company has the potential to generate substantial revenues in the 2025-2030 timeframe. We've also made solid progress putting in place the building blocks to build an entity capable of transforming the immuno-oncology landscape. Our own manufacturing facility is fully operational, filling GMP batches, and comparability work to the contract material used in our clinical studies to date is largely complete. In addition, our Chief Commercial Officer and his team are continuing the planning process to ensure, if approved, our products are widely adopted in the marketplace. Finally, we have a strong balance sheet to execute on our vision.
As a reminder of our technology and MOA on slide seven, tumor-directed oncolytic immunotherapy is the use of viruses that when injected into tumors, partially or completely destroy them through virus replication, bursting the tumor cells open and exposing all of the released cancer antigens to the immune system in an environment of necrotic cell death. This leads to the activation of a patient-specific systemic immune response and the disruption of uninjected deposits. On slide eight, our platform is based on the herpes simplex virus, which we believe is an optimal viral species for oncolytic use, it being highly lytic inflammatory and having the ability to carry multiple immune-stimulating proteins into the tumor microenvironment to further amplify the immune response generated.
Our strain of HSV has been deliberately selected for its lytic properties in human tumor cells, and from all our products as our base platform, we express a fusogenic protein that greatly increases direct tumor killing, immunogenic cell death, and systemic immune activation. These design features ensure maximum presentation of antigen on the MHC of antigen-presenting cells. We then expressed various proteins from the virus intended to maximize co-stimulatory signals at the APC T cell interface to ensure optimal T cell priming. Our lead product, RP1, additionally expresses GM-CSF. RP2 additionally expresses an anti-CTLA-4 antibody to stop the negative feedback loop at the CD28/CTLA-4 axis, and RP3, two further immune co-stimulatory pathway activating proteins targeting CD40 and 4-1BB, which also leads to downstream inflammatory cytokine release.
Our confidence in our ability to establish a broad skin cancer franchise with RP1 is underpinned by broad activity across a variety of skin cancers as monotherapy and in combination with checkpoint drugs, including in the checkpoint refractory setting, where clear systemic long-term responses have been generated. RP2 has generated high rates of response in difficult to treat tumors as monotherapy and in combination with anti-PD-1 in checkpoint failed patients. Our intended program for RP2/3 is targeted patient groups that are relatively immune and sensitive and will be detailed later in the presentation. As such, moving to slide nine, we believe we have the ability to drive growth across all segments of an IO portfolio. To improve IO effectiveness in the anti-PD-1 naive setting, we have generated a very high rate of complete response.
We've always said from the get-go that our modality and products can result in high rates of complete response. It is these responses that transform lives, give patients the potential for cure, and relieve them of disabilities and/or disfigurements caused by disease. While this further supports our expectation for a positive outcome in our registration-directed studies, including our lead CERPASS study in cutaneous squamous cell carcinoma, we also believe that if our well-tolerated products are pushed earlier into disease courses, the rate of complete response could go higher still and result in many patients never developing the type of end-stage disease we are currently treating.
In terms of overcoming IO resistance, as mentioned previously, we're seeing activity in very hard to treat patients who have failed anti-PD-1 in a number of different tumor types, not least melanoma, where we've seen a high rate of durable response and where enrollment is ongoing in a study with registrational intent. Finally, in terms of turning cold tumors hot, we've seen activity in immune-insensitive tumors with RP2, including as monotherapy in uveal melanoma and salivary gland cancer. This data, combined with encouraging reproducible activity in patients with liver metastases and very poor prognosis, gives us confidence in moving beyond skin cancer to establish a franchise with RP2/3 in GI cancers and head and neck cancer, where underlying response rates to IO approaches alone are generally low. We are planning additional studies in each of these categories, which will be further detailed in the presentation.
I will now hand over to Dr. Harrington to summarize today's datasets with RP1, including improved data in our completed IGNYTE cohorts in anti-PD-1 naive non-melanoma skin cancer and anti-PD-1 failed melanoma. In addition, Dr. Harrington will present new data in hard to treat patients, supporting our broader RP1 skin cancer ambitions with first looks at anti-PD-1 failed non-melanoma skin cancer data and RP1 monotherapy data in transplant patients with skin cancers. Kevin?
Philip, many thanks indeed. If I could just maybe skip past the biography slide and go straight to slide number 12, please. Well, it gives me great pleasure to join you, and so I'm going to provide you with an update of data initially from the IGNYTE clinical trial, on which I'm privileged to be one of the investigators. That study looks at patients with melanoma, non-melanoma skin cancers, together with initial data with RP1 monotherapy in patients with solid organ transplants, with non-melanoma skin cancer. First, I provide you with the updated aggregate safety data from RP1 combined with nivolumab. Now, please excuse the fact this is rather a busy slide.
You can see from the summary in looking at the grade 3 and the grade 4/5 toxicities, that this treatment is extremely well-tolerated and that the side effects are generally a self-limiting constitutional flu-like illness, typical of a virus exposure that lasts between one and three days, with grade 3 events being seen relatively rarely. It highlights the potential of the tolerability of this agent to allow combination regimens. Next slide, please. First of all, I'm gonna take you through data relating to RP1 in melanoma and give you some updates on the data that you've previously seen, perhaps in earlier presentations. Here I provide you with an updated slide on slide 14, looking at the melanoma response data. You can see here across the top of the table, the labels indicating the various scenarios in which patients are being treated.
You can see the program covers cutaneous, mucosal, and uveal melanoma, and also covers patients with PD-1 naive and also PD-1 failed tumors. What you can see here that the data at the last cut in June 2021 were already quite mature, so any changes have been relatively modest in terms of the scale. But what I can reassure you of and I'm pleased to be able to announce that we've seen that there have been a further uplift in the documented overall response rate that has increased now in PD-1 failed cutaneous melanoma to 37.5% from the initial 31.3% that we've seen.
In mucosal melanoma, we've seen a PR, a partial remission, convert into a complete remission of disease. On the next slide, which is slide 15, I show you data from the spider or the spaghetti plot, and you can see here that the various categories of patients are picked out in color coding. What I'd like to draw your attention to first of all, is the depth and the durability of response, which continues to be excellent, and certainly for patients with anti-PD-1 failed cutaneous melanoma indicated by the red lines. You can see that there are very durable responses and durable treatment benefit. In fact, the outcomes appear to be rather similar, depending on whether or not the patient has had or has not received a prior PD-1 therapy.
I draw your attention also to the highlighted patient, that blue arrow in the middle of the slide. This is a patient who had achieved a durable period of minor response or stable disease, who gradually began to progress on single-agent PD-1 inhibition and was reinitiated on RP1 and demonstrated a further response. This is really a very impressive and intriguing result. Next slide, please. Here you see an example of a patient treated, having had prior exposure to anti-PD-1 and anti-CTLA-4. This is melanoma disease in a patient who has had progressive disease to those treatments. You can see here a series of scans for baseline, indicating the presence of lesions in many sites, both in the liver, the spleen, and also in the lung.
The injected lesion is highlighted in red in the second column, and you can see over time the evolution of a response in the injected lesion. More compelling, in the yellow circles, you can see in liver, in spleen, and in lung, in uninjected lesions, you can see a patient here who is developing an excellent response in all of these sites. The patient remains as an ongoing partial remission with no metabolic evidence of disease by PET scan, now out to over a year and a half, at 19 months, in fact. Next slide, please. In this relatively brief update, I have been able to show you that in patients with both naive and PD-1 failed melanoma, we've seen incremental improvements in the dataset since our last data cut, with additional responses observed, further deepening of responses, and impressive increasing durability of response.
The response rate in the anti-PD-1 failed cutaneous melanoma has now gone above one in three, further highlighting the potential for this therapeutic opportunity for patients. On slide 18, I highlight to you the plans for registration-directed study. The treatment of anti-PD-1 failed melanoma remains a considerable problem in the clinic, as you know, and as many as a half of patients initially treated with either PD-1 monotherapy or CTLA-4 PD-1 combination therapy will fail to respond to initial treatment or will ultimately progress on this treatment. The response rate to further immune challenge with anti-PD-1 therapies in this group of patients is only around 6%-7%, and there are as yet no approved therapies.
Therefore, we believe that the promising data with RP1 combined with nivolumab in these patients represents an important opportunity for patients, and Replimune has an ongoing registration-directed clinical trial in 125 patients with anti-PD-1 failed cutaneous melanoma. We're going to see an interim output from those data towards the end of 2022, and are optimistic that these will be positive data based upon the data I've already shared with you. Next slide 18, please, takes us on to the next topic for conversation, which is another important opportunity for RP1, non-melanoma skin cancers. Next slide 20, please. Again, in this rather busy slide, I show you data, looking at anti-PD-1 naive non-melanoma skin cancer, looking at the responses.
You can see in the red columns, that is the recent data, the updated data we're presenting to you, and in the other columns, you can see the data from June 2021. You can see that now the cohort is fully enrolled, as compared to when we last showed you these data. As with the melanoma data I've already shown you, we've seen incremental improvement in the response rates. Cutaneous squamous cell carcinoma is particularly of interest, bearing in mind the ongoing registrational CERPASS study, combining RP1 with cemiplimab versus cemiplimab alone. The overall response rate in this group of patients has increased from 60% to 64.7%. I want you to just pay attention to the very high rate of complete remissions, which we have seen is maintained at 47%.
The activity continues to be seen also in other non-melanoma skin cancers. Basal cell carcinoma, Merkel cell, and angiosarcoma, with activity being particularly apparent in the latter two, Merkel cell and angiosarcoma, both tumors of unmet need. This again highlights the potential broad utility of RP1 across a range of different tumor types. In the next slide, I will show you an example of a response to an extremely unpleasant cutaneous skin cancer. This is in fact the last patient enrolled in the RP1 plus nivolumab cohort, and you can see here. The patient presenting with a deeply unpleasant, deeply ulcerating lesion in the region of the left temple. Over the course of five months, you can see that this is evolving towards an excellent partial remission with every expectation indeed, that this patient may achieve a complete response.
Slide 22 gives you the summary of the waterfall plot data for these patients, and you can see the depth of response. Notice this isn't just in cutaneous squamous carcinomas, but you're seeing excellent responses to angiosarcomas and also Merkel cell carcinomas. The black circles indicate patients ongoing, and you can see many of the patients with complete remission remain ongoing, deriving further benefit. Slide 23 demonstrates the spider or the spaghetti plot. Again, really giving very impressive indications of the durability and the depth of the response here. I also want to draw your attention to the patient in the middle of the slide. You can see on the spider plot the growth of the tumor that's occurring out to 600 days, and then the patient being re-initiated after a progressive disease episode, demonstrating a further response of treatment.
This is a cutaneous carcinoma, squamous carcinoma. Again, excellent responses. Now on Slide 24, just to conclude this part of the talk, I hope I've been able to share with you that as for melanoma, there have been incremental improvements in our data since the last data cut, with additional responses observed, deepening of those responses over time, and the durability continues to be impressive and demonstrable. In patients with cutaneous squamous cell carcinomas, the overall response rate has increased to now nearly two in three patients, and the complete remission rate almost one in two. These are remarkable results. We're seeing improved activity in other tumor types, and I've shown you the data for Merkel cell and angiosarcoma, which may be particularly compelling. Again, this highlights potential for this agent across a range of different cutaneous cancer opportunities.
On slide 25, I remind you of the design of the randomized phase II study and the CERPASS study. This is a randomized controlled clinical trial of RP1 combined with cemiplimab versus cemiplimab alone. This has dual independent endpoints of overall response rate and complete remission rate. It is actively recruiting in the United States, in Europe, and in Australia, and it is expected that it will complete enrollment around the middle of the year, with top-line data being available, we hope, at the beginning of 2023. From the results that we have seen thus far with nivolumab, we would be optimistic that there would be a positive outcome for this study, both in terms of the overall response rate endpoint and the complete remission rate endpoint, and also in terms of key secondary endpoints, including durability of response. Many chances for this study to win.
Next slide is number 26. We now turn to new data with RP1 combined with nivolumab in patients with non-melanoma skin cancer who have progressed while on prior anti-PD-1 therapy. These numbers of patients are rather smaller. As you can see for the anti-PD-1 failed melanoma, this is a difficult disease to treat. There are no approved therapies that are known to be effective for these patients. While this is a relatively early data set and the numbers of patients are small, the initial data cut that I share with you looks very promising. You can see here that there have been responses in anti-PD-1 failed cutaneous squamous carcinomas, Merkel cell cancers, and angiosarcomas with all of the responding patients in a maintained response to date, which is impressive.
The overall response rate for this group of patients as a whole is currently 1/3, 33%, and a number of other patients who have not been on study for long are still in stable disease, and we hope, indeed anticipate that these may evolve into further responders. As for the melanoma scenario, it seems that RP1 combined with nivolumab may be able to generate clinically meaningful responses in patients with prior anti-PD-1 exposure and failure of their disease, and it may represent an important new treatment opportunity for these patients. I'm gonna show you some examples of these different tumor types in the next slide. On slide 27, I show you a patient who has had prior anti-PD-1 therapy for a cutaneous squamous cell carcinoma.
You can see this unfortunate patient has a deeply unpleasant recurrent lesion in the preauricular area with involvement of the parotid bed. You can see that within six months of treatment, there has been a remarkable response of disease. You can also see in the biopsies taken at screening and at week six on treatment, there is a substantial increase in the number of CD8+ T cells infiltrating into the tumor. Indeed, the paucity of T cells at the outset of treatment may well have been one of the reasons underlying the failure of PD-1 therapy in this patient initially, which has been turned around by co-treatment, in this case, with RP1. On slide 28, I show you a patient who has had anti-PD-1 therapy for a Merkel cell carcinoma, who has developed recurrent or progressive disease.
Again, you can see here, again with the same color coding, red circles indicating injected lesions, yellow circles indicating uninjected lesions. You can see that this patient with multiple deposits on the forearm has had a dramatic response of treatment within three months in the setting of prior anti-PD-1 failure. Finally, we go for another example in slide 29, a patient with an anti-PD-1 previously treated angiosarcoma of the scalp. A typical patient with this disease, a rather elderly patient with disease on the scalp. You can see two baseline photos taken from slightly different angles, indicating the nodularity and the widely disseminated recurrence in the head and neck region. Then you can see, within four months, this patient has had a superb response.
As for cutaneous melanoma, the treatment effect seen with PD-1 combined with RP1 combined with PD-1 therapy appears to be impressive, and it doesn't appear to be affected by prior treatment stages of the patient, meaning we can see responses in those who've had prior anti-PD-1 therapy. On the next slide, I'm gonna briefly introduce the program ARTACUS, which is looking at the difficult problem of treating patients with solid organ transplants who develop skin cancers. This is a difficult scenario that has been addressed in a phase I study with RP1, where it's been used as a monotherapy.
Due to the immunosuppressed nature of patients who have received organ transplantation, they are particularly at risk of developing cutaneous malignancies, especially cutaneous squamous cell carcinomas, and these occur in up to 70% of patients by 20 years after their transplantation. While these tumors may well respond well to anti-PD-1 therapy, it raises the risk of rejection of the transplanted organ. This is clearly not something that's broadly acceptable to the patient or indeed their treating physicians. Under these circumstances, there's an opportunity to test monotherapy to see whether or not that can deliver responses. Here I show you data from the first six patients. Again, as for the anti-PD-1 failed non-melanoma skin cancer data I just presented, these are rather early data. In the first six patients, we have achieved two responses, one partial remission and one complete remission so far.
