Good day, and thank you for standing by. Welcome to the interim tagmokitug clinical data webcast. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Carrie Graham. Please go ahead.
Thank you, Heidi. Good afternoon and welcome to Coherus Oncology's tagmokitug interim clinical data disclosure conference call. Joining me today to discuss our results are Denny Lanfear, Chief Executive Officer of Coherus, Dr. Rosh Dias, Chief Medical Officer, and Dr. Theresa LaVallee, Chief Scientific and Development Officer. Before we get started, I would like to remind you that today's call includes forward-looking statements regarding Coherus' current expectations about future events. Actual results may vary significantly, and we undertake no duty to update or revise any forward-looking statements. Please see the press release that we issued today for more information on risks and uncertainties. I'd like to turn the call over to Denny Lanfear.
Thank you, Carrie. Today, I'll be speaking to you about a few things. We'll first talk about the t agmokitug opportunity in esophageal cancer, and then we will give you a data update on some additional indications. This will be followed by a KOL discussion and then some closing remarks and the Q and A. Joining me today is Dr. Rosh Dias, the company's Chief Medical Officer, as well as Dr. Theresa LaVallee, the company's Chief Scientific and Development Officer. Later on, we'll be joined by Dr. Doug Adkins from WashU, our Head and Neck Specialist, and Dr. Dan Feng from the Icahn School of Medicine at Mount Sinai, who will comment on the GI data.
Let me talk a little bit about the pipeline and just make one brief statement. I direct you to the bottom of this slide, where we talk about our casdozokitug program, which we shall not discuss today.
I will, however, indicate to you that casdozokitug is showing clear dose-dependent activity, both with respect to response and duration. We expect to have a data disclosure for casdozokitug in January of 2027. Our fight against cancer focuses on overcoming immune resistance because it is there that the battle for extending patient survival is fought and either won or lost. Appropriately, patient survival is generally the approval endpoint for regulators. While our therapeutic focus includes the shorter-term reduction in tumor size or ORR, as it is important, we pursue clinical benefit, duration of response, and stable disease, where we seek to provide patients more life. This is our commitment to cancer patients to extend their lives. You can see this clearly here. LOQTORZI nearly doubling the six-year survival of nasopharyngeal cancer patients on a background of chemotherapy versus chemotherapy alone.
This is a textbook example of extending survival by addressing immune resistance, in this case, with checkpoint therapy. Today, we report on our efforts to overcome a core part of cancer immune resistance and how the immune response mediation activity of Treg cells in the mucosal system, extending top to bottom from head and neck through the GI tract, is hijacked by cancer. We have investigated several cancers along various lines of therapy, including first-line esophageal, second-line esophageal, second-line gastric and GI, second-line head and neck, and fourth-line plus colorectal, which I would comment is a particularly challenging setting. Tagmokitug has demonstrated clinical activity across all of these. As you will see today, these multiple solid tumor types with over 120 patients treated. I summarize our findings to date here for you as well as our projected development direction in first-line and second-line esophageal cancer.
First, across these studies, we saw a durable response and disease stabilization in pretreated IO-resistant populations, thereby demonstrating the ability to reverse immune exhaustion and rescue T cells. With these studies, we saw broad pan-tumor activity of tagmokitug, including in head and neck cancer with enrichment for HPV-positive disease and in GI cancers, demonstrating clear dose-related activity. Very importantly, we saw no new safety signals beyond what is seen with PD-1 inhibitors and very manageable safety profile. The esophageal studies have shown particular promise with the confirmed overall response rate of 75% in all comers. That is inclusive of PD-L1 high and low and 100% in PD-L1 positive patients with an N equals eight evaluable patients in first-line esophageal. Dr. Dias will address this momentarily. The clinical benefit in first-line and second-line esophageal patients with PD-L1 negative tumors was also of note.
As I indicated, we now will proceed with an integrated development plan forward in both first and second-line, which Dr. LaVallee will further talk about. We plan to expand cohorts to add more patients and add more longer follow-up, and this year, leverage FDA designations as we discuss with them the path forward and these additional cohorts and patients. With that, I'll hand the call over to Dr. Dias to discuss the specific results in first-line esophageal for you. Rosh?
