Morning. I'm Adrian Rawcliffe, Adaptimmune's CEO, and thank you for joining us. I refer you to our disclaimer. More details can be found in the press release we issued earlier this morning. I'm delighted to be introducing this new data from our SURPASS trial and our plans for the SURPASS family of trials. This data set confirms the power of our SPEAR T cells to make a difference for patients. It identifies multiple tumor types for further development, and it continues our leadership position in making T cells effective against solid tumors.
Before we get into that, I want to provide a little background on Adaptimmune and our technology. For those of you who are perhaps less familiar with Adaptimmune, we engineer T cells to fight cancer, empowering a person's own immune system against their disease. Our unique technology platform enables us to enhance the affinity of T-cell receptors, or TCRs. T cells use TCRs to see targets on cells. If a target is recognized as alien, the T cell will kill cells with that target.
Our technology enables us to specifically engineer and enhance TCRs to target solid tumor cells. We then introduce these engineered TCRs into a patient's own T cells. This is our SPEAR T cell therapy. Unlike TIL therapy, our TCRs are engineered and enhanced to recognize specific targets on cancer cells. They then kill the cancer cells expressing this target and engage the rest of the immune system in an antitumor response.
Our lead program uses TCRs engineered against a target called MAGE-A4, which is expressed in cancer cells across many solid tumors. As well as binding to the target, our engineered TCR cell therapies can also incorporate next-generation enhancements that further improve their effectiveness. One such enhancement is the addition of CD8, which increases the potency of our T cells, and it is this next generation CD8 TCR T cell that is employed in the SURPASS trial.
We've been advancing this technology clinically for a while, and we're the leaders in engineering effective T-cell therapy against solid tumors. We're on the verge of submitting our first BLA this year for our first gen product targeting MAGE-A4 afami-cel. We've achieved these milestones, and we've positioned Adaptimmune for long-term success on the foundation of our integrated capabilities. Simply put, we've built Adaptimmune from the bottom up to design, develop, and deliver T cell therapies for people with cancer.
Afami-cel has been called a game changer for people with synovial sarcoma, and this product, once approved, will become the first engineered T-cell therapy for solid tumors. This would be a great milestone for the cell therapy space, for people with cancer, and for Adaptimmune. Our ambition lies beyond just our technology platform. We aim to be an integrated cell therapy company, bringing the benefits of cell therapy to people with a wide range of cancers.
In the short term, this will be achieved with the CD8 next gen product targeting MAGE-A4 that's been explored in the SURPASS family of trials. Those of you who are more familiar with the company will recognize our four focus areas for 2022. The SURPASS family of trials with ADP-A2M4CD8 are clearly all about building our MAGE-A4 franchise. MAGE-A4 is expressed on cancer cells in tens of thousands of people across a wide range of indications, including some sarcomas and ovarian, gastroesophageal, bladder, head and neck, and lung cancers.
15%-70% of these cancers express MAGE-A4 at a moderate to high level. We've previously estimated that almost 100,000 people die each year in the U.S. and Europe with MAGE-A4 expressing tumors. Almost 40,000 of those patients have the correct HLA to be treated with our current MAGE-A4 targeting TCRs. This is a very significant cancer target, and it's one that can really only be addressed through a TCR mechanism. We're very excited to discuss the data from the SURPASS trial.
SURPASS is a signal finding phase I study in people with late-stage cancers who are heavily pretreated and have advanced metastatic disease. This has been a great success. Firstly, it has successfully recruited. Last year, we presented data from 22 people who were evaluable for efficacy. This year, we present data from 43 evaluable patients. Secondly, the product is showing the enhanced activity of this next generation, more potent T cell.
In approximately 2/3 of patients, we see significant antitumor effects from the cells, and in roughly 1/3 of patients, we see RECIST clinical responses, both complete and partial. This is a massive improvement on the response rate seen in non-sarcoma indications with our first generation MAGE-A4 targeting T cell. Thirdly, SURPASS has identified developable signals in multiple tumor types. We now have response signals across four indications: ovarian, gastroesophageal, urothelial, and head and neck cancers.
We intend to convert these signals from this phase I study into products in defined patient populations. As you will hear, the signals are at different levels of maturity, and our development plans reflect that. These positive results demonstrate to us the mainstream applicability of this next gen CD8 product to treat a wide range of solid tumors with high unmet medical need. The trial is ongoing, and we intend to identify further signals to advance. As Dr. Hong says, this is an important and an exciting time.
These data are the latest demonstration of the power of engineered T-cell therapies, and Adaptimmune is well-positioned to be able to convert these signals, which are clear and unequivocal, into products to make a real difference for people with cancer. With that, I'll turn to today's agenda. In a minute, Elliot is going to discuss the data from the SURPASS trial and put it in context.
Dennis will then walk through our development thinking for those indications where we've seen signals. We're delighted that Dr. Kathleen Moore has joined us to provide an overview of the treatment landscape for ovarian cancer, including where our cell therapy fits and where it could evolve to over time. Then we will all be available to take questions. Now I'll hand over to Elliot. Elliot.
Thank you, Ad, and thank you everyone for joining us. We are extremely excited about the SURPASS trial and the responses we're seeing across multiple solid tumor indications. This trial has done and continues to do exactly what it was designed for, to assess the safety of our next gen product and find additional indications that we can take forward for further development.
Like most early phase trials in oncology, participants in SURPASS are heavily pretreated, having received a median of three prior lines of therapy, and these cancers are very advanced. This is incredibly important to understand when interpreting data from SURPASS. Most people in this trial have a very few treatment options remaining, and achieving any responses, let alone at the rates we are seeing, is truly remarkable. The overall safety of this next gen product continues to be acceptable and support further development.