Regrettably, one other patient who was already responding to treatment contracted COVID and succumbed to that disease, dying of COVID, and before we could assess the true benefit of the Replimune agent in that patient. This high risk of COVID, of course, in these patients is another example of why we have to be very cautious in how we treat these patients. We also know that COVID has significantly impacted the recruitment into the trial, and this has led to some slowing down of the initial recruitment. I'm pleased to say that this is now picking up as the pandemic is waning. One-third of the patients, two out of six, have had a response, and these data should be regarded as promising but early in nature. All of the patients presented here had cutaneous squamous cell carcinomas, and all of them were kidney transplant recipients.
On Slide 32, we look at the safety of this treatment. Clearly, when treating patients who are immunosuppressed, having had an organ transplantation, we might be worried about the administration of a replication-competent virus. What you can see here is that there is no clear evidence of a different safety profile of RP1 compared with the population of patients who are not immunosuppressed, and there has been no evidence, reassuringly, of organ rejection. Indeed, we wouldn't expect that. Slide 33 just allows me to summarize this. Initial data in both anti-PD-1 failed non-melanoma skin cancer treated with RP1 combined with nivolumab and RP1 monotherapy in solid organ transplant recipients with cutaneous squamous cell carcinoma again shows clinical activity with responses observed in 1/3 of patients.
This again further highlights the potential for RP1 as a treatment for patients with anti-PD-1 failed and other difficult to treat tumors, and also highlights the potential for monotherapy activity. With that, I have the pleasure of handing back to Rob Coffin, to continue with the presentation. Rob?
Thank you very much, Kevin. I'll now just briefly summarize our overall program in skin cancers with RP1 on the next slide, which is intended overall to establish a major skin cancer franchise, as Philip outlined and as Sush will further discuss later. From the data Kevin just presented, we believe the data in anti-PD-1 naive cutaneous squamous cell carcinoma and anti-PD-1 naive melanoma continue to support our registration-directed activities, represented in the top two boxes on this slide. For CERPASS, we expect this study to complete enrollment around mid-year, with the trigger for the primary analysis six months later. Final data cleaning and central review of response data will mean the top-line results should become available during Q1 next year.
For anti-PD-1 failed melanoma, interim data is expected at the end of the year, with top-line primary analysis data towards the end of next year. In addition to anti-PD-1 naive cutaneous squamous cell carcinoma and anti-PD-1 failed melanoma, we've also seen activity in basal cell carcinoma, Merkel cell carcinoma, and angiosarcoma, including with anti-PD-1 failed disease, as Kevin just presented. Within each area, the likely approach to commercialization being through compendia listing. Similarly, we've also now demonstrated RP1 monotherapy activity in solid organ transplant recipients with CSCC, where we'd also plan for potential future registration or compendia listing. Finally, we're now planning for a study in the neoadjuvant setting in cutaneous squamous cell carcinoma, which is a very substantial potential market, which likewise we'll discuss a bit more later.
Thus, overall, we have quite a broad range of activities ongoing in skin cancers, which captures nearly all of the potential segments in these tumor types, and which we believe can deliver substantial value to Replimune in the medium to longer term. I'll now hand over to Dr. Nikhil Khushalani, who's the Vice Chair in the Department of Cutaneous Oncology at the Moffitt Cancer Center in Florida, and also an investigator on the CERPASS clinical trial, as well as being an investigator on many prior studies in cutaneous squamous cell carcinoma and related areas, including the study which led to the approval of cemiplimab in the first place. Dr. Khushalani will now provide an overview of CSCC including disease background, current treatment options, and unmet need. Over to Dr. Khushalani.
Thank you very much, Rob. We can skip through the bio here. I appreciate the invitation and the broad strokes that were provided previously by Dr. Harrington set the stage very well for my portion of this discussion. What I've titled this is Going Beyond the Classic Management of Cutaneous Squamous Cell Carcinoma. As many of you would recognize, this is Janus, the two-faced Roman god, and looking back, looking forward, essentially. This is a disease that traditionally has not seen much traction until recently in the last, I would say, three to five years, where immune checkpoint inhibition has really transformed the management of these patients, particularly those with locally advanced unresectable disease or those with metastatic disease.
There's a lot of biologic rationale for the efficacy of these agents in this disease, primarily related to a high tumor mutational burden. It is very obvious that this would be one pathway that one would follow. The key issue then becomes this immune checkpoint does not work for everyone, and how can we actually better improve on the existing standards of care? Next slide, please. These are my disclosures. Next slide, please. Essentially from an epidemiology standpoint, skin cancer, keratinocyte carcinomas, which is the bucket term that we use typically for combination of basal cell carcinoma and squamous cell carcinoma, are the most common cancers that are seen. In the United States, the two of them together equate more than the sum of all other cancer incidences in the U.S.
If you specifically parse this down to CSCC or cutaneous squamous cell carcinoma, it is the second most common skin cancer that we see with roughly approximately three-quarters of a million patients on an annual basis. It is hard to accurately estimate the true incidence of this disease. Because it is so common, it often in many countries, including the United States, is not reported to tumor registries. There have been now concerted efforts in several European countries to really get a better sense and a better handle as to how many of these new patients or new tumors we see because many patients have a multitude of tumors over their lifetime. The primary etiologic factor is exposure to ultraviolet radiation, both ultraviolet light A and B, and particularly accumulative exposure over time.
What we have known is there has been a dramatic increase in the incidence of CSCC over the last three decades, an almost 250% or greater increase. Many of these patients have either locally recurrent disease that is evident on the skin or have evidence of nodal involvement, so regional nodal metastases in the absence of distant systemic metastases, which is where the neoadjuvant therapy, and I'll discuss this a little bit later in my presentation, really, offers us an opportunity not only to intervene with systemic and intralesional therapy ahead of time prior to definitive surgical resection or prior to radiotherapy, but actually from a scientific perspective, also allows us to study the biology of these diseases by obtaining serial biopsies as we go along.
Similar to the incidence, it's a little hard to truly estimate the mortality related to CSCC, but most of us believe that it is somewhere in the seven to 15,000 deaths on an annual basis. This again varies from publication to publication. I think it's important to recognize that many of these patients, unfortunately succumb to local regional progression, so locally recurrent disease or uncontrolled locally advanced disease rather than distant metastases. Another important etiologic factor is underlying immune deficiency and immunosuppression, where about 15%-30% of patients fall within this category, particularly with solid organ transplant or other immunosuppressive illnesses, including autoimmune disorders as well as hematologic malignancies such as chronic lymphocytic leukemia or HIV infection. This predisposes patients to developing CSCC. Next slide, please. The typical patient presentation, these tend to be older individuals.
The median age is somewhere between 70-75 years. That's important to recognize because these individuals then have associated comorbid factors, particularly from a cardiac as well as a renal standpoint. Previously, we used to utilize chemotherapy, typically platinum-based for these patients, but with renal insufficiency, many of them are not candidates for cisplatin, or similar type of drugs. Newer treatment modalities are critically important. The vast majority of these develop from what we call the classic sun-damaged skin or actinic keratosis. These are individuals who go to their dermatologist, often will have cryotherapy, to a multitude of lesions that are precancerous, and many of them eventually will end up getting a biopsy. What you see on the right-hand side is a micrograph of an individual with locally advanced recurrent disease on the scalp and clearly disfiguring, clearly a problem.
Many of these patients have foul-smelling discharge from their tumors, painful due to evidence of perineural involvement. Over a period of time, and this has not been very well studied, unfortunately, from a psychosocial aspect, there tends to be a delay in seeking care, and part of it may directly be associated with the social stigma, when these diseases are so visible on the head and neck area where it's most common. Given the local regional progression that occurs in many patients with high-risk disease, with superficial involvement or visible involvement, intralesional, intratumoral approaches offer an excellent avenue to try and help with disease control. Next slide, please. Really, this slide summarizes what the unmet needs are. We know that anti-PD-1 therapy works very well for these patients.
It is an effective option, and there are two approved drugs in the United States, cemiplimab and pembrolizumab. The key question is, can we actually improve on the overall and complete response rates with anti-PD-1 based combination therapy, so using anti-PD-1 therapy as the backbone? Many patients, unfortunately, will still not respond to anti-PD-1 based therapy. Is there an effective second line treatment post anti-PD-1, so in the PD-1 refractory patients? Dr. Harrington presented some early data on that population, both in melanoma as well as in CSCC. The specific subgroup of individuals who are high risk, but who unfortunately cannot get immune checkpoint therapy up front, is that an area that we can clearly develop additional treatment options? Again, a high area of unmet need, and I'll show you some of that transplant data as well.
Certainly try to move the needle earlier in the case of disease course. Try to mimic advanced disease success in earlier stage disease. It offers us the opportunity to consider this for neoadjuvant therapy, where there's still visible disease, but potentially resectable, and try to obtain long-term durable disease control in that setting. Next slide, please. This was a schematic of the original EMPOWER study that led to the approval of cemiplimab in this otherwise poorly studied disease, or I would have called it an orphan disease five years ago, not so much anymore because there's certainly a lot more attention being paid now to this particular group of diseases in keratinocyte carcinomas.
Just to recap, this was a phase I, phase II trial, and what this slide primarily highlights is the adult patients with locally advanced or metastatic disease who are not candidates for surgery. In the phase II portion, that was presented and published in The New England Journal of Medicine back in 2018, and I was privileged to be part of the team that participated in this trial as an investigator and saw some of the dramatic responses. At that time, these individuals got weight-based dosing, 3 mg per kg of intravenous cemiplimab every two weeks, and then up to 96 weeks in the phase II setting.
Again, the important highlight here is at the bottom in terms of exclusion, patients with autoimmune disorders that were treated with systemic immunosuppressive therapy, patients with solid organ transplant recipients were essentially excluded from this trial. Next slide, please. Similarly, we had a locally advanced cohort of 78 patients, and these were patients who had locally recurrent, locally advanced disease and were not candidates for additional curative intense surgery and/or radiotherapy. Between the two two arms or three arms of the study, in the metastatic setting, the response rates were between 45%-50%, 47-50%, specifically between arms one and three. In the locally advanced setting, which is arm two of that trial, the overall response rate as measured through clinical observation as well as RECIST traditional criteria was 44%.
The typical toxicity of cemiplimab was that with any other anti-PD-1 drugs, so really not different from that standpoint. What you can see here on the top left is the waterfall plot of the responses, and then the bottom was the swimmer's plot demonstrating durability of response as well. Next slide, please. This slide highlights the progressive increase with subsequent longer term follow-up on these patients, where we have seen across all three arms of this study, group one and group three are the metastatic patients. In the middle, group two are the locally advanced patients, where with the metastatic patients, we have seen a progressive improvement in the complete response rate, albeit small numbers, but now approximating anywhere between 18%-20% complete response rate.
I think that's important because that is one of the endpoints on the CERPASS trial as well in terms of trying to assess what is the complete response rate to combination therapy. More importantly, from a practical standpoint, does it even matter? If one looks at data in melanoma, it is very clear that patients who have deeper responses tend to have more durable responses. I think we're still scratching the surface in terms of understanding this phenomenon in cutaneous squamous cell carcinoma. As a treating oncologist, to me, it is far more gratifying to see a complete response that occurs in these patients. I then tend to be far more altruistic in aiming to stop therapy in those patients who achieve a complete response and have already completed the designated timeframe of therapy.
Next slide, please. This was a similar trial that was done with pembrolizumab that led to the approval of this agent in the similar type of population. What's highlighted here is the objective response rate to pembrolizumab in 105 patients with locally recurrent or advanced disease was 35%. Now, one may ask, why is there a difference between pembrolizumab and cemiplimab? Quite frankly, I don't believe that there is any difference. It is important to note that patients on the KEYNOTE-629 trial were far more heavily pre-treated compared to those on the EMPOWER study. Almost 87% of patients had some form of systemic therapy and/or radiotherapy, which may have blunted the second-line response rate to pembrolizumab.
If one specifically looks at the subpopulation of patients who did not have any prior systemic therapy, the response rate is approximately 50%, so very similar to cemiplimab. I think utilizing one or the other is very reasonable. Similarly, another smaller trial called the CARSKIN study showed very similar efficacy for pembrolizumab in this disease. Next slide, please. The question really then comes up is PD-1, anti-PD-1 therapy works for a subset of patients, and it can induce durable responses. What happens in those patients that either have primary resistance to anti-PD-1 therapy or who develop secondary or acquired resistance, i.e., in the course of their treatment, eventually stop responding. What do we have for them post anti-PD-1 treatment? I think this is a very broad arena and certainly ripe for further investigation.
Currently, there is no regulatory approval for any specific agent in this particular setting that have failed anti-PD-1 therapy. We in the clinic tend to use anti-EGFR agents such as cetuximab. We use chemotherapy, which is typically platinum-based or taxane-based. In some cases, we also use 5-fluorouracil-based regimens. All of these tend to have finite responses and certainly are replete with toxicity insofar as chemotherapy goes. That can limit the use, particularly in an aging population. New options are clearly needed for these patients, preferably those with better tolerance, lesser toxicity, and preferably, obviously, those with a higher overall response rate, complete response rates, and potentially durable benefit. Again, a lot of room for investigation in this area of high unmet need. Next slide, please. What about immunosuppression in skin cancer? I alluded to this earlier in the talk.
If you look at patients who have undergone solid organ transplant, the incidence of cutaneous squamous cell carcinoma is almost a hundredfold increased compared to those who have not undergone a solid organ transplant. This is very well documented data in a cohort study across 26 transplant centers around the country, coordinated through the University of California, San Francisco. When you look at the skin being the most common site of malignancy post solid organ transplant with an incidence rate of approximately 1,400 per 100,000 patient years, CSCC accounts for more than half of that. Putting it in different perspective, when you look at an immunocompetent population, the incidence of basal cell carcinoma is almost four is to one compared to cutaneous squamous cell carcinoma. In the transplant population, that's completely reversed.
The CSCC is a high area of unmet need within the transplant population, as are other skin cancers as well. Next slide, please. What is also known is that in these patients who are immunosuppressed to primarily preserve their allograft, the overall prognosis is noticeably worse compared to those who are immunocompetent. This is admittedly a small study that was published a few years ago, where they looked at 23 immunosuppressed patients versus 46 immunocompetent patients, organ transplant or hematologic malignancy. What they clearly found was that those individuals who were immunosuppressed did much worse compared to those who were immunocompetent. This highlights the fact that newer treatments are clearly the need of the hour for this population.
I think in terms of numbers, it is also important to recognize that we are doing many more transplants in the United States compared to two or three decades ago, almost to the extent of threefold. For example, in 2015, there were approximately 31,000 solid organ transplants performed, and that would include a plethora of kidney transplant, liver transplant, lung, heart, pancreas transplants, so on and others. This was about threefold higher compared to the transplant registry data from 1988. Next slide, please. Clearly, in these patients, the use of immunotherapy, specifically anti-PD-1 or anti-CTLA-4, is very limited. These were patients who were not included in the original clinical trials, primarily because of the concern for organ rejection or transplant rejection.