Thank you, Denny, and good afternoon, everyone. Today, I'll present data from our TREGCHECK program. As a reminder, this is an ongoing program with continuing data entry. What I'll be presenting will be the interim data from the program. We'll present data from our GI program in four tumor settings, starting with esophageal squamous cell carcinoma in both first-line with chemotherapy and in second line. Our esophageal squamous cell cohorts will be the main focus in our development presentation due to the strong activity we're seeing. I'll also cover upper GI adenocarcinomas and colorectal carcinoma, as well as data in the PD-1 refractory head and neck squamous cell carcinoma cohort. As I go through the various cohorts, I'll cover key efficacy metrics and safety data.
For efficacy, as you heard from Denny, the important metrics focus will not only be objective response rate as well as clinical benefit rate as well, a metric that includes CR plus PR plus stable disease greater than six months. CBR is an important measure of durability in early-stage trials, which is particularly important as the benefit of IO has been in extending the tail of the curve and improving survival, which, of course, is the approvable endpoint. Let me now start first with first-line esophageal squamous cell carcinoma. This was designed as a single-arm safety cohort with 12 treatment-naive patients with advanced metastatic disease, including patients that includes both PD-L1 positive and negative tumors. Enrollment is ongoing, and at the data cutoff date, 10 patients have been dosed and eight patients are evaluable.
We investigated our planned go-forward dose of 700 mg of tagmokitug in combination with toripalimab and with the U.S. standard of care chemotherapy, that is 5-FU and cisplatin, with safety as a primary endpoint and additional efficacy secondary endpoint. In terms of regional accrual, this was a multi-regional cohort with 20% of patients from the U.S., with 80% from the Asia-Pacific region. This slide outlines the interim clinical activity from the evaluable population in a waterfall plot. While the data set needs expanding, as you can see, tumor shrinkage was observed in 100% of evaluable patients.
As you can see from the legend below the waterfall plot showing PD-L1 status, the tumor shrinkage, importantly, was observed irrespective of PD-L1 status, so not only for PD-L1 positive patients, but also in patients who are PD-L1 negative, which, as you know, is not within the current approval in the U.S. label for PD-1s. In terms of best overall response of the eight evaluable patients, one patient had a confirmed complete response, and additionally, five patients had a confirmed partial response, of whom two patients continue on treatment as marked by the vertical arrows, overall representing a 75% confirmed overall response rate. For the two remaining evaluable patients on the far left of the waterfall, one had an unconfirmed PR. So meaning at the time of data cutoff, they had just received a single scan and are waiting for the next scan to see if this confirms.
The other patient had tumor shrinkage, not quite meeting the criteria for a confirmed PR, but showing durability beyond six months and continues on treatment. These two patients were PD-L1 negative, and again, they do not qualify at the moment for IO treatment in the U.S. For the PD-L1 positive patients, all responded with either a confirmed PR or CR, representing a 100% ORR in this population. Since our data cutoff date of October 14th, there has been some further improvement in activity with no attrition. We have since verified two additional participant scans that reflect the following. Firstly, the second from left patient with a PD-L1 negative unconfirmed PR has since confirmed. Secondly, a new evaluable patient who is not therefore currently represented on this waterfall has confirmed a PR.
If we were to include these additional scans since the October 14th date, the ORR in the evaluable population would go from 75% to 89%, and an ORR in PD-L1 positive patients would be maintained at 100%. For context, and bearing in mind that cross-trial comparisons do have limitations, the current standard of care of a PD-1 with chemo in the first-line setting have shown between a 44% and 59% ORR in PD-L1 positive patients. We do remain very encouraged by the interim activity demonstrated here. As we stress, durability and long-term stable disease is very important, and we look forward to these data continuing to mature. While these compelling data need to mature for durability, this does warrant cohort expansion to a larger data set, up to 30 or 40 patients.
This slide shows a representative CT scan from this cohort, and this is from the patient who had the complete response. Let me first orient you. This is an axial CT scan looking at a cross-section of the upper esophagus, showing an esophageal mass on the top panel and a supraclavicular node on the bottom, with baseline scan on the left and a follow-up scan on the right after almost eight months. The participant had a PD-L1 positive MSS tumor. Looking from baseline on the left to follow-up five on the right, what you can see is complete disappearance of the target lesion in the esophagus. This is marked by the white arrow at the center of the left scan, which is no longer visible on the follow-up scan on the right.
There is also very clear diminution in size of the supraclavicular lymph node that you can see on the scan below. Overall, there was an 88% reduction in target lesions at the time of the reported complete response, and the response had also extended beyond target lesions. All non-target lesions had disappeared after eight cycles, and no new lesions had appeared, representing a very deep response in this patient. The spider plot here represents the eight evaluable patients, and this reflects the speed and the durability of the response. Again, all participants demonstrated tumor shrinkage, with all seeing this at the first scan, so this represented a very rapid onset of response. In terms of durability, PFS is not as yet mature, but I can highlight a couple of relevant points.