We're reporting two deaths that were considered related to treatment by investigators in this trial. One was a 60-year-old woman with ovarian cancer who had extensive tumor burden in her lungs and died due to pneumonia and CRS. The other, as reported at ESMO 2021, was a 71-year-old man with adenocarcinoma of the esophagus and a history of chronic anemia who died due to bone marrow failure. These are the response data for SURPASS that Dr. Hong will present at ESMO.
These data build on and confirm the results we reported last year. On the top is the waterfall plot showing best overall responses across multiple tumor indications. As of the data cutoff, 12 patients had confirmed responses and two had unconfirmed responses. This corresponds with an overall response rate ranging from 28%-33%, depending on scan status. This response rate will continue to evolve, and I'll provide an update in this regard on the following slide.
When we take a more focused look combining ovarian, urothelial, and head and neck cancers, the response rate is even more impressive, ranging from 40%-44% in 25 patients. The majority of people experienced reductions in their tumors, and the disease control rate was 81%. Today, I am pleased to report that the two unconfirmed responses have now subsequently confirmed. Therefore, the response rate is firmly 33% and 44% in the subset combining ovarian, urothelial, and head and neck cancers only.
In addition, a third patient whose first scan was done two days early, shown here in black, is now an unconfirmed responder with their second scan. Therefore, the waterfall plot for these same patients now looks like this. I can also report that the 44th person with melanoma who did not have a scan as of the data cut is also now an unconfirmed responder. Taken as a whole, these data are strong validation that the CD8 alpha product has the potential to be a meaningful treatment for a broad range of MAGE-A4 expressing cancers.
This plot shows response and patient status in the ongoing trial. As of the data cut, 23 out of the 44 people who received our cell therapy are still alive, as shown in green. Importantly, we see a picture emerging in ovarian, gastroesophageal, urothelial, and head and neck cancers with some initial encouraging durability in these very late-stage patients who are heavily pretreated. Dennis will talk more about our clinical trial directions in these indications.
In these next few slides, I'll provide indication-specific subsets of the data and try to provide context around the unmet need. In ovarian cancer, the response rate of 36% we are seeing, including a complete response, is extremely encouraging. For comparison, treatments typically used in this population are associated with about a 13% response rate and median progression-free survival of 3-4 months.
Again, you will hear more about this patient population from Dr. Kathleen Moore and how our cell therapies can potentially be utilized in the platinum-resistant setting and beyond. Looking at gastroesophageal cancers, while response rate in this indication is lower than some of the other indications, there is a clear evidence of antitumor activity in a very challenging patient population. In these cancers, less than 25% of chemotherapy-treated patients even make it to third line.
For those that do, response rates are low, with a median progression-free survival of approximately 2-3 months. Given the advanced nature of disease in people in this data set, seeing meaningful reductions in tumor size is impressive, even if not meeting the threshold for a RECIST response. For example, the patient in this scan had very bulky disease with lesions in the liver measuring over 30 centimeters at baseline. Although the maximum reduction was 25%, this represents a massive decrease in tumor volume.
Furthermore, many of these patients experience symptomatic improvement with better ability to eat solid food and reduced pain medication requirements. They also enjoy a period of time after a single infusion without needing repetitive treatments. Dennis will share further insights on the plans for evolution of SURPASS-2 in this indication. For the first time, we are presenting an emerging signal in urothelial or bladder cancer.
Based on the updated scan data I just mentioned, in the seven people treated, there are now three confirmed responders and a potential fourth with an unconfirmed response. Current standard of care treatments with checkpoint inhibitors in the second line following progression on platinum-based chemotherapy is associated with about a 20% response rate and median progression-free survival of two months with pembrolizumab.
Most of the patients in SURPASS have already progressed after a checkpoint inhibitor, and many have received experimental later line treatments. This data looks similar to what we saw with ovarian cancer last year, and Dennis will discuss the best pathway to evaluating this indication. Finally, with head and neck cancer, we have treated four patients to date, and we are seeing impressive deep responses with three out of four being confirmed.
All of these patients had been previously treated with a checkpoint inhibitor, and three of four had already progressed with cetuximab. For context, first-line treatment in this indication is often with pembrolizumab alone for patients with a CPS score of greater than or equal to one, resulting in a 19% response rate and 3-5 months median progression-free survival. Standard of care in the second line and later settings with cetuximab, either as monotherapy or in combination, is associated with a median progression-free survival of less than four months.
Like urothelial cancer, this early pattern of response supports further development in this indication. Again, Dennis will elaborate further. Here with this scan is another example of a patient with significant tumor burden who had progressive disease following extensive prior therapy who achieved a partial response. In the baseline image, there is a hilar lesion that is completely resolved at week four. While the data from SURPASS to date is clearly compelling, we are always striving to improve the frequency, depth, and durability of responses.
To that end, we're focusing on several future directions. Our translational data consistently point to a correlation between efficacy and broader engagement of the immune system. We know that SPEAR T-cells infiltrate tumors expressing MAGE-A4. We also know that when this happens, there is a wider range of non-gene modified T-cells that infiltrate the tumor and participate in the antitumor immune response as well.
The combination with a checkpoint inhibitor and other possible combinations in the future are intended to further exploit this broader immune response by enhancing and maintaining T-cell activation. We also know that it can be more difficult to demonstrate the benefit of immuno-oncology products in patients with advanced disease who have progressed through multiple prior lines of treatment.
We believe this treatment will deliver greater benefit to patients in earlier lines of therapy, where there is likely to be a more favorable tumor microenvironment with fewer established mechanisms of resistance, and where we'll have the opportunity to harvest healthier T-cells that should result in a better product. Finally, this CD8 alpha next gen product is a reminder that we have the ability to modify the T-cells with other next gen and manufacturing approaches that can further enhance efficacy as well.