Case reports and smaller case series have shown an approximately 50% risk of allograft rejection, which is extraordinarily high. So we tend to back into consideration of these drugs for this particular group of patients only after they have exhausted other treatment options. What about other immunocompromised statuses? For example, patients with autoimmune disorders, patients with concurrent hematologic malignancies. Again, these were individuals who were excluded from the original registration trials. We in the clinic certainly use anti-PD-1 therapy on a case-by-case basis. But again, this is an area of unmet need where we can consider newer treatment options, including intralesional approaches for them. Next slide, please. Neoadjuvant therapy. This is a fourth arena where one could certainly consider intralesional along with systemic therapy. I just wanted to clarify what is the true terminology that I utilize and obviously many others.
The neoadjuvant therapy, specifically the administration of systemic therapy prior to surgery in patients who have accessible regionally advanced or metastatic disease, most importantly, with a plan to carry out resection after a finite period of time on systemic or intralesional therapy. You can assess the response rate radiographically or traditional means, and then postoperatively, i.e., adjuvant therapy may or may not be used. Again, the intent is these are surgically operable patients in whom the typical paradigm originally may have been surgery followed by consideration of adjuvant therapy. In the arena of immunotherapy, with evident tumor and potentially tumor-associated antigens in sight, neoadjuvant therapy certainly offers a lot of biologic rationale to pursue. Next slide, please. Again, this is palpable nodes which we see in our patients with CSCC. Again, it's hard to truly estimate the total number of patients who present in this manner.
Looking at a multitude of studies pioneered right here in Boston through Dana-Farber and Mass General, approximately 3.7% of patients with cutaneous squamous cell carcinoma will end up developing nodal metastases. If you look at the entire spectrum of over 700,000 patients presenting with this disease, that would equate somewhere between 20,000-25,000 patients with nodal metastases on an annual basis. Similarly, the disease-specific death related to cutaneous squamous cell carcinoma from prior cohort studies is approximately 1.7%-2%. That's how we tend to estimate some of the mortality rates associated with this disease as well. Again, neoadjuvant therapy would be very appropriate for patients with palpable nodes or radiographically evident nodes. Those with in-transit metastases, again, cutaneous or subcutaneous metastases that are visible and palpable on the skin.
One could biopsy these tumors, image these tumors, proceed with systemic therapy, either systemic or intralesional. We could re-biopsy them if necessary, to understand the biology of the disease. That I think is critical from a scientific aspect to understand the immune microenvironment and milieu. Then eventually take these patients to the operating room, assess the pathologic response. What does the pathologist see under the microscope? Is there any evidence of disease or not? Then based on that, even adapt adjuvant strategies to this. Next slide, please. Our colleagues at MD Anderson published a small cohort of patients of 20 in Clinical Cancer Research last year. Essentially what they did was treated patients with neoadjuvant cemiplimab, two doses of therapy prior to planned surgery.
In the vast majority of these patients, in 14 of these patients, 70% of them who underwent surgery, the pathologic response was either a complete pathologic response or a major pathologic response that was identified. Eleven out of those 14 had essentially a pathologic complete response. Why is that important? It's a little too early to tell whether in CSCC, a pathologic complete response equates long-term disease control. In melanoma, we have already identified that pathologic complete response to immunotherapy or MAP kinase-targeted therapy portends long-term disease control in a large number of patients. I believe personally this, a similar scenario will play out over time in CSCC as well.
I think this is also important because we can then potentially limit the amount of treatment that is administered to patients prior to surgery, and then risk stratify or risk adapt postoperative therapy based on the response that we actually see. We may be able to change paradigms and clearly benefit patients with very specific tumor-directed therapy in this particular setting. A larger trial of neoadjuvant cemiplimab in CSCC has already been completed. Results would be anticipated sometime in this calendar year. Next slide, please. This slide essentially highlights what other avenues exist, and where the field is going. It's a busy slide. I won't belabor the point, but essentially it shows you that this is almost like melanoma déjà vu.
Given the propensity for CSCC to experience immune manipulation, we can utilize multiple other agents that are targeting the immune microenvironment to try and see how we can build on our existing blocks that we utilized for the management of this disease. A lot of room for improvement and certainly a lot of room for additional clinical and scientific investigation. Next slide, please. In summary, what I've hoped to have been able to show you in the last 20 minutes or so is cutaneous squamous cell carcinoma clearly has a rising incidence. It is an increasing public health problem and certainly greater urgency both in the treatment of patients that I tend to see which would have advanced disease, but I think a lot of avenues for consideration of prevention strategies as well.
While we do know that anti-PD-1 therapy is standard of care for the appropriate patient with advanced CSCC, almost 2/3 of these patients eventually still progress or may not benefit at all from this avenue of therapy. Oncolytic immunotherapy clearly provides a promising option to help a broader spectrum of these patients, and you saw a lot of objective data on that previously. Certainly our understanding at a molecular standpoint will eventually hopefully lead to therapeutic advances, setting the stage into combination therapy, adjuvant therapy, and neoadjuvant therapy. I thank you for your time and attention.
Thank you, Nikhil, for that very nice overview of cutaneous squamous cell carcinoma. Now I'm gonna just spend a couple of slides talking about our initial launch of RP1 in skin cancers. Next slide, please. We believe that if we can replicate some of the transformative data that we've seen from some of our early studies in our pivotal data sets, this will allow us to nicely progress towards many aspects of our vision that you see outlined on this slide here. Firstly, it's important. It's a really critical 12 months for us on the commercial side as we prepare for our initial launches. Importantly, our first goal is to rapidly establish RP1 in cutaneous squamous cell carcinoma. I'll explain in the following slides why we believe this is an ideal first launch for our modality.
We plan to have a second launch in checkpoint failed melanoma shortly after our cutaneous squamous cell launch, which will allow us to continue to build the momentum, customer experience, and enable us to develop a meaningful skin franchise. We also, as we have seen earlier, with compelling data in other skin cancers, basal cell, Merkel cell, angiosarcoma, et cetera, which I think provides an opportunity to further expand our skin franchise. Next slide, please. We're really excited about advanced cutaneous squamous cell carcinoma as our first launch, as we believe our product and the mode of administration really makes a lot of sense in this tumor type.
Given the unmet need in CSCC that you heard from Dr. Khushalani, we believe we can provide a potential option, either alone or in combination, for all key segments of the market, including providing an important option for those who have failed checkpoint inhibitors. Ultimately, if we can produce strong CRs in CSCC, RP1 could be a powerful option for many more patients in the neoadjuvant setting and really help redefine the treatment paradigm and achieve our goal of cure. In totality, these various segments represent an estimated U.S. treated population of around 40,000 patients. Next slide, please. One of the questions we often get is, "Well, you know, how are you different to T-VEC, and why do you believe you're gonna be successful in your launch?" I just wanna say a couple of comments here.
Firstly, I think T-VEC was great proof of concept, but it didn't launch with strong data or a label. We aim to come to market with strong data set and a compelling value proposition. The whole reason for being for Replimune was really to build a more potent oncolytic immunotherapy platform, and that really starts with RP1, including developing a more lytic strain, as well as additional modifications, really aim to drive a stronger systemic immune response. It's also important to remember that RP1 can be used in combination with standard of care, and so we're not really asking customers to replace their IO, which we know is a bigger burden. When we think about our critical success factors, there's really two areas we need to focus on. The first being establishing really strong HCP confidence.
Beyond the obvious awareness and education about key data, we need to make sure that there's trained injection champions at every key account, and that includes nurses, nurse practitioners, or M.D.s. Secondly, what's gonna be really important is to have a positive experience, making it as easy as possible for the whole care team by simplifying dosing, logistics, and cleanup. One of the things that we've seen that's different to T-VEC is that we have improved stability at 2-8 degrees, which is at normal refrigeration, versus T-VEC, which was stored at -70. Also, I would say, given the superficial nature of the tumors that Dr. Khushalani mentioned, our initial launch is really gonna allow healthcare professionals and patients to actually see what the therapy is doing to them, and so that's a powerful modality and a powerful option for us to bring this to market.
Next slide, please. As we think about the next stage of this presentation, we're gonna focus on. We're gonna move away from RP1 and now focus on RP2 and RP3. This transitions into some of the clinical development discussions. Before we get into some of the clinical development discussions, we're gonna discuss some of the considerations of deeper injections, which we believe will be key to enabling our use of our assets in more solid tumors. Next slide, please.
Now, one of the important aspects of our modality will be making intratumoral injections, and as we like to say, tumor-directed treatments easy and routine. We think about this in three steps. As mentioned, we start with CSCC, where it's largely an outward growing cancer, where patients drive local regional progression with a high percentage of patients who have lesions that can be injected. However, we do believe that to drive even stronger immune and systemic immune activity with RPx, we will need to inject deeper locations such as lymph nodes, other visceral mets. We are also doing this in a stepwise fashion. Today we're gonna focus on why step two, that you see on this slide here, is an obvious gateway to getting to step three.
I think importantly in step two, this includes indications where delivery is part of routine medical practice and can be easily adopted, e.g., primary liver cancer or liver metastases, where use of ultrasound and repeat injections of the liver already occurs. Hence, in these indications, we're really swimming with the tide versus against it. Next slide, please. Firstly, I just wanna reiterate that we believe skin cancer alone represents a sizable opportunity, and that's about 50,000 patients if you now include, in addition to the CSCC number I gave you before, checkpoint-failed melanoma patients. In the next wave of our development strategy, one of the important things we've considered was how to best move along this continuum.
What has become clear in our market research and talking to key opinion leaders such as the ones you're hearing from today is that not only are HCC, CRC, and locally advanced head and neck areas of unmet need, but are indications where we can more easily do deep injections. Now, if we specifically consider liver cancer and liver mets, there's a strong rationale for doing deep injections in addition to significant commercial opportunity. In HCC, CRC, and uveal melanoma that you see on this slide, patients die of liver failure or liver mets, and the liver tumor microenvironment really is an issue for existing IO treatments. Deep injections of RP2 and RP3 has the ability to really alter the tumor microenvironment. Now, if we turn to second-line HCC and third-line CRC, these account for about 30,000 treated patients.
Again, given the unmet need, if we can show proof of concept activity in these later line settings, it'll allow us to rapidly move into much larger opportunities in earlier disease. Ultimately, we believe deeper injections in other solid tumors, especially in the neoadjuvant and locally advanced settings, could provide significant patient opportunity and unlock a large additional commercial value, as this is really where the whole market is moving to. Next slide, please. On this slide, I wanna just orient you to the top of the slide initially. If we think about intra-tumor injections, they really are not one size fits all. So if we're thinking about injecting accessible lesions, this really should not be any harder than doing an IV, and as I mentioned, a nurse or another trained healthcare professional can very much do this.
Now, if we think about deeper injections, we've done detailed buying process and market research, and certainly there are some barriers to overcome, but this is not complex like cell therapies such as TILs or CAR-Ts, and importantly, these barriers can be overcome. You're gonna hear more about this shortly, but firstly, it's important to note that technically this is not particularly challenging, and in fact, there are far more complicated intra- procedures that interventional radiologists do, such as yttrium-90, et cetera. A lot of deep injections can actually be done by ultrasound. Now, what we've seen from our research is the hurdles really fall into three categories outlined here. While some of these are gonna require some new behaviors and the processes to be adopted, again, nothing came through in the research as insurmountable without appropriate education and training.
Ultimately, if the data is compelling, this modality really addresses unmet needs for patients. We believe HCPs will find a way to incorporate RPx into the treatment paradigm. Oncolytic immunotherapy importantly provides an opportunity for radiologists to become part of the treatment of systemic IO treatments, which is something they're very excited about. Many of the procedures they do, such as TACE, are largely local treatments, and this again provides a new opportunity to bring them into the treatment paradigm. Next slide, please. To wrap up, if we bring together our initial skin launch use and work done on feasibility of deep injections, there is a logical and stepwise adoption ladder.
It starts with CSCC, and we recognize that the first launch really does set the trajectory for the portfolio and the company, and we believe CSCC is a great starting point as it will showcase our product attributes and provide HCPs hands-on experience with RP1. We then build with more experience in skin, this time in checkpoint-failed melanoma, and start to get adoption of some deeper injections, including in lymph nodes. Finally, as discussed, given the unmet need and feasibility, we feel liver cancer and liver mets are a strong next gateway to broader adoption in other solid tumors for RP2 and RP3. Now, next slide please. It's now my great pleasure on this to introduce Dr. Muneeb Ahmed, who's the Division Chair, or Chief of Interventional Radiology at Beth Israel and is the President-elect of the Society of Interventional Oncology. Over to you, Muneeb.
Thank you, Sush. I'm happy to be participating in this. Next slide please. As we have heard, when we think about deep visceral tumor injections, these are really tumors that cannot be injected via direct visualization or palpation, and often will require imaging guidance in order to be injected, and that includes CT or ultrasound guidance, which I'll talk about. When we think about this, it's often solid organs such as the liver, the lung, kidneys, the spleen, but also includes lymph nodes in deep locations in the retroperitoneum, in the pelvis, in the chest wall and thorax. If we think about targeting some of the deeper injections, liver tumors present a compelling first place to start.
There's a rising in incidence of liver metastases overall, and these often determine outcome of the, you know, patients regardless of their primary cancer of origin with an associated 50% higher risk of mortality. Liver metastases themselves are often very resistant to current immunotherapy options, in part due to the unique immune resistant landscape of the liver. The direct injection concept for liver tumors has actually been around for decades, so it's not a new concept to implement in clinical practice. Therefore, targeting liver metastases really represent an opportunity to treat multiple cancer types. Next slide.
When we think about what this involves from a technical perspective, again, these are often done with ultrasound or CT guidance, and approximately 80% of liver tumors can be injected with ultrasound guidance, meaning that this is an easy to do and easy to implement technique. The needle is placed in the target lesion. When it comes to RPx injections, up to 10 mL can be injected, and the agent is distributed across the tumor through needle repositioning. As an example of this, these two images demonstrate that. The image on the left is a grayscale ultrasound image. It demonstrates a dark hypoechoic focus of metastases within the center of the liver. Then we see a thin echogenic white line representing the needle with the tip positioned in that.
On the image on the right, this has been injected with an agent, and we can see that white effect from local injection that covers the entire tumor. Now it's important to remember that this type of technique can be done by any radiologist, either a diagnostic or an interventional radiologist. These are outpatient procedures, usually with conscious sedation. Logistics are similar to commonly used FNA or biopsy procedures. The infrastructure and process to do this is in place at almost all centers and hospitals. This is a 20-minute procedure. Monitoring is required for two to four hours afterwards. All of this speaks to the potential wide translatability and scalability of this type of technique at later stages of commercialization for this technology.