Firstly, 50% of patients, so four patients, still remain on therapy, as noted by the red arrows on the end of the relevant patient line. Secondly, two patients have demonstrated activity for close to eight months, with the patient that is in stable disease still continuing on treatment. Note again that this is the patient who is PD-L1 negative, again reflecting activity irrespective of PD-L1 status. We do anticipate the potential for continued evolution of durability as the median PFS continues to mature. Let me now move on into the second-line esophageal setting. This, as you know, is a tumor setting where there is a huge unmet medical need, where the current standard of care remains chemotherapy for PD-1-experienced patients or a PD-1 inhibitor for PD-1-naive patients.
This cohort is an advanced or metastatic esophageal squamous cell population, with patients who have experienced progression after treatment with chemotherapy, with or without a prior PD-L1. We have a target enrollment of 20 total patients with 300 or 700 mg of tagmokitug in combination with toripalimab, with 10 patients in each dose level. Safety is the primary endpoint, with efficacy as secondary endpoint, and 17 of 20 patients have been dosed thus far. This is also a multi-regional cohort, and around 30% of patients were from the U.S., and this was a population that included PD-L1 refractory as well as PD-L1-naive patients. Let me orient you first to the waterfall plot that you see here. The green represents the 300 mg dose of tagmokitug with 700 mg in blue, of course, both in combination with toripalimab.
On the legend below, you see best overall response, prior PD-L1 status, and time since last PD-L1. As you can see, of the eight evaluable patients, all but two had a best overall response of either stable disease or partial response, with one patient having a confirmed partial response equating to a confirmed ORR of 16.7% in the 700 mg dose and an additional patient having an unconfirmed PR, with treatment still ongoing. The confirmed PR was in a patient whose tumor was PD-L1 positive, whereas the unconfirmed PR was in a patient with PD-L1 negative tumor, again representing activity irrespective of PD-L1 status. The CBR, and that is, as a reminder, CR plus PR plus stable disease greater than six months, was 33.3% in the 700 mg target dose, representing the potential for this doublet as a chemo-free regimen in this tumor setting.
The swimmer's plot for second-line esophageal squamous cell, this showed all dosed patients, and this really does outline the activity we believe to be compelling in this cohort, and that is the clear tagmokitug dose response. As you can see, there is a very clear dose response in this randomized cohort. The 700 mg tagmokitug with toripalimab in blue shows benefit, whereas the 300 mg dose in green is not sufficient. At the 700 mg tagmokitug dose, we saw both the confirmed and the unconfirmed PR, and also what's pretty striking is the long-term stable disease, showing durability of activity in this dose level. Of note, two patients are still continuing treatment close to eight months, including one patient with a PD-L1 negative tumor. Whilst the dataset is small and still maturing, the current median PFS of 5.5 months is encouraging.
With six patients in this cohort still continuing on treatment, several of whom are either in stable disease or unconfirmed PR and awaiting further scans, we do look forward to this data continuing to mature further too. As a relative comparator, again with the usual caveats of cross-trial comparisons, the current standard of care provides a median PFS of between two and four months and overall survival of less than a year. The safety profile for both first line in combination with chemo and second line as the tagmokitug/ toripalimab doublet is very consistent with the overall integrated safety that I'll outline later. In the first-line setting, the discontinuation rate is around 40%, but of course, this is in combination with chemotherapy and is also very similar to the overall discontinuation rates reported, for example, in CheckMate 648 in the same setting.
Across both lines of therapy, there were no grade five tagmokitug-related events. The most common AE is related to any study drug I have shown, and the safety profile for both esophageal squamous cell cohorts support continued development. Let me now hand over to Theresa to talk about the integrated plan moving forward for ESCC.
Thanks, Rosh. We recognize we need more mature follow-up and clearly more patients. But the signal to date is compelling. While we see activity across tumor types, which Rosh will show you in a couple of minutes, the early interim data here are exceeding benchmarks. The Coherus objective for additional tumor types for toripalimab approval beyond NPC has always been through improving standard of care with PD-1 beyond where it is today and bringing immunotherapy to patients who are ineligible. We see that that objective is possible in these data sets. Let's move on to the benchmarks. Shown on the left in gray in the first-line setting, you see the three approved PD-1 inhibitors plus chemotherapy in the United States, showing an overall response rate about 50%-60%.