In summary, with the SURPASS trial, we continue to demonstrate an acceptable safety profile and have now identified efficacy signals in four tumor types. With that, I will turn it over to Dennis to talk more about how we're going to pursue these development opportunities.
Thank you, Elliot. As Elliot outlined, the SURPASS phase I trial enrolled people with advanced cancer in multiple solid tumor indications, and this trial has been successful in identifying any tumor signals in multiple cancers. We are planning further clinical development of these indications with the goal of developing cell therapy products for market approval. There are three pillars of the clinical development strategy. One, advance further clinical development in indications based on any tumor signals observed in the phase I SURPASS trial.
Two, explore combination strategies to enable enhanced efficacy, including durability. Three, evaluate options for introduction of our next-gen cellular therapy into earlier line treatment based on the indication strategy. I want to take a few minutes to walk you through our plans at a high level for our SURPASS family of trials. We started the phase I SURPASS trial with the goals of establishing safety and identifying any tumor signals.
This trial is ongoing, including enrollment into a combination arm to investigate our next gen cell therapy with nivolumab, the checkpoint inhibitor. Using a checkpoint inhibitor with our TCR T-cell therapies makes sense because checkpoint inhibitors work by taking the brakes off the immune system to enable a stronger anti-tumor response. We anticipate that combination therapy has the potential to increase the anti-tumor activity of our engineered cells, as well as a person's broader immune system.
Elliot outlined the tremendous data we have in platinum-eligible ovarian cancers, and we plan to initiate SURPASS-3 later this year. Dr. Kathleen Moore will give an update after me. Dr. Moore has treated people with ovarian cancer in our phase I trial and contributed to the design of the SURPASS-3 trial along with her Gynecologic Oncology Group, or GOG colleagues. Patients with gastroesophageal cancers were the second most frequent tumor type after ovarian treated in SURPASS phase I .
Last year, based on signals we saw in advanced gastroesophageal cancers from phase I , we initiated SURPASS-2. We plan to amend SURPASS-2 to improve the frequency of response and to achieve more deep and durable responses in these difficult to treat cancers. As Elliot mentioned, we are seeing emerging signals in head and neck cancer as well as urothelial cancers. Although these data are early, we have initiated early development planning activities based on these signals.
I want to walk you through these target indications on our plans in more detail in the next few slides. We have seen great responses in ovarian cancer, and we plan to initiate SURPASS-3 later this year. We have worked closely with GOG to design SURPASS-3, which is a phase II trial for women with platinum-resistant ovarian cancer. We will evaluate our next gen cell therapy in both monotherapy as a single dose, just like phase I trial, and in combination with nivolumab in a two-arm design.
Both treatment arms will be compared against historical response rates for standard of care chemotherapy in platinum-resistant disease. The data for SURPASS phase I continued to show activity in heavily pretreated advanced gastroesophageal cancers. We started SURPASS-2 last year, a phase II trial with people with gastroesophageal cancer who received a maximum of two prior lines of systemic treatment for advanced disease.
We are amending SURPASS-2 to include an additional cohort in combination with a PD-1 inhibitor, and we are also exploring options to combine our next gen cell therapy in earlier line treatment. Although data are early, we are seeing promising signals in urothelial as well as head and neck cancers. We will place additional focus on these indications in the SURPASS trial, and we will continue to enroll people with these cancers in the phase I trial, including the combination arm.
As the signal in these cancers matures with the accrual of additional monotherapy in combination data from the SURPASS trial, we will progress to further development activities, including evaluation of combination strategies and/or later-phase clinical development. In conclusion, we have a strategy to advance development of our next gen cell therapy. We will continue to enroll people in the signal finding trial, including the combination arm, with the aim of identifying more responses in additional indications.
The SURPASS family of trials is an excellent example of innovative cell therapy development for cancer from signal to late phase development with trial design informed by data. We will leverage our experience from our afami-cel development program and apply these learnings to our next gen cell therapy.
These are innovative therapies, and we are leading the field in developing engineered TCR T-cells for the treatment of solid tumors. It is expected we will need to adapt, as our name implies, to design trials to serve as many people with cancer as possible. With that, I will turn it over to Dr. Kathleen Moore.
Hello, everyone. My name is Dr. Kathleen Moore, and I'm a professor of Gyn Oncology, Associate Director of Clinical Research and Director of phase I Clinical Trials at the Stephenson Cancer Center in Oklahoma City. Really, it's my great pleasure to give you this short overview of the landscape in ovarian cancer and why I'm excited about the potential for engineered cellular therapies, such as the SPEAR technology, for women with ovarian cancer.
Just to sort of give you a lay of the land, this is sort of the epidemiology around ovarian cancer. There's about 20,000 new cases per year in the United States and about 13,000 deaths. Both of those numbers are actually going down, which is a good thing. The prevalence is going up. In fact, about 2018, we crossed the 200,000 mark, so we're no longer considered an orphan disease. Why is this? I wish it was because we were curing more women or preventing ovarian cancer, but we are not.
We're getting better at treating things in the recurrent setting, which is good. We're piecemealing together progression-free survivals, and so more women are living longer with the disease, but we still have a long way to go to cure. This is really the natural history we see with ovarian cancer. Despite a lot of effort, we cannot screen for this disease. Women present with advanced stage disease, which usually is exquisitely chemosensitive in the frontline and responds to platinum-based chemotherapy with surgery.
Ultimately, the majority of women will recur, and they'll be retreated with multiple lines of therapy, ultimately becoming resistant to platinum. Then there's a series of monotherapy chemotherapies we use until women ultimately succumb to their disease. Even here, I'm just gonna start right off and show you where this technology could fit. SURPASS-3, which you're gonna hear about, is in the platinum-resistant space, and so certainly, this is the first place for discovery.