The formal injection protocol for RPx has actually been developed with input from a number of KOLs and interventional radiologists. Next slide. This is just an overview of safety profile and adverse events. This was actually presented at the recent Society of Interventional Oncology annual meeting. Really looking at early data from RP1 and RP2 on liver metastases injection. I'll call out that essentially overall these side effect profile is very similar to other types of injectable therapies. There is an increased incidence of fever, nausea, and chills afterwards, which can be seen in liver injections regardless of the therapy due to the vascularity of the organ, but these are extremely manageable as well.
There's also slightly increased injection site pain, again, well within what might be expected for liver injections. Next slide. This is an example of a patient with liver metastases who was treated with RP2 monotherapy. It's a patient who had uveal melanoma, had extensive liver metastases that are shown here, and had been previously treated with ipi and nivo and progressed at 15 months. Just to walk you through these images, the image on the left-hand side demonstrate a large liver metastases circled in red, and several smaller liver metastases circled in yellow. The large one was injected with RP2 monotherapy, and over time we can see over three, six and nine months that the injected lesion has decreased in size from direct injection.
As well, we can see a regression of multiple other sites of uninjected lesions. Really speaking to both the local and off-target systemic effects of this agent. Next slide. Now, one of the keys to success is really engaging key stakeholders and understanding where they live, and we've heard, you know, Sush outline that very nicely in earlier slides. Really tumor-directed therapy requires a success of key stakeholders. There are two groups in particular when it relates to deep visceral injections. The first is the medical oncologist, obviously general or specialized to their specific cancer type, are often the main point of contact. Interventional radiologists as well are a key group to engage.
They are often already treating liver cancers primarily through liver-directed therapies such as tumor ablation and embolization. They're gonna be a gateway for all image-guided procedures, in particular deep injections, whether it's in the liver or elsewhere. One of the ways to really engage them is through societal involvement. In particular, Replimune is engaged with the Society of Interventional Oncology, of which I'm the president-elect, to really identify these key stakeholder groups early as a way to ensure both identification of clinical trial sites that are gonna be successful, but also for a more longer term engagement with this for commercialization as well. It's important to remember that many of these.
Many of these individuals do engage commonly in the form of virtual or multidisciplinary tumor boards or clinics. We have a well-established one at Beth Israel as well. So there are several ways into these key stakeholder groups for early clinical trial site engagement. Next slide. When we think about intratumoral therapies, they're actually really increasing in overall use at multiple centers. This is an example of that with a clinical trial data that was published by MD Anderson from their interventional radiology group, really reporting the use of direct intratumoral injection across a number of immunotherapy trials in a total of 1,300 injections. It speaks to the wide range of potential injection sites. We can see here on the left, they injected multiple organs in multiple sites.
They also were able to perform core biopsies both at the injection site and at non-injection sites. The ability to collect non-target data is part of clinical trials and routine practice. Overall, the serious adverse rates were very, very low, regardless of which trial they were in, just speaking to the fact of the overall safety profile of a direct intratumoral injection strategy. Next slide. To summarize, really intratumoral immunotherapy injection is a very compelling proposition for liver metastases, as this is a frequent site across multiple tumor types, and usually associated with both poor prognosis regardless of the primary tumor type, and with associated reduced activity of systemic immunotherapies as well.
RP1 and RP2 can be safely administered repeatedly to hepatic metastases and have demonstrated activity both locally and systemically. Ultimately, intratumoral immunotherapy injection of these organs can likely be safely escalated to other sites as well. I will pass it back to Rob. Thank you.
Thank you very much indeed, Muneeb, for that overview. I'm now going to provide an overview of the RP2/3 program, including the data to date, and the development plans for phase II, which is really the first time we've presented these. As a reminder, RP2 and RP3, which are really one program, leverage our ability to express multiple transgenes from our high oncolytic potency backbone, enhanced through the expression of the fusogenic protein, as Philip already described. RP2 and RP3 focus on delivering potent immune activators to tumors and draining lymph nodes, delivering molecules which function at both the time and the place of immune response activation, and which also have a level of clinical validation, which is part of the thought process behind which proteins to include.
RP2 expresses an anti-CTLA-4 antibody, as has been clinically validated by both ipilimumab and tremelimumab, with RP3 further expressing immune co-stimulatory molecules, CD40 ligand and 4-1BB ligand. Agonistic antibodies against both CD40 and 4-1BB have shown evidence of activity in the clinic, but also been shown to be somewhat toxic. As for anti-CTLA-4, we believe that direct delivery of each of these into tumors should enhance not only their activity, but also minimize systemic toxicity. Altogether, this approach seeks to maximize immunologic signal one, that being antigen presentation through the lytic effects of the virus killing the tumor and releasing antigens, and also signal two, that being immune co-stimulation, and resulting signal three, the release of inflammatory cytokines.
Each of these should be enhanced through the expression of both the anti-CTLA-4 and the co-stimulatory used. Preclinical data demonstrates the promise of the approach. In this experiment, we've grown tumors in both the left and right flanks of mice. The right tumor's then been injected with either vehicle or a low dose of RP1, which is itself not highly effective, particularly in uninjected tumors, at that low dose. That's the second panel down on the left.
However, when we further encode an anti-CTLA-4 antibody, CD40 ligand or 4-1BB ligand, or indeed in another co-stimulator, OX40 ligand, in the virus, and then inject at that same low dose, we see that not only are the anti-tumor effects improved in the injected tumors, but effects are improved even more in the uninjected tumors, as indicated by the three other red-circled groups on the left and the right. Therefore, we can conclude from this experiment and other similar experiments, that the local delivery of each of these molecules into tumors increases not only the local benefit, but also the systemic immune-mediated benefit, which we achieve.
If we come on to clinical data, as we previously presented both last year and the year before at SITC in a phase I population of nine patients using RP2 monotherapy at two different dose levels to determine the recommended phase II dose. While five patients of those nine rapidly progressed, as would be expected in an advanced phase I population, three of the patients achieved an overall objective response. This was durable out to 15 months in uveal melanoma in the uveal melanoma patient, and ongoing at the last data cut in the other two patients who had esophageal cancer and mucoepidermoid carcinoma, a type of salivary gland cancer.
This durability further speaks to the immunological potency of the approach, 'cause without durability, you wouldn't expect the immune system to be kicking in. All patients have failed standard of care, including checkpoint blockade for both esophageal cancer and the uveal melanoma patient. This is one the first example in mucoepidermoid carcinoma, which is actually one of Karen's patients, who will speak again in a minute on head and neck cancer, who's achieved an ongoing complete response following injections into only the upper lesion in the neck. The lower lymph node wasn't injected, but the patient over-achieved an overall durable, complete response, which is still ongoing out now, I think, at around two years.
This is the esophageal cancer patient who'd failed multiple therapies, including an anti-PD-L1 antibody, on a clinical trial. The patient had relatively limited liver disease, and also other lesions in the abdomen, and it was just the liver lesion which was injected. All achieved a response, and this patient actually has an ongoing metabolic complete response, although a RECIST partial response out now to over 18 months. Very clear single-agent activity with RP2. When we combined RP2 with nivolumab, we also saw clinical activity and with no new safety signals as compared to when we combined RP1 with nivolumab. Here we had a 30-patient phase I cohort of patients with advanced disease, all of whom having failed standard of care, including immune checkpoint blockade, where they were eligible for that.
Out of that group of 30 patients, we saw seven overall responses as of the last data cut, which was presented in November. This included responses in patients with uveal melanoma, cutaneous melanoma, and head and neck cancer, with all of those responding patients having failed prior anti-PD-1 therapy. Biomarker data with RP2, as for RP1, has also been promising, indicating broad and potent immune activation. A snapshot of some of that data is shown here. In biopsies on the top left panel, we see very strongly increased expression of CD8 and PD-L1 in patients whose tumors had initially low levels of these. Gene expression analysis on the bottom left panel shows that all of the classes of genes associated with immune activation are indeed increased, as we would hope.
We also see that there's no association of either baseline PD-L1 levels or CD8 levels with response, as shown on the right panels, indicating the ability of RP2 combined with nivolumab to induce responses, whether or not tumors are immunologically hot. As you can see, the data with RP2 clearly demonstrates clinical activity, also with promising supported biomarker data warranting movement into phase II. I'll now hand back over to Professor Harrington to run through the phase I clinical trial with RP3, on which Kevin was one of the investigators along with many other of our trials, in fact. Over to Kevin.
Many thanks, once again, and if I could go straight to slide number 83, please, which gives us a summary of the initial arrangement that we had for this RP3 phase I trial. Trial design, as you might anticipate, the inclusion criteria were typical for a phase I study, offering this treatment to all-comers patients with any tumor type, having failed all standard of care or other known treatments that were available to them. Now, in the first instance, we dosed three patients at the low dose, and you can see on the slide that's indicated by an initial dose of 10 to the 5 PFU per mL, followed by four doses at 10 to the 6 PFU per mL, up to 10 mL of injectate.
Then subsequently, we followed those patients and were treated with three patients at the higher doses. As you can see, that was a log higher across each of those dose levels. Both groups could have been expanded to six patients in the event that we'd seen a DLT. That actually wasn't necessary. Safety was assessed, and scans were performed at one and three months following the last dose of treatment, with five doses being the total dose of injectate that was given. There was no prolonged dosing in this group of patients. Dosing could be given both by direct intratumoral injection, which indeed we did for many of the patients, and also by an image-guided injection, as you've heard so elegantly earlier on in this set of presentations, and that was for deep tumors.
Once we had achieved the recommended phase II dose, we had the opportunity to enlarge the population of patients with herpes simplex virus seronegativity in order to expand that group to at least three patients so that we would be able to understand the safety in that group of patients. Then subsequently, the opportunity to recruit a 30-patient cohort using the same inclusion criteria and now combining with nivolumab, opening that study which is now recruiting, I'm pleased to say. On slide 84, I give you some data regarding what's happened with these patients. The current status is that the first three patients enrolled at the low dose did not demonstrate dose-limiting toxicity. We then went on to the higher dose, and again, we did not see dose-limiting toxicity.
The recommended phase II dose therefore was declared as the higher dose, so 10 to the 6 followed by 10 to the 7 times four. The combination with nivolumab enrollment that's been initiated at that dose level. As I've told you, we were able to recruit an initial seronegative patient to complete the dataset that we have around safety with that. The current available data is for these first six patients dose. It's a relatively early view of the data dosed as monotherapy. I'm not gonna share with you the data around the combination therapies. This is currently being expanded both in the U.S. and in Europe. On the next slide, please, slide 85, I show you the summary of the safety data.
Again, you can see readily for yourselves on this relatively busy slide. If you focus on the grade 3 and above toxicities, you see a paucity of toxicity there. Again, what we've seen is flu-like constitutional symptoms that tend to resolve within the first 72 hours, the vast majority of those being grade 1 and grade 2. However, I think one thing that doesn't really come through very clearly on this slide, and I think those of us who've been investigators on the RP1, RP2, and now on the RP3 program would attest to, is the fact that this virus is significantly potent, and we do see patients developing very significant reactions. Indeed, shortly before coming to give this presentation, I injected a patient in the clinic this morning in London.
This patient previously with their last cycle of treatment had really quite profound fever and rigors, which settled with conservative management, and the patient was entirely fine. This is a potent virus. I think it betokens the fact that it is very well endowed with payload agents, which are really designed to activate immune responses. On the next slide, I show you an example of a pleomorphic sarcoma, and you can see at baseline and then at day three, the impression that you get here really for this lesion, which is superficial enough for us to be able to capture this phenomenon, is really localized inflammation at this injection site, again, suggestive of immune activation.
If I had been able to show you pictures from the patient I treated today, again, you would see really quite impressive peritumoral inflammation in this patient following his injections. These agents are potent. I now go on the next slide, 87, to show you the nature of the patients recruited. This was a cohort of patients thus far, as you might expect in a phase I study, where the disease burden was extremely high. You can see here across the various patients, really very widespread disease, both in terms of the dispersion of the disease across multiple organ sites, but also within organs, you can see heavy disease burden. For instance, I draw your attention in the bottom right-hand corner to the volume of liver disease in this patient. This is typical of a phase I population.
Next slide, please. Here you see in really quite detailed analysis, the various features of those, first six patients, and you can see a range of different tumor types, not just the ones that you would expect or have been tested or are part of the initial RP1 program. You can see here, sarcoma represented, esophageal carcinoma, head and neck cancer, about which I will say more in a few moments. You can see that the patient population is heavily pre-treated with extensive multi-organ, multi-site disease. You can see that injections were given both, superficially and into deep sites. Although we have established a recommended phase II dose and demonstrated safety, it's probably a little early to be able to comment on responses.
You can see that a number of patients didn't complete all five injections due to early progressive disease given the advanced nature of their disease. Indeed, unfortunately, three of the six patients, both of the melanoma patients and a patient with colorectal cancer, died of progressive disease within four months of starting treatment. However, one patient has achieved stable disease for a year, then regrettably progressed in liver lesions, and one of my head and neck cancer patients is still in survival follow-up. Although the overall population that's been enrolled has given us the information around safety and allowed us to determine this recommended phase II dose, I think for the subsequent efficacy endpoints within the trial, we need to look to the later population of patients being recruited.
I'm now gonna hand back to Rob, who's gonna discuss the intended phase II development program with RP2 and RP3. Rob, back to you.
Thank you very much indeed, Kevin, for that, great overview of where we are with RP3 to date. I'm now going to re-summarize, I suppose, the data with RP2 and RP3. In summary, both of these agents have been well-tolerated, with, as you've heard, maybe slightly more marked side effects with RP3, as might be expected with the additional payloads encoded. These generally resolve within 72 hours, and we think indicate that RP2 and RP3 would be expected to be able to be combined across a spectrum of different anticancer modalities, which we do indeed aim to do in our phase II program with RP2/3.
RP2 has shown durable clinical activity, both as monotherapy and combined with nivolumab, including a clear signal in uveal melanoma, which we're further exploring now. We're also enrolling a cohort of patients with GI cancers, lung cancer, breast cancer, and head and neck cancer, rather than just the all-comers patients enrolled so far, with RP2, although these are still phase I patients. RP3 has shown very good tolerability, although somewhat more robust side effects than RP1 and RP2, and is expected to provide enhanced efficacy as compared to RP2. While safety has been able to be provisionally established and the RP2D declared for RP3, it's too early to draw any conclusions as to efficacy.
As for RP2, a focused cohort of patients with lung cancer, breast cancer, GI cancers, and head and neck cancers is to be enrolled rather than just the all-comers patients, as we've enrolled so far in the two monotherapy cohorts just reported upon. Overall, we believe it appropriate to keep our options open as to which of RP2 and RP3 to progress in particular situations as the data with RP3 catches up, which is really a year or so behind RP2. We're therefore writing the phase II protocols I'm about to come on to use both RP2 and RP3, the intention being to open one or other of the cohorts with RP2 or RP3 based on the totality of the data available at that time.
This also provides optionality to open both, if we so choose. We'll follow the data and decide which to use in each case, as we get towards actually opening the protocols I'm about to come onto. With RP3 clearly ready for broad phase II development and the data with RP3 running somewhat behind, these are the overarching principles which helped us determine the range of phase II indications which have already been alluded to earlier in the various talks, and the combination drugs to pursue. First, we wish to choose settings where, in general, there's the opportunity to show a signal in a single arm setting compared to the combination drugs used, usually the standard of care.