While toripalimab, through the JUPITER-06 study, is approved in China and Europe, it is not recognized by the U.S. FDA because it uses a different chemotherapy that is not used in U.S. medical practice. It did not include U.S. patients. The TREGCHECK program incorporates U.S. standard of care and U.S. patients, and we see an overall response rate in the PD-L1 positive patients of 100%. Importantly, patients with PD-L1 negative tumors, the FDA removed the label from PD-1. The only standard of care therapy is chemotherapy. It was the lack of benefit that made them revise the labels. Here we are seeing activity. 75%, 100% are big numbers. What always you would expect with more follow-up is attrition. We were pleased to see at the first look where we have another partial responder confirmed and a new evaluable patient as a partial response.
We maintained 100% and improved the 75% to 89%. In the second-line setting, Rosh showed you that swimmer's plot. When those patients are so sick, they cannot swallow, they are malnutritioned, they have gone through first-line chemo. When they fail, they fail fast. In the under-dosed tagmokitug dose with toripalimab, we see only one patient made it past six weeks on study treatment. In the 700 mg dose, we see a number of patients on past 33 weeks. Eight months is the chemotherapy median overall survival endpoint. That is why we focus on the clinical benefit rate, because this long-term stable disease is meaningful. What we show you here is that adding tagmokitug to toripalimab has improved on PD-1 treatment, in PD-1 naive patients, and in less inflamed tumors such as PD-L1 negative. In the second-line setting, we have shown activity in PD-1 resistance.
Tagmokitug can add to PD-1 in all settings. Shown here on the right-hand side of the slide is the data that we've talked about for JUPITER-06 with toripalimab and chemotherapy from the China study, where we see activity irrespective of PD-L1 status, as shown by the hazard ratio being the same. Why do we think this is true? We see this due to potency. Toripalimab has a higher binding affinity and a unique epitope. When used in combination with chemotherapy, the less inflamed tumor can have activation of anti-tumor immunity due to this potency. That is not true in the absence of chemotherapy. In the second-line setting, where IO alone is showing activity in PD-L1 negative patients, that can be attributed to tagmokitug, bringing in that remodeling of the tumor microenvironment and overcoming a less inflamed tumor.
Exactly the objectives of what we wanted with depleting Tregs from the tumor and remodeling the tumor microenvironment. How do we take this forward? We said expand the patient data set to 30- 40 patients, get more mature follow-up, and engage with FDA about favorable regulatory strategies. With this compelling activity, what we see is two drugs, two approvals, or two drugs, two indications that can really change the treatment landscape in ESCC for a best-in-disease opportunity. Bringing in the opportunity to take two studies with randomized controlled trials and looking at accelerated approval endpoints with surrogates of ORR and DOR early on, and in the same study, using it to convert using the overall survival endpoint.
This has been done in the first-line setting by an initiative from FDA called Project FrontRunner, where they're encouraging development in earlier lines of therapy, and this was successfully implemented by Pfizer with the BREAKWATER study, where they achieved accelerated approval at the end of 2024 on the ORR/DOR endpoint, and about a year and a half later, got full approval based on the OS data. Immediate next steps are to meet with FDA and align on the go-forward dose. We've shown you the 700 mg data. Here, you'll see in the next set of studies that the GI tumors do show nice dose response. We see in the head and neck cohort that both dose levels are active. We think this is consistent with the biology of that viral-driven tumor and it being highly Treg sensitive.
The lower dose is able to overcome in a highly inflamed tumor to bring antitumor immunity and see activity. When we look at the tumor biopsy data in the head and neck cohort, we do see higher immune activation with the 700 mg dose level, consistently giving us confidence in the 700 mg dose as the go-forward dose. I also want to call your attention to the far right portion of this slide, where we talk about the full BLA package, in that 50% of the spend, 50% of the risk is also on the CMC components. Given the biosimilar heritage of Coherus, we feel confident we can put together a robust and quality CMC package for a BLA submission. Importantly, we've moved all manufacturing for our investigational agents to the U.S., really enabling ease of inspection for the FDA.
We will look at all expedited programs and all ability to move these programs forward, the last being Project Orbis, because in maintaining two drug approvals, which adds complexity. In Europe, toripalimab is approved in first-line esophageal squamous cell carcinoma. Project Orbis is an initiative by FDA that allows for concurrent submission and review of BLAs to multiple health authorities, including Europe, Japan, Singapore, Canada, U.S., working collaboratively together. So having toripalimab approved in this indication could be leveraged to decrease the complexity in getting both drugs approved in the U.S.