I really think we can move it up, and I'll talk a little bit more about this as we go, to potentially be a consolidation therapy after frontline or even after platinum-sensitive disease in patients at very high risk, for short durations of response, to platinum-based therapy. When we think about frontline chemotherapy or frontline therapy in general for women with epithelial ovarian cancer, we think about all of these things.
It's become much more complicated, than in the day where if you had ovarian cancer, we gave you paclitaxel and carboplatin, and we operated, and that's what we did. You know, now we really think about the timing of surgery. Histology is hugely important. We're looking at high-grade serous differently than clear cell, for example. That's appropriate for some interventions. The genomic profile, of course, BRCA and homologous recombination deficiency, test positive or negative, have also become important.
When we think about what we get with paclitaxel and carboplatin alone, I'm just showing you this progression-free survival from what will likely be the last clinical trial ever done with just paclitaxel and carboplatin and no maintenance therapy in the frontline. The two things I want you to see here is in the upper left, you see the shouldering. That's about 20% of women who will progress on, or more likely within six months of completing platinum-based chemotherapy in the frontline.
This primary platinum-resistant, phenotype is a very poor prognostic group of tumors that despite a lot of effort, we have not made big inroads there. That's an area of high unmet need. By about 2-3 years, about 80% of patients will have recurred and entering in this sort of gauntlet of treatments which are effective, but they are treatment, until the end of someone's life. There is no chance of cure once you recur.
Now, we had a small advantage with bevacizumab in the frontline, and this is very old data just showing about a 20%-30% reduction in the hazard of progression or death with incorporation of bevacizumab within the follow chemotherapy, but no improvement in overall survival. It is a standard of care, but not the standard of care. PARP inhibitors have really transformed the frontline for ovarian cancer, especially for women with BRCA-associated cancers.
I'm showing you the four clinical trials here which use monotherapy PARP following response to platinum-based chemotherapy in the frontline. Then in the lower right, you see PAOLA-1, which is PARP plus bevacizumab. The take-home here is that use of PARP for 2-3 years following chemotherapy reduces the hazard of progression or death by about 70%, so it's unprecedented. It is the standard of care in BRCA-associated cancers.
Now, we haven't seen overall survival yet, although you will see some data updated from SOLO-1 at ESMO at this meeting. We have five-year follow-up from SOLO-1, which was olaparib following frontline therapy. What I'm showing you here is the two-year mark where we discontinued assigned therapy, either placebo or olaparib. You can see the differences in the women that remain without disease at this time point, 74% versus 35%.
Here we are out to five years, with a flattening of the curve, in both arms, really, indicating to us, we hope, that we may have a higher fraction of women cured in this particular group, than we've ever seen before. Time will tell, and you'll see that actually at ESMO this year. Now, if we look at the other subgroups, this is BRCA wild type, but homologous recombination deficiency test positive. Again, unprecedented improvement in progression-free survival. You see about a 40%-50% reduction in the hazard of progression or death.
We will see some updated overall survival data from PAOLA at this meeting, and that's going to be very important to really seeing what the impact here is. What percentage of patients actually got to the two-year mark and complete PARP and come off versus how many progressed on PARP. These studies have not had long enough follow-up to report that out yet. Those are kind of key questions that we have, but very important and positive results.
Now, the group that is a very high unmet need is this group that is homologous recombination test negative, which they do benefit from PARP. About a 30% reduction in the hazard of progression. But still, you can see these survival or progression-free survival curves are very vertical. So this group of tumors have a relatively poor prognostic outcome than their counterparts that are homologous recombination test positive, inclusive of BRCA.
This group, which is 40%-50% of high-grade serous or high-grade endometrioid, are very high unmet need for better outcomes. PARP is good. You know, I love PARP inhibitors, but we can do better. Now, we're talking about kind of an immunology intervention today. What about kind of standard immune checkpoint inhibitors? Why haven't I talked about them? Well, because they have not worked, unfortunately.
We had two big studies, JAVELIN 100, incorporating avelumab, and IMagyn050, which I had the privilege of leading, which is bevacizumab with or without atezolizumab in the frontline. They measured PD-L1 positivity. These were pre-specified stratification factors by different assays, but it's about the same in each group. It's about 60% are PD-L1 positive, but there was absolutely no signal. In fact, in JAVELIN 100, the patients actually looked like they did worse with avelumab.
In IMagyn050, they didn't do worse, but they didn't do better. Absolutely no signal here that immune checkpoint inhibitors alone or with bevacizumab improve outcomes in the frontline. There is some thought that there's synergy with PARP inhibitors plus minus bevacizumab. These four combination studies have finished and are maturing. We will see some of them read out in 2023. These three all have immune checkpoint inhibitor, PARP inhibitor with or without bevacizumab.
I think we're waiting to see the readout here to really figure out if immune checkpoint inhibitors have a role in ovarian cancer, 'cause elsewhere, they really don't. When we think about the frontline, we have these three buckets of BRCA wild type, HRD, and then HRD test negative. PARP inhibitors are here. That's true. We can do better, and there are groups of patients. I think for BRCA, PARP is gonna remain in play.
For BRCA wild type HRD, and specifically for HRD test negative, most patients are progressing on PARP and sometimes very quickly. This is an area of high unmet need. Really, when you think about the SPEAR technology, this is a place where we could bring back that concept of consolidation therapy, which was chemo in the past. We all know that didn't work. This could work here. I'm very excited about the potential to move this technology up once, of course, we get it done in the platinum resistance space.