There needs to be a clear unmet need and an attractive underlying landscape for development, and feasibility of injection clearly needs to be taken into account too. We aim to develop across a spectrum of areas where an oncolytic immunotherapy, which can directly kill tumors and ignite a systemic anti-tumor immune response to turn cold tumors hot, might be used. This includes truly immunologically cold tumors, where IO doesn't work, tumor types where only patients with high PD-L1 respond, and patients with responsive tumor types where IO has failed. This includes developing in settings with locally advanced disease, and for neoadjuvant use too. Finally, we aim to combine with current standards of care to move earlier in treatment, ideally to the first line setting in at least some cases with the potential for synergy with these other, anticancer approaches too.
Following from that, we've also identified some high conviction, high reward indications for initial prioritization, as you'll see in the coming slides. A first area where we wish to establish, develop RP 2/3 is in the liver cancer and liver metastasis setting, as both Muneeb and Sush have previously discussed, for reasons we've set out indeed before. The liver is a very common site of metastasis, and patients with liver mets have a very poor prognosis and also respond very poorly to IO. Liver mets appear to eliminate tumor-specific T cells through the action of tumor-associated macrophages. We expect that the destruction of the tumor by RP 2/3 and the induction of new tumor-reactive T cells will help to overcome that.
Primary liver tumors and liver mets are also routinely injected as standard of care, as Muneeb discussed, indicating the practicality of targeting those tumor types. The areas we've identified for development here are first-line hepatocellular carcinoma combined with standard of care immunotherapy, which is atezolizumab combined with bevacizumab, and second-line hepatocellular carcinoma combined with anti-PD-1. The second-line setting is an area where there's no effective standard of care and where any level of activity would provide a clear signal and a potential path to registrational development. Additionally, we'll also conduct a study in third-line colorectal cancer, where there's also no standard of care and where any activity would provide a clear signal and a potential path to registrational development. This likewise would be in combination with anti-PD-1.
I'll come back to some more details of all of these towards the end of the session. The next area of interest is to move into treating patients with earlier disease. Here we believe there's considerable opportunity and where often the objective can be to achieve actual cures. Tumors are also often easily accessible earlier in disease, and we believe the safety profile of RP2 and RP3 is appropriate for use both in patients with earlier disease and in combination with the other therapies which might be used in earlier disease. As already mentioned, we're planning for a study in the neoadjuvant setting in CSCC, which will be with RP1.
As part of the phase II program with RP2 and RP3, we're planning a study in locoregionally advanced head and neck cancer, combined with standard of care chemoradiation, with curative intent, to be followed in fact by, adjuvant, anti-PD-1 therapy. Following an initial safety run-in phase in that clinical trial, we intend to rapidly move to randomized controlled trial, with registrational intent. Additionally, in patients with early disease, we'll also be supporting a number of investigator-initiated trials about which you'll hear more, over the year, including in early breast cancer and additional trials in skin cancer, including in particular settings, some of which Nikhil discussed earlier, in CSCC. The final area is that of overcoming IO resistance.
As shown, RP viruses can turn cold tumors hot and deliver responses irrespective of baseline PD-L1 and CD8 T cell status, including in patients who've failed prior IO. Here, we'll further work in head and neck cancer, targeting first-line recurrent patients who, while eligible for anti-PD-1 therapy, don't respond well to it, those being patients with low levels of PD-L1. Here we'll combine with standard of care chemotherapy and anti-PD-1. I already mentioned the phase II study in second-line HCC, which while being in the liver category, also falls into the IO resistant category as well. We'll also be planning for some additional signal finding studies in some other cancer types as well.
I'll now hand back to Professor Harrington, who will talk about the background and current treatment landscape in head and neck cancer, and the areas of unmet need, following which Dr. Tony Saab of the Mayo Clinic, with whom we've been working on the phase II development plans, in GI cancers, will do the same for HCC and CRC. With that, handing back over to Kevin.
Thanks again, Rob, and the audience will be pleased to hear, I think this is my last segment just for now. Next slide, please. I'm gonna try to explain to you some of the issues relating to the treatment of head and neck cancer and where there may be opportunities. For those of you not particularly familiar with head and neck cancer as an entity, on the next slide, please, I show you just the background. These are tumors that arise between the skull base and the clavicle, affecting areas of the pharynx, the oral cavity and the larynx. This is a common disease actually worldwide. 1 million cases per year projected by 2030.
The standard historical etiological events being alcohol and tobacco consumption, but more recently, we've been seeing an epidemic of patients relating to infection with typically type 16 human papillomavirus for oropharyngeal cancers. The majority of these tumors are of squamous cell histology. We know that these agents are active against squamous histologies, of course. Next slide, please. On this slide, I show you a summary, and this is a rather complicated schema, and I'm not gonna walk you through all aspects of this.
I ask you to focus on patients with locally advanced squamous carcinoma of the head and neck, the non-resected population, where the gold standard of treatment in the vast majority of centers around the world is concurrent chemoradiation, and you can see that the NCCN guidelines give Category One optionality for three of those approaches, but by far, the majority of patients will be treated with a combination of platinum and radiotherapy, usually platinum on a three-weekly schedule. Next slide, please. Here you can see data which have been increasingly maturing over the last 20 years from the MACH-NC meta-analysis g roup, in which we look at the addition of systemic therapy to loco-regional therapy mainly radiation, so radiation plus chemotherapy.
You can see that there is a highly statistically significant improvement in overall survival to the tune of about 6.5% at five years. I think the thing that I take away from this as a head and neck oncologist is that there is a very significant unmet need here. Most of the patients, regrettably, still succumb to their disease within a relatively short period of time. Next slide, please. We have tried to integrate immunotherapy into standard of care chemoradiotherapy regimens, and I'm gonna rehearse for you one or two studies that have been conducted and published and presented within the last year or two. The first of these is the JAVELIN Head and Neck 100 study.
In this rather complicated schema, you can see that patients with high risk, locally advanced disease, almost 700 patients randomized one to one between gold standard treatment, which would be platinum plus seven weeks of radiation, with either placebo given 1 week beforehand, during and then after for one year as adjuvant therapy or the experimental arm, in which we interceded with the use of an anti-PD-L1 antibody avelumab. The endpoint of this study, looking for an early positive readout, was progression-free survival measured by investigator per RECIST 1.1, looking at this as an early one and two-year landmark. Next slide, please. The groups are well-balanced, but what I show you here is the data for the primary endpoint.
You can see, much to our disappointment, the placebo curve lies superior to the experimental arm of avelumab here for the progression-free survival endpoint. You can see that the addition of concomitant induction, concomitant and then adjuvant immunotherapy in that schema was not successful. The other message to take away from this is, this is a disease truly of unmet need. At the 24-month landmark analysis, you can see that up to 50% of patients in each arm has relapsed of their disease. Next slide, please. When we look at the overall survival analysis from these patients, you can see again, the curves from the point of view of the investigators are in the wrong place. The avelumab arm is doing inferiorly to the placebo arm. No benefit. Indeed, the hazard ratio 1.31.
Not a statistically significant detriment, but nonetheless a clear indication that there would not be a survival advantage. Again, the take home message here is that at around about 36 months, 1/3 of our patients have died of their disease. This represents a significant medical problem. I show you very briefly on the next slide, another study that had been conducted this time with the drug pembrolizumab, looking with a slightly different approach in a group of patients less well able, less fit, to receive concomitant platinum-based chemoradiation. You can see the randomization is between cetuximab radiation versus pembrolizumab radiation. The projected locoregional control at 15 months with cetuximab radiation by the investigators was 60%. They pretty much nailed that. It was 59% in the study. Pembrolizumab did absolutely no better.
Again, you can see that the odds ratio and the P value indicate no benefit here from the addition of pembrolizumab to radiation when compared with another gold standard, cetuximab radiation. Where should we go, and what are the opportunities? On the next slide, I just want to rehearse with you some data published most recently in full paper form, but this is the slide design from the original ESMO Congress. You can see a small randomized phase II study of a novel immunotherapy agent. This is xevinapant, which is a SMAC mimetic, a drug that modulates the way cells die. It's an inhibitor of inhibitors of apoptosis. Here you can see xevinapant combined with chemoradiation versus placebo plus chemoradiation. The primary endpoint of this study was a locoregional control endpoint done at 18 months.
If we go to the next slide, I show you really the stunning data for progression-free survival, albeit with relatively small numbers. You can see here a marked difference between the experimental arm and between the control arm of chemoradiation. Now, this chemoradiation arm is admittedly performing less well than we may have expected from historical controls, but this was a highly advanced population of patients. I think the take home message from me from this study is that we have an opportunity here truly to combine novel immunotherapeutic approaches above and beyond the simple PD-1, PD-L1 approach, and maybe to use other agents. This is an approach that Rob Coffin and I have explored before.
On the next slide I show you, the design of a clinical trial that we published now fully 12 years ago, in which we designed a study with standard of care chemoradiation in which we gave a herpes simplex virus, an oncolytic herpes simplex, talimogene laherparepvec, T-VEC, as you will know, during that treatment, given at each dose of platinum and then a further dose three weeks after the end of chemoradiation, delivered intratumorally into patients with neck disease and a heavy nodal burden. Next slide, please. Here I show you an example of one such lesion that was injected, a patient with a hypopharyngeal tumor, the white arrow indicating the large nodal mass. You can see on the right-hand side of the slide, panel C indicating a complete response. Next slide, please.
Here I summarize for you the data from that phase I/II clinical trial. Treatment was extremely well tolerated. No grade 3-5 toxicities. Significant number of patients showing response by RECIST. Pathological complete remission confirmed in the neck dissection specimens of 93% of the patients. We were also able to detect the fact that the virus was replicating in and spreading within the nodes that we had injected. We showed that there were very impressive disease-specific and overall survival data. Locoregional control achieved in every patient and a relapse-free survival rate in the initial publication of 76.5% and at the latest update of this, more than half of the patients still in remission on long-term follow-up. Next slide, please.
The conclusions from this approach, which is a concomitant approach with a novel immunotherapeutic agent, is that although we have the opportunity of having effective primary therapy with chemoradiation, a large number of patients will relapse, especially those with high risk disease. It doesn't look as if anti-PD-1, anti-PD-L1 therapeutic approaches concomitantly with chemoradiation are gonna be the solution to this. I think that means that the field is wide open and in urgent need actually of development of better therapeutic opportunities. I believe that oncolytic immunotherapy is just such a treatment opportunity, the ability to kill and sterilize tumor cells through the oncolysis, but also the activation of the immune response to help clear up the disease and protect against subsequent relapse. We will anticipate synergy both with the radiation and the chemotherapy. Indeed, those data have been published.
In addition, the treatment beyond the completion of chemoradiation with adjuvant nivolumab, as per the PACIFIC study in stage III non-small cell lung cancer, may be another way to amplify this benefit. In the final session, I'm just gonna discuss about unmet need in relapsed metastatic head and neck cancer on slide 110. On slide 111, I rehearse for you the way that we have been developing immune checkpoint inhibition therapies in head and neck cancer. Typically, of course, as you know, working from the right-hand side of the slide, from the bottom to the top, the direction of development is usually in relapsed end-stage disease progressing back towards curative opportunities.
That's exactly what we've been doing with approvals in second line for pembrolizumab and nivolumab, and in the first-line setting for pembrolizumab monotherapy or pembrolizumab plus chemotherapy. As yet, there is a wide open opportunity, both in adjuvant therapy and in concomitant therapy with chemoradiation for the development of a novel therapeutic approach. Next slide, please. Here I show you some summary data from the KEYNOTE-048 study. This is the study that demonstrated that the addition of pembrolizumab to platinum and 5-fluorouracil was superior to gold standard platinum 5-FU cetuximab. Here you see the data for the patients with the PD-L1 CPS greater than or equal to one. This is the most broadly applicable license for this treatment globally.
You can see that there's a benefit, clear cut, but what you also see is that the vast majority of patients, unfortunately, still succumb to their disease. There is a need for better treatments. On the next slide, number 113, I show you data from a long-term follow-up analysis where we've looked at patients with very high CPS greater than or equal to 20, excuse me, or CPS greater than or equal to one on the right-hand side. You can see, in fact, most of the benefit here is deriving in the high CPS values, for patients treated with chemotherapy plus pembrolizumab. Even for that small group of patients who benefit, we have to remember the vast majority of patients who sadly die of their disease and the need for further better treatments. Next slide, please.
Here I conclude where I think the opportunities might lie, both in the first-line setting for in the setting for first line and recurrent metastatic disease. We may have two new standards of care, but they're not yet good enough. Although we see benefit for chemotherapy plus pembrolizumab combinations, there is an opportunity to do more. We believe that the use of chemotherapy can reduce the rate of early progression. There's a significant unmet need for the patients who have a relatively low CPS value, less than 20, so between one and 19, and indeed less than one. We have a real opportunity here for intratumoral RPx agents directly killing tumors, turning cold tumors into hotter tumors, increasing expression of PD-L1, and inducing systemic immune responses.
We have every expectation, and the data thus far from the program suggests that this will be potentiated by anti-PD-1 therapy, and there may indeed be a synergy with chemotherapy drugs, including taxane-based chemotherapies. We believe that there are new opportunities here for intratumoral RPx platform viruses, RP2 and RP3, with chemotherapy and immune checkpoint blockade, especially targeting the CPS less than 20 population. With that, I hand you back to, I think, Philip, who will introduce our next speaker, I believe.
That's Tony Saab, Leader of Gastrointestinal at the Mayo Clinic. Over to you, Tony.
Thank you. All right. We'll go through data regarding hepatocellular carcinoma and colorectal cancers, specific considerations for unmet needs. The next slide, please. You know, these cancers are certainly both colorectal and liver cancer are some of the most common cancers in the world. They're in the top seven, and you can see colorectal cancer is in the third spot and liver cancer in the sixth spot. When we look actually at cancer death, now these two cancers are actually in the top three cancer killers in the world, and thus continue to represent a significant unmet need despite the improvements that have been occurring over the last few years. Next slide, please.
First, I'm gonna start with liver cancer and go a little bit through the landscape and where the need lies. Next slide. When looking at the high-level overview for the treatment landscape in HCC, and we typically use this Barcelona Liver Clinic classification to look at the various stages from the zeros to A and C and D. Zero, of course, is the very early stage, where mostly it's a surgical or transplantation issue, liver transplantation. The stage D is unfortunately the last stage of the cancer. The focus of the discussion will be primarily around the advanced stage, the C.
Although a lot of what is applying now to the C is moving a little bit into the B as well, as we continue to enhance our likelihood to see responses in a disease where we haven't traditionally seen responses with therapeutics. Therapy overall has advanced relatively well with immune therapy. You know, for the longest time, we didn't have any standard. After 2007-2008, we had a multi-kinase inhibitor, sorafenib. For many, many years until just 2020, we haven't had any meaningful regimens in the first line, immune therapy specifically to move the needle further, and we have this with atezolizumab and bevacizumab and now with durvalumab and tremelimumab in advanced HCC.