Once we use frontline chemotherapy and maintenance, hopefully we've cured more patients, and I do believe we are in the BRCA subset, but we probably are not as many as we would like, if at all, in the others. Patients will recur, and they will likely be classified as platinum-sensitive.
Mm-hmm.
Which means they haven't recurred within six months of their platinum. What do we do here? Well, it's really determined by what you've already received. If you'd received a prior PARP and you hadn't received bevacizumab, we use chemo with bevacizumab and bevacizumab maintenance. If you received prior bevacizumab and you didn't receive a PARP, we do chemo, and if you respond, key point, you get a PARP. If you've received both, which many people have, there's nothing currently.
Now, there is data for PARP after PARP, the OReO study read out, and it is a positive study statistically, but it is a negative study in terms of really how well these patients do and how well their tumors respond, and is more a call to action that we need something much better in this space, in this post-PARP space that's wide open.
Mm-hmm.
At a high unmet need for all the patients who recur, are platinum sensitive, and need something active in the maintenance setting. There's a number of studies that are ongoing here. The first three are either completed or almost completed, and we may see Adelante readout at ESMO. Up next in GLORIOSA are antibody drug conjugate maintenance strategies. These are just launching. Again, this is a place where the SPEAR T-cells could play a role post-chemotherapy of those that respond.
These are very high-risk tumors. This actually may work to consolidate and prevent recurrences. I'm excited to explore that once we get SURPASS-3 done. Once patients recur, ultimately, their tumors become platinum resistant. Then our standard of care is chemotherapy and bevacizumab based on AURELIA. That is the standard of care. Once we're beyond this, it's monotherapy chemos, which have dismal expectations of response, and in the 13% range with very short progression-free survival.
There's a lot of drug development going on in this space. This is an awesome figure that I borrowed, but I just think it's great because it shows all of the activity. Lots of combinations with weekly paclitaxel, several antibody drug conjugates. You can see mirvetuximab here is closest to the bullseye, as it's under review right now, at the FDA. This is a high-risk space. There's a lot of active, exciting things, but they don't often work. VB-111, which we're all very excited about, with paclitaxel.
We all heard the press release on this was negative. This is the first one on my little figure to go out. I think we will see mirvetuximab approved based on the SORAYA trial data, which is a folate receptor alpha-targeting antibody drug conjugate, single-arm phase III trial with a response rate of 33% and a duration of response of seven months. The confirmatory trial is MIRASOL, which in full disclosure, I lead. We'll see results in quarter one of 2023. This may be our next approval.
This is really exciting data, and I pulled this from Dr. Hong's ESMO presentation. You'll see a lot of this data presented. These are small numbers, and often quite heavily pretreated tumors. This is one treatment with T-cells, and you see these responses, which can be of really substantial duration. Personally, having treated some of these women, they are so excited to have access to engineered cellular therapies.
They tolerate the therapy incredibly well because we have a cellular therapeutics team that is excellent at what they do and can deliver this therapy safely. I can screen and counsel them, and then I can turn them over to an expert team that gets them through the therapy with really very little complaint. We follow them, and they're off treatment, and they feel so much better off treatment. It's kind of amazing to see, especially when it works.
You'll see, I think, some of my patients presented in the slideshow, so I can't show them to you here. But this is early I understand the small numbers, but it's very exciting. Even in this heavily pretreated population, to see these responses is really encouraging because we all know that this is going to work better the earlier we use it, before the T cells are exhausted. The opportunities for incorporation of this technology into high-risk patients after frontline, maybe to prevent recurrences, is incredibly exciting.
Platinum-sensitive recurrence, where we have nothing for maintenance post-PARP, and a very high-risk tumor post-PARP, they tend to not respond as well to platinum. Two big opportunities, for a novel cellular therapy with proven efficacy in the platinum-resistant space is really exciting, and I can't wait to see this move forward, and we're excited to get SURPASS-3 up and running. In conclusion, I'm excited about the SPEAR technology in SURPASS-3, which is the platinum-resistant space.
We're already participating in the basket trial, so we'll just convert that to SURPASS-3, of course. We do a lot of screening with bridging therapy, so that patients are kind of on something while we're assessing them for HLA and MAGE, and that works incredibly well, and I'm excited to really teach that to my gynecologic oncology colleagues as this goes national.
I think just kind of tips and tricks to, like, look at Caris reports and know who's HLA positive really before you even test can streamline testing and really make this a very feasible option for those women whose tumors are positive for MAGE and who are HLA-A*02. This is a really doable therapy for patients and should generate a lot of excitement. I hope this was helpful to you. I look forward to answering questions, during this session, and thank you for your attention.
Thank you very much, Dr. Moore. That was phenomenal. Thanks to everyone who's online right now for listening to these presentations. Now we will take questions from the audience. As a reminder, you can ask questions using the Q&A chat function on your Zoom menu. If we don't get to your question today, we will follow up by email. As I've been going through and looking at all the questions, we have several, so we're going to get right to them.
Dr. Moore, it's fortuitous that you said you would be happy to answer some questions because I have a couple to begin with for you. The first is from Marc Frahm at Cowen. Given the added complexity of qualifying for and recruiting this type of therapy, what is a meaningful response rate and durability for ovarian cancer that you would be looking for?
Very similar question from Mara at Mizuho. What is the feasibility of treating patients in an earlier setting with ADP-A2M4CD8, and what kind of durability would you consider meaningful? If you could maybe bundle those together, that would be wonderful.
Yeah, these are great questions, and I think we're gonna learn more about this as we get more information from SURPASS. By the way, greetings from Paris, everyone, from ESMO. It's already been exciting here. So let's talk about late line first. I do think I do agree with the question, or I understand the question. This is different than sort of standard off-the-shelf therapy or even something that we have to send immunohistochemistry for, you know, anticipating mirvetuximab's approval, for example.