There's still a significant need, and as we go through the data, you'll see that although we are improving, we certainly are hitting a plateau. There are novel approaches that are being investigated, primarily local interference or direct interference with the local immune milieu or microenvironment, that we believe will continue to enhance further the likelihood of seeing meaningful responses. Then, beyond the first line, it becomes quite tricky. We have agents, mostly multi-kinase inhibitors, mostly tested for sorafenib. However, these have moved the needle very little for the most part. This represents, again, another significant unmet need and important to continue to explore the role of immune therapies. Next slide, please.
The first experience with first-line PD-1 inhibitors immune therapy had been with single-agent nivolumab, CheckMate 459, which compared it to sorafenib, suggesting that essentially a small subgroup of patients may end up benefiting, but it wasn't meaningful enough to actually lift the curves beyond sorafenib. Unfortunately, it was negative. It was a setback. The thought is that in HCC, a single agent PD-1 or PD-L1 would probably not move the needle enough for most patients.
Therefore, combinations that were rationally designed based on early clinical data as well as significant preclinical data suggesting that adding essentially agents like anti-VEGF agents with bevacizumab or multi-kinase inhibitors would essentially enhance the immune competency of the milieu and help cells migrate to the tumor and therefore enhance the activity. Next slide, please. Additional data also suggested that where PD-1 blockade on its own may not be sufficient, adding a CTLA-4 inhibitor would actually enhance further the activity, and therefore increasing significantly the likelihood of seeing more meaningful responses in more patients. Next slide, please. In fact, this certainly has translated into improvements. We'll see the results next. In this situation now we have two standards of care.
The preferred one is atezolizumab and bevacizumab for first-line HCC. For select patients, those that are at risk for severe bleeding, and I can tell you for the selected group, it's very few patients, perhaps tremelimumab and durvalumab. There is still a significant proportion of patients. We've heard quite a bit from previous discussants about patients who essentially either are transplant or solid organ transplant patients or those patients essentially with, in this case, with severe autoimmune diseases. There is a contraindication to PD-1 or CTLA-4 inhibitors. Those patients, at least in HCC, and remember, HCC is a disease where we transplant the liver for the early stages, yet many of those patients can have local recurrences, and they're not eligible for IO therapy anymore.
Those patients would be eligible for lenvatinib or sorafenib and also create opportunities for local manipulation of the immune microenvironment without going systemic with PD-1 and CTLA-4 inhibitor. You know, an area that could be explored certainly with direct injections into the tumor site. Next slide, please. This just shows you where we are at today. We have three phase III studies, but two I'm gonna focus on that essentially change the landscape of how we treat patients in the first-line setting of hepatocellular carcinoma. COSMIC-312, the one on the right, actually looked at cabozantinib and atezolizumab versus sorafenib. This study was positive on the progression-free survival, but was negative on the overall survival.
These were two co-primary endpoints. Unfortunately, the lack of a survival benefit will make this a very difficult proposition to move forward with, especially that the toxicities appear to be amplified. The response rate was 11%, and that's frankly no better than what you would expect from single agent, a PD-1, PD-L1 inhibitor. Certainly a disappointment. IMbrave150, which looked at atezolizumab and bevacizumab. Bevacizumab, a monoclonal antibody, to VEGF, and atezolizumab, PD-L1 inhibitor, has shown essentially improvements across all efficacy parameters from survival to progression-free survival to response rate. Now notice the response rate is 30% with 8% complete responders, and that's fantastic for liver cancer, given the fact that we previously haven't expected responses above 11%. Certainly we're not there yet.
We're not even close to the 50% mark of response. It's an improvement, but certainly significant, but certainly not where we wanna be yet. With HIMALAYA, with durvalumab and tremelimumab, a combination called STRIDE, there was a little bit more modest improvements historically, at least, with median overall survival. Disappointingly, the progression-free survival was not as good. In fact, you know, at the median at least, was a little bit lower than sorafenib, but the hazard ratio about the same. The responses was observed in 20% of the patients with only 3% of complete response.
This is why, you know, atezolizumab and bevacizumab would remain the primary standard with backup for a few patients for the STRIDE regimen. The toxicities are relatively tolerable and mostly acceptable in this group of patients. Next slide, please. Now, when we hit the second line, it becomes more obvious that two things become obvious. One, the outcomes remain very modest when improved. Two, the responses are few and far between. Three, the toxicity specifically with the multi-kinase inhibitors can be very limiting for this group of patients. As you can see in the CELESTIAL/RESORCE, CELESTIAL was with cabozantinib, RESORCE with regorafenib, and REACH-2 was with ramucirumab. Although the alpha-fetoprotein marker was supposed to
In this study was above or equal to 400, which is about 40% of patients with HCC. There were almost no responses in those with those agents. The improvements with both survival and progression-free survival were incredibly modest. Ultimately, these were in the setting of prior sorafenib. Today, in a world where we've moved to atezolizumab, bevacizumab, so IO primarily in the first line, it's very difficult to put in perspective how exactly those studies continue to fare in a landscape that gets more complicated. KEYNOTE-224 looked at pembrolizumab and then was a follow-up study, KEYNOTE-240, with pembrolizumab single agent versus placebo that, although numerically did show some improvements, but these improvements was not statistically significant versus placebo.
There's a China study looking at the same that appears to be positive, and so the combination of the two studies may actually keep pembrolizumab as an option. Again, those studies were done in the setting of post-sorafenib, and not post atezolizumab or bevacizumab. CheckMate 040 did have a nivolumab and ipilimumab arm. The response rate was very promising. This was a single-arm study. The first-line study comparing it to standard of care TKI is ongoing. However, you know, one consistent element here is although all these studies were performed following failure of sorafenib, we continue to see that IO is, if I may use this, the way to go.
Meaning IO in this disease seems to move the needle a little bit further historically than tyrosine kinase inhibitors. Especially as you amplify the utilization of CTLA-4 inhibitors or VEGF inhibitors as you move even further towards an improvement of outcomes versus PD-1 or PD-L1 inhibitors. Next slide, please. It's also important to note that a lot of these tyrosine kinase inhibitors that are used have significant toxicity, especially in this patient population. How can we continue to expand the benefits of immune therapy? I mean, we've hit a plateau. We have improvements, but we've hit that 20%-30% response rate plateau. One of the thoughts is essentially to continue to move forward with enhancing essentially the tumor-associated antigen exposure and primarily targeting intratumoral treatment.
There are different ways to do that. The less specific, meaning applying a radiation, whether externally or internally, that certainly appears to improve outcomes somewhat. These are very nonspecific ways to do this. Next slide, please. Again, in the spirit of all the discussions today, is applying oncolytic virotherapy, virus infection directly to the tumor. Now, these are tumors that primarily, in HCC, stay in the liver. A few metastasize outside the liver. The liver, you know, remains the primary target. We know that liver tumors intrinsically across multiple malignancies tend to be immunosuppressive. Local milieu manipulation makes a lot of sense.
In this instance, injecting oncolytic virus directly into the tumor that, you know, may end up releasing antigens and recruiting innate effector cells, which essentially, you know, bring those coveted T cells and other immune cells to the milieu. They're primed, expanded, they travel to the tumor from the lymph nodes. Ultimately, with these activated T cells, as they infiltrate the tumors, this ends up exposing the area to higher level of antigens and cells that are essentially ready to kill those cancer cells. This antitumor response can be boosted by immune checkpoint inhibitors. That presents essentially a great asset with the hope to enhance further the benefits we've seen in HCC with immune therapies. Next slide, please.
Thinking about this, you know, in perspective, immune therapy obviously with atezolizumab and bevacizumab and somewhat with STRIDE has moved the needle for us. We've hit a plateau in first-line HCC. Beyond first line, there's absence of data post-IO. Now that our world in the first line moved to atezolizumab, bevacizumab, or STRIDE, we do not have that data in the second line. We don't have much data in the second line. Lo and behold, knowing that IO seems to be driving the post-IO, whether reversing resistance, such as with priming with injected oncolytic viruses into tumors, whether that essentially can prolong the benefit that we've seen with IO and enhance it further.
The tumor-directed oncolytic immune therapy, you know, appears to have promised to improve IO effectiveness in first line, and we hope that it may actually overcome resistance in the second line and therefore extending the life of IO and enhancing the response. As you've heard, liver procedures by interventional radiology are pretty routine in HCC. In fact, you know, one can foresee how we can continue to move this into that stage B, so earlier stage disease stages and even into the neoadjuvant settings to continue to enhance outcomes. Next slide, please. Now I'm gonna move on to colorectal cancer, specific focus on refractory colon cancer. Next slide, please.
We've recently published this summary about essentially improvement in outcomes with the advent of a lot of these agents that are either specifically and biologically targeting certain subgroups of colorectal cancer patients or in the case of a very small percent of patients, about 2%-3% with MSI-High, with immune therapies. As you can see, essentially, the response rates can improve further up as we are able to identify the targets better. That also is translated into an improvement in progression-free survival. Many things here that are important to keep in mind.
One is, although we're starting to break down colon cancer into these subgroups, the totality of these subgroups, if you put all these together, remains less than 20% of patients where we have an identified target that we can go after, or an immune target that we can go after. About 80% of patients with colon cancer in the refractory setting will have liver metastasis. In fact, you can make that argument for most metastatic patients with metastatic colorectal cancer. These the liver metastatic disease for those patients with heavy involvement in the liver end up being one of the main reasons why patients die from colon cancer. Next slide, please.
When we look at the landscape for the other 80% of the patients who frankly do not have a targeted therapy, you can see that the outcomes are relatively poor, modestly improved at best, but there also remains significant toxicities for patients who are not as performant as they reach this line of therapy. Two agents are available to us. One is a multikinase inhibitor, the other one is a cytotoxic agent, that's TAS-102, regorafenib, the multikinase inhibitor. As you can see in the box down there are no responses typically seen with these agents. The improvements in both survival and progression-free survival are incredibly modest, and the toxicities can be quite pronounced with these agents. Next slide, please.
There has been tremendous effort to try to move IO from those patients, what we've seen with MSI-High colorectal cancer, significant improvements, but this remains limited to 2%-3% of patients. The majority of the patients are microsatellite stable or proficient MMR. For those patients, trying to move IO into the settings where we can actually see similar responses has been incredibly challenging. We've recently published this study in JAMA Network Open and essentially looked at the contribution of atezolizumab, a PD-L1 inhibitor, to standard chemotherapy. One arm had atezolizumab, the other arm had a placebo. What we've seen interestingly is that there is a small subgroup of patients that seems to benefit in the microsatellite stable from the addition of IO from atezolizumab. The majority don't.
Next slide, please. These trends appear to be similar, whether it's regorafenib plus IO, whether it's lenvatinib plus IO. You do see these trends. This, by the way, is the first randomized study prospectively assessing that. But what appears to be a common theme across the board is that patients who do have liver metastases do not appear to benefit as well from the addition of atezolizumab versus placebo, unlike the patients with no liver metastases that appear to drive some relative benefit. When we look at response rate, for example, it's less than 10%, it's 5.8% to be exact, if the patient had liver metastases, and it's 23% if the patient did not have liver metastases.
The main reason for that, we think, and that's been actually shown in multiple studies, that, the immune milieu with liver metastatic disease, not just in colon, but here, since we're discussing colon across the board, tends to be immunosuppressive and therefore challenging, in terms of going directly with PD-1, PD-L1 inhibitors. You really need to act on that immune milieu to enhance the likelihood of activation of these agents. Next slide, please. In summary, how can we turn these microsatellite stable colorectal cancer tumors from cold to hot, understanding that this is 96%+ of patients with colorectal cancer will have microsatellite stable tumors, and more than 80% of those patients will not have an identifiable target to go after.
It's a significant unmet need, and we've seen that the agents available to us in the setting right now certainly are not meeting the need. They're toxic. They end up giving very little improvement in outcomes. In immune therapy, specifically PD-1, PD-L1 inhibitors and VEGF targeting agents do show some limited promise, except that promise appears to be mostly limited to the non-liver metastatic disease. 'Cause the presence of liver metastases is consistently associated with resistance to PD-1 and PD-L1 inhibition, as I said, in microsatellite stable colorectal cancer. Also we've seen these trends across the board in other cancers as well. There's this immunosuppressive microenvironment that's present in this liver metastatic disease.
It appears, you know, from preclinical data and early clinical data that tumor-directed oncolytic immune therapy may reverse this immunosuppressive microenvironment in liver metastases, and specifically when we look at colorectal cancer in microsatellite stable tumors. It gives us hope that this may enhance the role of IO in this disease. With this, next slide, please, I finish this discussion and pass it back on to Rob.
Thank you very much indeed, Tony. I'm gonna provide a little bit of a summary in relation to the intended phase II development program for RP2 and RP3. In summary, we believe that the phase II development plan outlined by myself and Tony and Kevin hits all of our areas of interest and provides a risk-balanced approach to further developing RP2 and RP3. This includes potentially very large markets with high unmet needs, such as third-line colorectal cancer, as Tony's just described. On improving IO effectiveness on the top left, we're adding first-line hepatocellular carcinoma to our portfolio, which currently includes first-line CSCC. On overcoming IO resistance on the top right, we're adding second-line HCC and also first-line recurrent head and neck cancer with low PD-L1.
In bringing IO to new tumor types, on the bottom left, we'll be working, as already said, in third line colorectal cancer and also continuing to develop the signal we've already seen in uveal melanoma. Finally, in the early disease setting on the bottom right, as well as planning for a study in neoadjuvant cutaneous squamous cell carcinoma, we'll also, as high priority, be working in locally advanced head and neck cancer in combination with standard of care chemoradiation, in each of those cases with the objective of achieving higher rates of cure. These clinical development plans are further summarized here in my last slide.
In locally advanced head and neck cancer at the top, we'll initially have a safety run-in in combination with chemoradiation, and then rapidly aim to move to a randomized controlled phase. This is intended, then, following an interim analysis, to expand to full registrational size. It's sort of a two-step or even three-step approach. In the first-line recurrent head and neck cancer setting, we'll conduct an approximately 30-patient initial signal finding trial to look at response rate in combination with chemotherapy and anti-PD-1, i.e. the standard of care. Then depending on that data, the intent would be to move to a registrational setting. In hepatocellular carcinoma, one box down, we'll run an initial clinical trial with two signal finding arms.
In the first line setting, that will be in combination with standard of care atezolizumab and bevacizumab. In the second line setting, in combination with anti-PD-1, whereas Tony indicated there's no effective standard of care with which to combine.
Both of those would then be intended to move to a registrational development phase, depending on the data seen. Finally, we'll run a signal finding trial in third line colorectal cancer, in combination with, again, anti-PD-1, where again, there isn't a known to be effective standard of care with which to combine, which again, is intended to move to registrational development, dependent on the data seen. We think that really does provide a good risk-balanced approach with multiple shots on goal, including targeting areas of very significant unmet need, and also commercial potential. With that, I'll hand back over to Philip, to sum up what we've heard before we move to a Q&A session.