This is a several-step process. I do think it's something that can be incorporated into the sequence of therapies, even now in the platinum-resistant space. Once we just kind of get it in front of our investigators, especially as they see these responses start to pick up and be presented, and think about it early. What I meant when I was in the video talking about the Caris report, for example, and I certainly wasn't trying to do a Caris commercial, but they do HLA testing.
Probably no one pays attention to that in gynecologic oncology or medical oncology for ovarian because it's never been relevant before. You already know it if you send Caris. Once you know that, if you have a patient, you're like, eh, CA-125's going up. I may get a couple of more months of this. You can launch MAGE testing at that point and know if this is on kind of the lineup of potentials for the next therapy or not.
You can start planning that bridging therapy, which is a really nice feature of all of these, protocols that you can kind of continue if something's, you know, putting some brakes on the growth, until you're ready, and have the cells manufactured and are ready to infuse. That just takes a little bit of time and coordination with the cellular therapeutics team, but once you get those kind of, processes ironed out, it really moves very smoothly. Now, I would say the same thing is true moving it up.
This is. I don't know if this is going to work, but I'm very excited about this potential. You know, we are at ESMO. We just saw overall survival data presented from one of the big phase III studies where, unfortunately, about half the patients who have high-grade serous ovarian cancer homologous recombination deficiency test negative. While PARP inhibitors have modest efficacy here for PFS, we just saw that they do not have benefit, at least for OS. That indication may go away.
You know, when we think about even with PARP inhibitors, the median progression-free survival is 8-12 months. This is an incredibly high-risk tumor, and we know who they are during frontline chemo because we send the testing.
You could actually see once we prove kind of feasibility, and safety in a broader population, if you know you have that patient in front of you, with a HRD-negative tumor, someone who's gotten neoadjuvant, which is like 60% of the population, you can send the HLA, you can send the MAGE, and then have your maintenance or consolidation strategy ready. That you're just ready to roll once they come off of chemotherapy, have a few weeks to recover and can consolidate.
I just wonder if that would prevent recurrences or markedly delay them. Your benchmark is 8-12 months. I think we can beat that with this in appropriately selected patients, and it is gonna be a niche population, but so are a lot of things in oncology. You look y ou save every starfish you can. You can't apply the same thing to the whole ocean, but you kinda save the starfish in front of you, and if she's HLA positive and MAGE positive, then I wanna put her on this. I think that consolidation opportunities are where I'd wanna move it.
I didn't talk to Adaptimmune about this before I put it in the video, so hopefully they're not stunned that I sent this, but that's where I would wanna move it next, once we prove its efficacy in SURPASS-3.
Wonderful. Thank you very much, Dr. Moore. The next question will be directed to our colleagues in the U.K. Ad, I think this is probably one for you. We got a question from Michael Schmidt and a similar question on the online portal as well. Any particular explanation for the stronger efficacy signals we are seeing in certain tumor histologies? The related question is why do you think you are not getting responses in other types of tumors beyond ovarian, head and neck, gastroesophageal, and bladder?
Thanks, Michael. I think our hypothesis, which we've been attempting to demonstrate through the SURPASS trial, is that actually the key driver of response is likely to be expression of MAGE-A4 on a tumor independent of tumor histology. I think, you know, we've seen activity even with the first generation product across a broad range of tumors. The response rates there were not sufficiently high.
Moving into SURPASS, our view was that this is a highly potent T-cell. It can see MAGE-A4, and when it does see MAGE-A4, it should be able to mount an immune response against the tumor. That's what I think we are demonstrating sequentially. You know, initially, with afami-cel, we got that in sarcoma. Now with the SURPASS trial, we're seeing it sequentially. Last year, I was talking to you about gastroesophageal and ovarian. Now we're talking to you about bladder and head and neck cancer, where we're seeing very high levels of response.
Actually, in every indication where we have amassed sufficient patients, we are seeing a reasonably robust response rate. That's why, as Dennis referred to, we're gonna carry on recruiting in the SURPASS-1 trial and focus on those histologies where we have not yet got to sufficient patients to be able to make that determination. It is our belief that the opportunity is pan MAGE-A4 and that MAGE-A4 is an important novel tumor target that is expressed across a very broad range of tumors and to which cell therapy is a particularly useful therapy.
Thank you very much, Ad. Turning here for a question to our US colleagues, and this, I will ask first to Dennis and then maybe Elliot can comment, as well. For patients who progress after achieving an initial response, can you tell us more about why these patients progress? And does this activity achieve correlation with MAGE-A4 expression level?
Thank you. For patients that progress on therapy, so those that have responded initially and then subsequently progress, we're still evaluating mechanisms of acquired resistance. Unfortunately, we do not have biopsy data on all patients, so our knowledge is still evolving here. What we do know is, patients that are treated with this product, we see infiltration of our T-cells, our SPEAR T-cells, and we certainly see infiltration of endogenous cells. This is true for both in cold tumors and inflamed or hot tumor phenotypes.
As far as MAGE-A4 expression is concerned, we do see, for example, responses across the broad range of MAGE-A4 expression that we enrolled in this trial. Although responders tended to have higher expression, we haven't necessarily seen loss of antigen as a reason for progression, but here again, we're still evaluating.
Dennis, actually, maybe a quick follow-up to that. Is the H-score in these patients similar to the initial cohort that you saw at ESMO 2021? Do you see a correlation there with ORR?
You know, actually, the MAGE-A4 expression in this trial is actually quite high. To give you some context, it's actually by median, it's even higher than what we see with afami-cel and SPEARHEAD-1 in sarcoma. So of the patients that we treated in this trial, in general, if they had MAGE-A4 expression, they had a lot of MAGE-A4 expression. I think it's in general, the H-score is mostly similar to what we saw previously. Obviously, as the trial continues to accrue, we see, you know, some heterogeneity, but MAGE expression is high.
As far as the response rate, whether by H-score or P score, essentially the P score is the percentage of cells that are two + staining intensity or higher. We see responses across the range. In fact, the lowest P score that got into this trial actually was a responder. But here again, responses tended to be more prevalent in those with higher expression, but the data is still early.
Thank you, Dennis. It's a question for our UK colleagues. Jo, I will direct this to you. It is from Tony at Roth. Can you discuss in some greater depth the biology between afami-cel and the second-gen product with CD8, especially as it relates to cytokine production?
Yeah. Thanks, Bill. That's a great question. With our first-gen product with afami-cel, we have just the TCR and the T-cells, and that's able to recognize the mesothelin peptide and the HLA. We know that that works well in sarcoma patients, which are a very cold tumor. We also know from that gen one trial that we really don't see much happening in the CD4 cells. Our CD4 cells don't really persist.
When you move to the SURPASS trials and you look at the cells, what we've really done here is bring the CD4 cell component into the mix, and they are active in our SURPASS patients. The CD4 cells, by giving them extra CD8, they're able to recognize the tumor just as well as the CD8 cells do, and they kill the tumor just like the CD8 cells do. I think it's more important, in fact, that when they bring their CD4 helper functions, and so that does relate to the cytokines.
What they do is they get into that tumor. You saw the infiltration in the presentation today. They switch to a Th1 phenotype, which means they're pumping out interferon gamma, they're pumping out IL-2, and that's making the tumor environment more pro-inflammatory, which helps the other cells. As again, you see from the infiltration data, not all of those cells are T cells. There are plenty of other T cells in the mix too.
Another helper function of CD4 cells, which we think is really important, is that they activate dendritic cells, and they help the other T cells around them. They help through cytokine support, through interferon gamma and IL-2, and they also help through activating dendritic cells, which we see in our translational data as an IL-12 signal.
That's also the reason for thinking that adding a PD-1 combination with these cells makes sense. If you break into the tumor, you start a pro-inflammatory response, you bring in other cells, and then you give them PD-1 combo as well. The PD-1 combo has something to work on, and that's what we think is really important here.
Great. Thank you very much, Jo. Here's a question for one of our US colleagues here, and this I think I'll direct to you, Elliot. How is the duration of response evolving, and what percentage of our initial responders are still in response? This is a question from Michael Schmidt.
Yeah. Thanks very much. I think the real answer is that the duration of response is still evolving. This is an ongoing trial, and as of the data cut, there were 12 responders, and we've updated that to being 14 responders as of the more current look. Within the 14 responders, there are still seven patients ongoing, seven or eight patients ongoing that have ongoing responses or ongoing unconfirmed responses.
When you're talking about, you know, seven patients out of 14 or 14 + the unconfirmed responders, there's still quite a bit of room for the median duration of response to improve. I wanna sort of also state that this is as a signal finding study, this has been successful. We will still continue to see the duration of response evolve. We're independent of that.
We're confident in the results that we're seeing as it relates to these various tumor types and the activity that we're seeing, and that there are signs of patients with meaningful, durable responses and some signs of patients who remain alive, you know, even after progression. Again, we're very encouraged.
Thank you, Elliot. Don't go far, though. Another question. This is for you from Tony at Roth. Can you discuss your view of CRS in future trials, especially those cohorts which are combining with nivolumab?
I th ink that cytokine release syndrome is a part of cell therapy. I mean, I think we have to accept that. Over time, we have become increasingly adept at identifying and managing cytokine release syndrome. I think it is possible that the addition of checkpoint inhibitor could affect the frequency and severity of cytokine release syndrome. In our initial evaluation of checkpoint inhibitor, we're treating in combination, treating patients with checkpoint inhibitors starting approximately one month after T-cell therapy.
Most of the patients who are going to have cytokine release syndrome will have had it and recovered from it before they would get their checkpoint inhibitor. I mean, ultimately, the timing of the combination may be such that it's better to give checkpoint inhibitors earlier, and that may be a feature that we explore, you know, in future iterations. At which point I think we'll need to pay more attention to that.
I am confident that in the treatment centers where we're giving this therapy, who have real expertise in cell therapy, and really understand identifying and managing cytokine release syndrome, and I think it continues to improve over time, and we select the patients more intelligently over time, that this product will continue to actually get safer, in the way that we use it. And I'll leave it at that.
Actually, Elliot, you can stay up there. Have you parsed the data by prior lines of therapy, and are you seeing differences in the responses based on looking at the number of therapies that we have, the patients have received?
Yeah. I think that the best, the most evolved data that we have as it relates to influence of prior lines of therapy, is in SPEARHEAD-1 or in the combined data that we presented at ASCO just in June, in with the first generation product and synovial sarcoma. It's clear there that prior lines of therapy make a difference with respect to response rate. That being said, there are patients with multiple prior lines of therapy that do respond. While it's important, I don't think that it's absolutely exclusionary as it relates to whether or not the product will work.
I do believe that patients with fewer prior lines of therapy will have a less affected tumor microenvironment with fewer mechanisms of resistance. In general, those patients will be healthier.
I also think it gives us an opportunity if we're treating patients in earlier lines of therapy, and that is clearly a direction that we intend to pursue, that we'll have the opportunity to harvest their T-cells at an earlier juncture in their tumor cancer journey. In which case, those cells will be healthier and more fit and will translate into a more potent product that should ultimately improve efficacy.