Yes, some brief concluding remarks. With RP1, we are on course to establish a major skin cancer franchise. We are maintaining guidance that we expect to complete accrual from our registration-directed CERPASS study in cutaneous squamous cell carcinoma mid-year, and to release top line data in early 2023. Further, we expect to release directional data from our registration-directed study in anti-PD-1 failed melanoma in late 2022. Large-scale manufacturing has been established and commercial planning for launch in the U.S. is advancing. With RP2/3, we have an exciting mid-stage program to pursue in GI cancers and head and neck cancer, where expedited approvals in some of these settings could be feasible. Finally, we have a strong cash position to drive value through multiple meaningful data catalysts. We will now turn over to Q&A.
Thanks, Philip, and thanks again for everyone for joining this morning. We'll start with our Q&A. Before we do so, just as a quick reminder, to ask a question, please do so using the text box at the bottom of your screen. Let's start with a question that's addressed to the KOLs that are on the line here. There's a debate on the logistics and value of the intralesional approach that persists on the street. What are your views on this modality, particularly in indications like CSCC and anti-PD-1 failed melanoma?
As the question is directed to skin cancers, let's ask Nikhil and then Kevin to comment.
Sure. I think if I've understood this correctly, it's a question of what is the value of an intralesional approach. I think there's a two-pronged benefit to that. Number one is you have accessible tumor that can be easily injected and with little or no morbidity at all. It can be done in the office-based setting. Admittedly, in the United States, I think a key issue becomes is, if I take time out of my day to actually inject these patients in the clinic, does it take away from seeing other patients? I think that is a real issue. But within a multidisciplinary setting, where we have surgeons who help us with this, but more importantly, taking advantage of the expanding, what I call advanced practice professionals, so our APPs.
Our nurse practitioners as well as our physician assistants, who can be easily trained, and we've already done that at Moffitt. We routinely have that in terms of clinical trials as well as standard of care. It's very doable and very targeted.
Kevin, anything to add?
I would agree with all of those comments, and specifically the question asked about cutaneous squamous carcinoma and melanoma. You know, for me, those are by and large the most easily accessible tumors. We tend to do those routinely in our outpatient facilities, I guess what in America is called the office. These are done really very routinely. I think again, I would fully endorse the comments that you can train people to be experts in this relatively straightforwardly with appropriate educational programs.
Actually, for your workforce, I think it's a really strong development because of course it gives that level of autonomy, it gives that level of job satisfaction that skilled allied healthcare professionals are basically upskilling, and they're able to take part in the treatment of the patient in a way that hitherto they haven't been able to. I think it's actually not the problem that people imagine it might be. It's actually very doable.
Actually, we do have a request for perhaps Dr. Ahmed to respond to that same question.
Yeah, absolutely. I mean, I think, as we have talked a little bit about more palpable or visible lesions as it relates to cutaneous cancers. Obviously in the metastatic phase, there are gonna be deeper lesions that might need to be injected. Those are easily accessible and visible through kind of standard techniques, as we've talked about, that are already implemented, you know, widely in clinical practice, including, you know, biopsies, direct access via ultrasound or CT guidance. You know, even in some of these cancers that have metastatic nodes that might be getting ultrasound-guided biopsies, again, that's part of routine clinical practice. It's a very short step towards using those methodologies to inject into those tumors as well. I think with the widespread development of portable.
You know, what's happening in parallel is development of portable point-of-care ultrasound technologies as well that make this very cost-effective and accessible even in potentially office situations.
Great. Thanks. Our next question is for Dr. Harrington and Dr. Khushalani. Do you think the approval of relatlimab for first line melanoma could change how patients respond to second line PD1 combination therapies?
Sure. That's a very, I think, a loaded question, if I may call it that, given that nivolumab plus relatlimab as combination in the same vial was actually approved, about 10 days ago on March 18th in the United States for the treatment of patients with advanced unresectable melanoma. Do I think that this will impact subsequent line therapy? I think it's too early to tell. The way I look at this is there will likely become three buckets of patients that we will be utilizing various anti-PD-1 based regimens in the frontline setting for advanced melanoma. I certainly would be curious to see what Dr. Harrington has to say in his opinion. One bucket will be clearly the nivo plus rela patients based on the approval.
I anticipate that that will take primarily from those patients that we were previously utilizing anti-PD-1 monotherapy, so either nivolumab or pembrolizumab. There will still be a place for anti-PD-1 monotherapy in a small subset of patients in the front line, where we, as clinical practitioners, feel that they may not be able to tolerate combination therapy for a variety of reasons. Now, one could make the argument because the manuscript said that the incidence of adverse events, treatment-related adverse events, was not noticeably higher. I would actually caution that interpretation because almost 15% of patients in the nivo-rela arm discontinued treatment for toxicity as opposed to 8% of patients in monotherapy arms. There is an increase in toxicity, particularly hepatitis, particularly adrenal insufficiency, both of which could have longer term consequences for patients.
The third bucket will still be the combination ipilimumab plus nivolumab. I think many of us in the field would still like to see more data on nivo-rela for what we traditionally consider the poor prognostic or poor actors. That is high LDH, bulky disease, CNS metastatic disease, where ipi/nivo has clearly been shown to be beneficial, particularly in asymptomatic patients or patients with metastatic mucosal or metastatic acro melanoma, where anti-PD-1 therapy doesn't work as well. I think those patients, we would still utilize ipi/nivo combinations, based on a longer-term data on that. In terms of subsequent therapy, I don't think we clearly understand the immune microenvironment following PD-1 plus LAG-3 inhibition, and therefore, using an ipilimumab-based regimen or an alternate regimen potentially on the backbone of anti-PD-1.
That could be a second drug to restore, or overcome primary or secondary resistance to anti-PD-1, and that could include intralesional therapy as well.
Dr. Harrington, could you particularly focus on whether or not you think the approval will?
Yeah.
affect the second line, the need for second-line options?
Yes, indeed. I mean, that was a fabulously comprehensive answer, which makes my job very easy here. I mean, I guess I'd point out a couple of things. There are jurisdictions around the world, sadly, that do not necessarily adopt very quickly these relatively new treatment alternatives. It may well be that there'll be plenty of patients around the globe who do not have the opportunity of the combination of PD-1 LAG-3 first line. The question is really about the mechanisms of resistance that will emerge to patients who have been exposed to dual blockade with PD-1 and LAG-3 targeted therapies. The honest truth is we don't know the true answer to that at the moment.
I would imagine that the sorts of things that we're likely to see, and biopsy studies will need to be done in order to document this, is that we will see T cell exclusion, we will see loss of immune heat, and we will see lack of inflammatory microenvironmental changes, all of which, of course, are changes that we can reverse by the use of intratumoral therapies of the potency that we see with RP1, potent enough, but RP2 and RP3 really enhance potency agents. I would still be confident that we have a suite of agents available to us that can reverse that profile of resistance when we understand what it is. I don't see this as an overwhelming threat, but it's certainly something that needs to be studied.
I think if I could just add one more. I don't know how many of you saw the ASCO plenary session from the March series. ASCO has started monthly plenary sessions, and Georgina Long presented the first look at response rate to nivo-rela and the first look at the interim analysis for overall survival. The combination of nivo-rela, the response rate is approximately 43%, compared to 35% with nivo alone. Certainly numerically higher. Overall survival at that look did not achieve statistical significance. The hazard ratio was 0.8. While the combination clearly improves the time to progression or progression-free survival, we have not yet seen any tangible benefits yet in overall survival.
Now, admittedly, some of that could be due to second-line therapy, and I think that's where we will clearly need to parse out, how do patients do with second-line therapy? That clearly remains that opportunity to improve on our second-line options for refractory disease.
Thank you. Our next question is for Sush. Sush, how do you see oncolytic virus adoption in the academic setting versus the community setting?
Yeah, I think firstly this is a great question. I think, you know, firstly, we're gonna have to see compelling data. I mean, anytime you want anyone to adopt anything, whether it's in the academic setting or the community setting, we're gonna need to generate that compelling data set. As we said, as we talked about, we believe cutaneous squamous cell is a nice opportunity to do that in addition to the data we're looking to generate in the checkpoint refractory melanoma space. In terms of the adoption, I think it's gonna be difficult to say in terms of. If you mean from a technology perspective, I don't think that when we talk about the community nowadays, and at least in the U.S., most community practices are either associated with a hospital, some sort of hospital network, an integrated delivery system.
In many ways, they have the capabilities to do the injections, if that's the question, and especially deep injections. I don't think that'll be a major hurdle right now. If you've got a community practice that doesn't have that accessibility to more of an integrated delivery network, you know, then I think what Muneeb mentioned around even private practice radiology practices should be able to do this with portable ultrasound, ultrasounds, other equipment. Maybe Muneeb, I'll just ask you to comment. Is there anything else around the community practice that you would see as a hindrance to adoption versus academic?
Yeah, absolutely. Well, I'll make a couple of points. I think the first thing is that even in early trial success, engagement with kind of the key stakeholder groups, in particular both medical oncology but interventional radiology will be critical to that success. I think that's something that this team, the leadership team here understands very well. I think the second piece is that translating that practice into a broader more community-based setting also includes review of protocols and establishment of sort of standard operating procedures that account for potential barriers in that.
Engaging early in sort of key stakeholder groups, getting input from interventional radiologists, both in the academic center and private practices, will really facilitate that transition, in understanding what needs to happen and also, sort of, dealing more proactively with barriers to and concerns around kind of oncolytic virus injections. Overall, I think there is a large community of interventional and procedural radiologists, including diagnostic radiologists, who are, you know, have the skill set, have the technology and capability as well, to perform these.
The last thing to a point that was mentioned, I think earlier in this discussion, is really some attention to reimbursement strategies and regulatory strategies to ensure that, you know, intratumoral injections and the reimbursement that goes with them properly reflects the effort and level of work, I think will be critical as well to broader adoption.
Yeah.
I mean, to clarify, our first potential launch in cutaneous squamous cell carcinoma will be launching in the community and academic centers in tandem.
In that situation, as Nikhil said, you know, these injections are not particularly complicated. Even in a community practice, it can be done by a nurse practitioner. In fact, that was already happening with T-VEC when they launched as well. We need to make sure there's appropriate training for cutaneous squamous cell to do this safely and effectively. From a technical perspective, I don't know, Nikhil, if you have any other comments on that.
No, I think you're absolutely right. I think encouraging the allied health professionals to practice at top of license is absolutely critical. I think, you know, investing in their education and investing in the techniques of delivery would be important. I would preface this by saying that it all comes down to data. If the data is very compelling, and it clearly demonstrates that intralesional plus systemic therapy offers benefit to patients, I think we follow the data, and we say, "That is how we would modulate or modify our practices if we needed to carve out, you know, based on obviously reimbursement as well, carve out a selected time.
This could be our time for intralesional office-based injections. That's exactly how we do it right now, as opposed to interrupting my day to go and give an injection. That is not very efficient use. Actually carving out time within the day just for these patients, we can easily make that work.
Thanks. Our next question's on RP1. Initial data for PD-1 failed NMSC. You mentioned that some non-responders were showing signs of tumor reduction. How many does this apply to, and how much are you expecting the ORR could uptick?
Well, I think it's probably a little too early to comment. I think there's 5 patients with stable disease indicated in that data. A number more than 1 and less than 5 are in the group of patients who have clearly seen a reduction. Obviously, we just need to wait for the data to mature a little bit to see where they really get to. All I would say is the early impressions of the investigators is that some of their additional patients are clearly doing well and their tumors are beginning to reduce.
Next couple questions are on future development. What could a registrational study look like in neoadjuvant CSCC, and when could you be in a position to start that trial?
Well, again, it's a little too early to answer that question in detail. We are in the planning stages of clinical trial design in the neoadjuvant setting. The intention is to get that going around the end of the year. A number of different trial designs, including with different potential control arms and combinations are currently in discussion. Unfortunately, I can't answer in detail at the moment until that planning process is complete.
Thanks, Rob. Another one. Do you plan to run registration-enabling studies for MCC, BCC, and/or angiosarcoma since RP1 has shown robust efficacy in these tumor types?
We're still working out what the appropriate route forward to potential commercialization would be in those tumor types. Obviously, one could run actually registrational-directed studies in them, although they are relatively rare, at least in the latter two tumor types of tumor. We're also thinking about compendia listing as a route forward. Likewise, all will become clear in the fullness of time. There's two potential avenues. Both could be employed, and it's really a sort of commercial consideration as to which is the best approach to commercialize in those tumor types. Maybe Sush might comment further too.
Yeah, I think you said it, Rob. I think it really depends on the size of the opportunity. We haven't done a lot of work on the actual opportunity size. I mean, for example, angiosarcoma, based on the incidence numbers I've seen published, is a very, very small market. That being said, we've seen quite a lot of patients come onto our studies, and it makes you wonder if there's more patients out there. I think we need to do more work on that, and it could be the compendia listing of 20 or so patients could be sufficient.
Could I add something from a clinical perspective for the angiosarcoma team? You know, in my previous life, in addition to cutaneous, I did sarcomas as well, so I saw a lot of angiosarcoma at a referral academic center. Certainly with angiosarcoma that is considered unresectable, our treatment options are primarily either systemic taxane use, which works very well, but it works for a finite period of time. Then almost all of those patients eventually develop either local regional progression or distant metastatic disease. Similarly, anthracyclines, so Adriamycin or equivalent drugs, are utilized in angiosarcoma, but cannot be given to everyone because of the obvious cardiac toxicity and comorbidities.
Given that many of these tumors are, again, on the scalp and easily accessible, and with at least some of the early data in a rare subtype of tumor that this would qualify for, I think the bar for potential regulatory approval is certainly lower.
I think our observations do suggest that the sort of official numbers may underrepresent the reality of the disease because, as Sush says, we do tend to get quite a number coming in, which suggests there must be, in inverted commas, more out there than people think, in a similar way as there turned out to be many more out there, as it were, in CSCC once an effective drug became available to treat it.
I'd add uveal melanomas to that as well.
Great. Thanks. Another question, with RP1. What's the potential regulatory path in solid organ transplants, and could the ARTACUS study be that registrational study?
The ARTACUS study was actually designed as to be of a size which could in itself support registration in a tumor type where there's not vast numbers of patients, but still a clear unmet need. We could therefore with the full 65 patients recruited choose to actually file a supplemental BLA for that indication. However, the alternative approach is still being considered as well, which again could be compendia listing. It's a sort of commercial consideration as to which approach is appropriate, but we have the flexibility for either based on the current development plan.
Maybe just to add, we're definitely looking at this market from a commercial perspective and doing some research. It's quite hard, as Nikhil said, to sort of get an actual handle on what the opportunity is. There's clearly a lot of patients out there, but are they gonna be actually treated is something we're really thinking through. It also depends on what organ transplants you're talking about. These patients can develop cutaneous squamous cell carcinomas at any different time point. It could be years after their transplant. It's a bit hard for us to get a sort of exact number today, but we're doing that work. It could be that we go forward with a registrational study or that a compendia listing could be sufficient to treat those patients given the unmet need.
I don't know, Nikhil, if you have anything?
No, I would agree. I think, you know, having seen these patients at our center, even though Moffitt Cancer Center does not have its own transplant program, we are part of the University of South Florida and the large teaching hospital, which is Tampa General Hospital, does the solid organ transplants there. If you look at the transplant registry data, the number of solid organ transplants on an annual basis continues to increase by roughly about 5% compared to the preceding year. For example, in 2021, about 41,000 solid organ transplants were performed, the vast majority admittedly kidney transplants. And if you then extrapolate further, about 8%-9% of those patients over time will develop CSCC.
Certainly about 15%, depending on various registries, you know, both from the United States and the United Kingdom, will develop keratinocyte carcinomas, including basal cell cancers as well. Those patients certainly cannot receive, or at least upfront, should not receive immune checkpoint inhibitor therapy for compromise of the allograft. I think that certainly serves as an opportunity.
We will also separately be looking at, in particular in one of our investigator-initiated studies, other immunosuppressed populations as well as solid organ transplant recipients, i.e., patients with autoimmune diseases, HIV, et cetera, to gather data beyond just solid organ transplant recipients.
I think in ARTACUS, Rob, we're talking about sort of expanding beyond some of the different organs, right? That's a discussion we're having.
Yes.
Great. We've got a question for Dr. Harrington. A bit of a long one, so bear with me. You provided data of responses in skin cancer, slightly more than one in three for anti-PD-1 failed melanoma and somewhat similar outcomes, demonstrated in an anti-PD-1 failed CSCC. The question is around the roughly 25% of patients that have progressive disease. Are there any characteristics you can speak to of patients that progress?
That's a good question, and I wish I had a really clear good answer to it. The fact is that the patients who respond. This, I think gets a little bit to the question that was asked of Rob Coffin a moment ago about what's happening to the patients currently with stable disease. We often see quite an early response, but the actual full resolution of the lesion, and I think it was shown in one of my slides, as the tumor regressed towards complete remission, it can take many months to achieve that state. For the patients with progressive disease, we tend to see that progressive disease is relatively slow, but tends to be relatively early and relentless, is our experience of these patients. I'd be interested to hear if others have a similar experience.
We don't see a true hyperprogressive response that is sometimes spoken about, certainly in head and neck cancer with anti-PD-1 therapies. We don't see that occurring. We do tend to see that patients who are responding, we often get an early readout of that, often with the patient saying they've got symptomatic benefit, and then we see the reduction in the tumor. For patients where the disease is not responding, we see a relentless progression, albeit rather slowly.
Can I slightly add, which isn't directly answering the question, but I think an observation, is that where patients get through to their second scan, whether or not they're responding by that point, tend to do really very well, in the longer term. With often at the first scan or first assessment, some evidence of increase or new lesions appearing, which then regress by the second scan. While it doesn't tell you which patients were those who were going to get to that second scan, it certainly is the case that if you do get to that second scan, you've really got a good chance of a long-term benefit.
Great. Our next question for anti-PD-1 refractory CSCC patients, is there a spider plot for patient responses over time, or is it too early in their treatment?
It's too early. There's not a big enough n yet for a spider plot. As the table says, there's still four patients with stable disease on study that could go either way. We'll do that when we next update the data maybe later in the year.
Yeah. It really is a first data cut of early data, which is definitely directionally promising. More patients and longer follow-up are needed before it's appropriate to plot out in those ways, which we certainly will be doing, as Philip said. From what we've seen so far, I think it'll look very similar to the spider plots we've already shown in the other skin cancer situations.
Great. Thanks, Rob. The next question is, thank you all for the updates in skin cancer. When do we get updates on non-skin cancer programs?
Well, we're running phase I expansions for RP2, RP3, focusing down on the tumor types we're more interested in for phase II development that we've unveiled today, including GI cancers and head and neck cancer. We hope to have an update on those phase I expansion patients around the end of the year. Obviously, the phase II program doesn't start until the year-end itself, and therefore data will be pushed out in early 2023 for the phase II program.
We've got a manufacturing question. How much more work do you need to do to be ready to file the BLA on time?
Well, I'd say work is progressing on track. We have completed the comparability work from our Framingham in-house material to material that's been used in our studies and put the report back into the FDA. We're having further discussions with the FDA over the months to come. We've also had good clarifying discussions with the FDA on release assays, and it's all on track. The bulk of the work, the back has been broken.
Great. Philip, this is a question directed towards you. It's a broader strategic question for the company. The slides noted that you are capitalized to build U.S. commercial infrastructure. I guess the question is how are you thinking about current development status for RP1 through RP3 and balancing that with potential timing of an OUS partnership?
Well, we have a very broad ambition to become a cornerstone of IO regimens, which involves going into a number of different cancer types, some of them being quite large cancer types. We've also seen activity from the, you know, all the way from the anti-PD-1 failed setting, also have reason to believe that there is compelling reason to go to the neoadjuvant setting. That's also a broad spectrum of potential development. I think it's kind of intuitive that to extract the most value across all those stages of disease and different disease types, at some point a partner would help us extract more value than a
Got it.
The downside of pursuing a loan. However, we have, as you noted, the funds and the plans to build U.S. infrastructure for our initial launches. What that does is allows us to have destiny in our own hands. Quite when the timing of such a development commercialization package may take place, we're not beholden to any particular timeline. In terms of the value creation, we will see at any given point in time, depending on the value created, whether or not the terms of a more holistic commercialization and development plan makes sense to the company.
As I reiterate, we're in a very strong position, $420 million on the balance sheet, to have destiny in our own hands, and the default pathway at the moment is to build U.S. commercial infrastructure for the launch of CSCC and PD-1 failed melanoma.
We have a next question. Have you looked for the biomarkers in responders versus non-responders, over the treatment, with RP1?
I think really we don't have yet enough data from enough patients to draw any hard and fast conclusions as to what the predictive biomarkers they could be for response. We do see some characteristics in responding patients which are not present in non-responding patients, but they're probably the aftereffects post changes rather than things you can necessarily see at baseline. However, I do think the CERPASS dataset which will be really rather large when we finish the trial will be an excellent place which we will be going to look at biomarker effects in both responding and non-responding patients in a truly homogeneous population where we may then really begin to see something which is predictive.
The answer is, at the moment, it's too early. We definitely see very positive changes indicative of a broad immune activation, but we haven't seen any clear baseline prognostic characteristics which could suggest which patients respond and which don't. As you've seen, patients, whether or not they have PD-L1 or CD8 or other immune markers at baseline, can respond in a sort of non-correlated way.
Thank you. Next question is for Dr. Harrington. Can you provide any insight into how toxic chemotherapy is in first-line metastatic HNSCC? If you think using RP2/3 plus PD-1 makes sense, given that HSV could provide rapid tumor killing.
For first line treatment of relapsed metastatic head and neck cancer, we know that the standard of care regimens, such as the EXTREME regimen, which was previously the gold standard, are associated with very appreciable grade 3 toxicity rates in excess of 60%, 70% in many studies. We know that it's a toxic regimen, and therefore, patients need to be reasonably robust with a performance status of at least one, preferably zero, in order to withstand those. We also know that single agent immunotherapy, pembrolizumab, for instance, is well tolerated and that the grade 3 toxicity rates are something like 1/2 to 1/3 of the rates that we see with standard of care chemotherapy. The tricky thing, of course, is to combine both the immunotherapy and the immune checkpoint inhibition.
We see that the toxicity looks very similar, but with the absence of the cetuximab-related toxicity. Again, in order to deliver cytotoxic chemotherapy plus an immune checkpoint, patients need to have a strong and a good performance status and be able to withstand the toxicities. Our experience previously, not yet with the RP platform of viruses, but with our previous experience around the work with the T-VEC agent, is that the addition of a virotherapy to chemotherapy combinations adds little or no additional toxicity. I would feel that it would be highly likely that for patients who are fit enough to withstand chemotherapy plus IO combinations, the addition of intratumoral oncolytic virotherapy with an RP2 and RP3 platform would be entirely sustainable.
This next question is for Dr. Saab. How excited would you and your colleagues be about a novel approach like oncolytic immunotherapy to move the needle in HCC and CRC? How quickly would something like that enroll based on need and anticipated interest?
You know, I think the approach itself is very exciting. As I mentioned, you know, if you wanna talk about HCC, in HCC, you know, we obviously have hit a plateau. Although we have moved the needle, we haven't moved it far enough to essentially have done the job for that, right. An approach that essentially targets specifically the liver tumors would certainly be desirable, especially in a disease. Let me start with HCC first. A disease that you know has already shown some level of immune competence, meaning that out of all the therapy options that we've had over the last 20 years, IO seems the one to hold the most promise.
In that sense, you know, oncolytic viral application, you know, holds quite a bit of a promise. There is some precedent, not just in preclinical settings, but certainly in early clinical settings that does show that we can enhance that activation. Certainly very exciting, very feasible. You know, as I mentioned, you know, those tumors are mostly in the liver. They're in our setting and other settings as well, you know, easily reachable by ultrasound injection. We've done quite a few of these studies in the past, and we know they're very feasible.
Certainly, you know, looking at the promising data, both early clinical as well as preclinical, I mean, that's a very exciting area in HCC. As to colorectal cancer, you know, this one has been a bit more challenging. Again, you know, looking at those microsatellite stable colorectal cancer certainly seems that outside the liver, we are seeing those responses. Immunotherapy, in my viewpoint, remains a promising option for patients as long as we're able to move those liver metastatic lesions from immunosuppressed to essentially immunocompetent.
This is where, again, looking at the totality of the data we have today and where we may be moving, you know, in the near future, it appears that tumor-directed oncolytic immune therapy may actually reverse that local immune suppressive microenvironment and therefore, you know, bringing those tumors into where we're seeing the non-liver metastasis and colorectal cancer responding. In that setting, you know, I'm again pretty excited about the opportunity. As I said, 80% of those tumors will be present in the liver, or 80% of metastatic colorectal cancer will have some level of liver involvement, you know, from some to extensive liver involvement.
Reaching those tumors with ultrasound-guided, you know, strategies to inject the virus are done pretty routinely on clinical trials in our practice and others as well.
Great. Thanks. We've got a number of questions regarding RP3. First, how do you compare the patient baseline-
Chris, we can't hear you, unfortunately.
Can you hear me now? Great. We got a number of questions on RP3. First, how do you compare the patient baseline prior line disease lesion for RP3 versus RP2 monotherapy?
Well, I'll make some opening comments.
Yeah, I mean, these were both standard phase I populations, and to some extent, it's a lack of the draw—luck of the draw, sorry, who is enrolled into those populations. However, I do think it's a very obvious conclusion that the patients enrolled into RP3 did, through luck of the draw, happen to have more widespread, both with regards to number of disease sites and the burden of disease, than the phase I populations enrolled with RP2 monotherapy. There were certainly similar patients in the phase I monotherapy for RP2, which was five out of the nine who did progress rather rapidly. So yeah, they by luck of the draw had more disease, more widespread and a greater burden, and as a result, were also very heavily pretreated.
Great. The second one is, compared to RP2 monotherapy, how do you view RP3's IO PD marker and abscopal effect?
Really with all of RP1, RP2, and RP3, we're expecting sort of similar, but more of the same with RP2 compared to RP1, and more of the same again with RP3 as compared to RP2. They should be upregulating the same sorts of things in both cases, reversing the immune suppressive effects on tumors, turning cold tumors hot. In each case, each doing more than the predecessor, and therefore with the potential for greater local benefit, and also greater systemic, i.e., abscopal benefit. It's obviously too early to conclude conclusively that we are seeing that, but the early data with RP2 certainly suggests we are seeing a higher frequency of responses in patients with PD-1 failed disease that we've seen with RP1.
As the RP3 data catches up, we would expect that we will begin to see promising results there as well. While it is only anecdotal, I do think the slightly more enhanced side effects we see with RP3 as compared to RP2, which likewise has slightly more enhanced side effects as compared to RP1, is relevant in drawing a conclusion that it does seem to be doing what is intended to do, which is provide more potent immune activation. Which as Philip and others otherwise said, we're exploring in more patients over the course of this year in a more focused way.
Thanks, Rob. The last one on this RP3 is, what is the reason for not going for a higher dose of RP3 monotherapy given that you've not seen any dose-limiting tox?
Kevin can further comment too. However, we are seeing substantial inflammation. We do see if we go to higher levels than 10 to the 7 with RP1. With RP1, we did go up to 10 to the 8, and then concluded there was no benefit based on biomarkers, and other effects being seen, and also based on the fact there was a considerably greater degree of shedding from the tumor with 10 to the 8 as compared to the 10 to the 7. With RP1, having gone up to 10 to the 8, we decided the RP2D was appropriately 10 to the 7.
It would expect to see similar with RP2 or RP3 if we went up to 10 to the 8, finding no benefit based on biomarker, but probably increased shedding, which on balance, we believe means that 10 to the 7 is the most pragmatic and appropriate level to go forward with.
I think, Rob, if we did go to a further log to 10 to the 8 with the RP3 agent, I think we might begin to see, you know, cytokine release syndrome type DLTs. We might actually get into that territory at those sorts of levels from what we're seeing at the, you know, the 10 to the 7 dosings. I think the important thing to stress with oncolytic virotherapy, oncolytic immunotherapy, is that the paradigm of, you know, thou shalt escalate the dose until you can't give any more, is not proven and is not necessarily clear-cut.
I think that getting a dose that achieves a biologically meaningful effect, for instance, at the 10 to the 7 level, but is appropriately tolerable and allows you to work around by adding other agents to this without causing overlapping toxicities, is really what for me is very attractive about these agents. I think we can achieve a huge amount with the RP platform without necessarily having to expose patients to excessive toxicities. That would be my take on this, is that I think we're in the sweet spot without necessarily having to overdo the tox in order to prove that we can do that.
Thanks, Dr. Harrington. Perhaps one more question. Can you expand on the go-forward plan for RP3?
As it relates to kind of RP2, on whether we're gonna choose between RP2, RP3? Do you wanna take that, Rob?
Yeah.
Yes.
While it wasn't in the slides, I did discuss that the intention is to keep our options open for the moment as the RP3 data catches up. The phase II protocols which are being written are written to have groups or cohorts for both RP2 and RP3. The intention is to open one or the other based on the availability of data at the time we begin to open those trials, which will be towards the end of the year. We are anticipating over the course of this year, the RP3 data will begin to catch up, and therefore we'll have a greater level of information upon which to make the decision.
Such that we're not slowed down, as I've said, the protocol has been written with both to maintain flexibility up until the last moment, and also potentially to provide the opportunity to test both and at least maybe one of the protocols, if we think that would be advisable based on what we know when we need to make the decision. We aren't able to say today whether it'll be RP2 or RP3 in any particular protocol, but we will be saying when we start those protocols towards the end of the year as the data catches up.
Thanks, Rob. We do have other questions, but we are out of allotted time. We will do our best to follow up and answer the remaining questions. Philip, I'll turn it back over to you.
Yes. Obviously happy to answer questions individually after the event. We are past the top of the hour, so just some quick thank yous. Thank you to the key contributors. Thank you to all those that supported the event on the outside. A very special thank you to the leading physicians that joined us for the session, including with me here today, Dr. Khushalani.
Thank you for having us.
Dr. Ahmed and virtually Dr. Harrington and Dr. Saab, very much appreciated. With that, I look forward to giving further data updates towards the end of the year as the year progresses, and wish everyone a good rest of the day. Thank you for joining.