Thank you very much, Elliot. Turning to the U.K. for a question, Helen, this is likely a question for you from the online portal. Given this data that you've now presented, how are you starting to think about partnering and looking at these different indications from partnering perspective?
Yeah. Thanks, Bill. Great question. As you can imagine, there's quite a lot of interest from potential partners in this data. I think everyone in the cell therapy field is exquisitely focused on solid tumor data and compelling data. That's why we're so excited about this data and, you know, obviously, various discussions progressing as this data has been evolving.
Clearly, I'm not gonna be able to tell you very much about exactly where we are with those discussions, but I will say that any partnership that we execute for Adaptimmune will obviously be really focused on accelerating the development and expansion of the work we're doing here in the SURPASS family of trials and other associated MAGE-A4 activities. It will also add meaningful value to Adaptimmune, and those are our two priorities for how we think about partnering.
Thank you very much, Helen. Turning back here to the U.S. , Dennis, this is a question for you from the online portal. What are you thinking about as a threshold for additional numbers of patients or responses you're hoping to see to potentially initiate a phase II trial in head and neck or urothelial? Then a related question also from the online portal, trying to group these. How are you thinking about the potential of combining the cells with the standard of care checkpoint in earlier lines in bladder and urothelial in head and neck?
Thanks for the question. Yeah, our focus right now for SURPASS-1, among trying to generate additional signals is really to focus in on those tumor types, both head and neck and bladder cancer. The goal will be to generate additional monotherapy data as well as the inclusion of those patients in combination. I think with the limited number of patients for today with four patients with head and neck cancer, certainly wanna we wanna bolster those numbers and further characterize this impressive signal we're seeing to date.
This is a good point that this was raised in this question because as we generate further data with combination cells plus a checkpoint in phase I, this is a great opportunity to step into our ultimate goal. Our ultimate goal is to go into earlier line therapy.
Since single agent checkpoints are used as standard of care in both of those diseases, this would seem to be a great opportunity for us to move into earlier lines where there are more patients that can benefit from the therapy. We can have a greater response to the course of their disease, and we can explore things like time to event endpoints.
Great. Thank you, Dennis. And also don't step too far away. One question for you from Michael Schmidt. What percent of patients in ovarian cancer, GEJ, head and neck, and bladder respectively would be treatment eligible based on HLA status and your MAGE-A4 biomarker cutoffs? How are you feeling about the patient population that's available?
Thank you for the question. In general, in our trials, we've published data previously at AACR about this. For HLA positivity, we generally see in the neighborhood of 45% of the patients are eligible, which is consistent with the population demographics of where we run trials.
For MAGE-A4 expression, the expression level we use for clinical trials, for the diseases that you just mentioned, the expression level ranges from about 20%-30%, depending on the tumor type. It's a little bit higher in bladder, head and neck around the 20%-25%, ovarian cancer is around 20-25%. Gastroesophageal cancers is a heterogeneous mix, right? There are squamous and adeno, depending on the type, but in general, it's also around that 25% range.
Sorry about that. Still parsing through a couple of questions. This question, I believe, would be for, Dennis again, if you could come back up. What ovarian cancer patient population will you focus on in SURPASS-3? What durability are you seeing for different tumor types? And how many are still ongoing treatment by tumor type? This is a question from Peter Lawson.
The population that we're studying in SURPASS-3 is platinum-resistant ovarian cancer. Those women who have a platinum-free interval, basically they progress and their platinum-free interval is less than six months. You heard Dr. Moore speak to this perhaps much more eloquently than I can. That's really the area of focus, right? Here again, how are those patients treated today? They're treated with non-platinum-based single agent chemotherapy, where response rates are, you know, in the low teens.
Progression-free survival is poor. Overall survival is roughly around one year, right? This, as you heard Dr. Moore say, is an area of high unmet medical need, and that's where we're focusing this first trial. Garner experience, some of the things that Dr. Moore mentioned about perhaps other areas where we can introduce cells therapeutically in this disease, we're certainly interested in exploring. 'Cause our goal ultimately is to bring cellular therapy earlier, where we can make a bigger impact to the trajectory of the disease of these patients.
The second question about the percentage of patients that are in response that are ongoing, it runs the gamut, actually. There are currently patients who have ongoing responses in synovial sarcoma. There's one patient actually with this disease in this trial. Ovarian cancer, esophageal junction cancer, bladder cancer. There are a number of responses. In fact, in some of those diseases, there are more than one ongoing response.
Thank you very much, Dennis. With that, I'm gonna turn it over to the U.K. and give it to you for the close, Ad.
Thanks, Bill. Thank you everybody for joining us and for your questions. I'm particularly grateful to Dr. Kathleen Moore for her insight today and also for her work on our trials. I'm also very grateful to Dr. David Hong, and I would encourage you to listen to his presentation at ESMO tomorrow. Behind these data that we've talked about today are people with cancer. As a company developing and delivering autologous cell therapy, we see that connection with the patients that we manufacture and treat with our cells every day.
'Cause in reality, they're not our cells, they're their cells. We and the cancer patients of the future are eternally grateful to these early patients in the SURPASS trial. We're grateful to them, we're grateful to their caregivers, we're grateful to their physicians, and we all owe them a debt of gratitude for these data. There are three things I want to leave you with. Firstly, these data are a dramatic demonstration that we can achieve high levels of response and benefit for patients across a wide range of tumors that express MAGE-A4.
Adaptimmune has been built to design, develop, and deliver these cell therapies. We are well-placed, therefore, to be able to pursue these development options in ovarian, gastroesophageal, head and neck, and bladder cancer. We continue to believe that these data demonstrate that our MAGE-A4 franchise will be a game changer for cell therapy in solid tumors, and it reinforces our leadership position in this important and exciting space. With that, I'll close the call. Thank you.