Thank you, Theresa. As you can see, we have launched a very well-considered clinical program with five different indications or lines of therapy. We have now elucidated a particular indication, esophageal cancer, where we believe we have a very synergistic and executable approach for first and second line. First of all, it leverages the differentiated activity and high unmet need in both settings. We believe there is a highly efficient development path, and as Theresa outlined, one with the potential for accelerated approval, leveraging various FDA indications. There are multiple paths to market, and there is a broad patient population, given the ability to address both PD-L1 positive and PD-L1 negative with no selection. It is also potentially a global program. As Theresa indicated, toripalimab is approved in Europe for esophageal irrespective of PD-L1 status, which creates the opportunity for, we believe, ready partnerships.
There is also a high disease burden ex-U.S., particularly in Asia, in China, and in Japan and other places, which opens the global development and partnering opportunities given this very promising data. Here in the U.S., there is approximately 5,000- 7,000 patients to be addressed across these lines of therapy. As we will be using two novel agents for Coherus, this translates to an economic opportunity of about $1.5 billion and a rare indication, which is very suitable for our commercialization efforts. With that, now, I will turn the call back over to Dr. Dias, who will talk to you a little bit about some of the other indications that we evaluated, Rosh.
Thank you, Denny. Let me move on now, first of all, to our head and neck squamous cell cohort. As a reminder, this builds upon the data that we presented last year in 2025 at AACR from earlier stages of this trial, where with tagmokitug monotherapy, we showed clear tumor remodeling to a more cytotoxic state with depletion of the intratumoral CCR8 positive Tregs and an influx of CD8s. As you can see in the immunofluorescence slide on the top left panel, and clear anti-tumor activity with the addition of toripalimab on the bottom left panel with a PR in a fourth-line patient whose tumor was refractory to a prior PD-1, a taxane, and a TKI. The current cohort I will report on is interim data from the second line specific population. This is a relapsed metastatic second-line head and neck population who must have received a prior PD-L1.
We enrolled 43 patients, all in the U.S., 25 in the HPV population, of whom 23 were evaluable, with 300 or 700 mg of tagmokitug in combination with toripalimab, with a roughly equal split between the two doses. Safety was the primary endpoint, with additional efficacy measures as secondary endpoints. We communicated at our last earnings call that we have seen activity both in terms of response as well as duration, with enrichment of activity in HPV positive patients. You can see this in the waterfall plot here. The waterfall shows HPV positive evaluable patients with both doses, 300 mg in green and 700 mg in blue, in combination with toripalimab.
The majority of the patients with HPV positive disease, as shown here, did have activity reaching criteria for either a partial response or stable disease at active doses, suggesting that tagmokitug is able to rescue PD-1 resistance at both of these levels. In this HPV positive population, there were three confirmed PRs and one additional unconfirmed PR, with activity in both PD-L1 positive and PD-L1 low patients, resulting in an ORR of 13% and a CBR of 26%. The durability, in particular, was encouraging, with several patients in the second-line HPV positive population out past six months of treatment. We also saw a patient continuing treatment for the past 1 year, and this patient still remains on treatment. This is encouraging for a couple of reasons.
Firstly, as we've mentioned, durability is a very important measure of activity because this, of course, is the best correlate to survival, and survival is the approvable endpoint. Secondly, the enrichment of activity in the HPV positive population represents a key area of unmet medical need, as many of the emerging therapeutics are either focused in on the HPV negative space or have activity that may be driven by HPV negative populations. This suggests the potential for further study in this HPV positive population, importantly with this as a chemo-free regimen, which represents a relative white space in terms of key development opportunity for patient benefit. The other area for potential enrichment that we've seen is with the baseline immune context. The Tumor Immune Regulatory Index, or TIRI, is a tumor-derived CCR8-containing biomarker score, which defines the baseline immune context.
We know that HPV positive tumors exhibit greater immune sensitivity and Treg-driven immune suppression. What our correlative work shows is that TIRI further enriches for both ORR as well as CBR in this HPV positive population. On the left, we have the HPV negative patients. On the right, HPV positive. I'll make a couple of observations. Firstly, both ORR and CBR overall are higher in the HPV population over the HPV negative population. Secondly, TIRI does enrich for activity in the HPV negative population. However, in HPV positive patients, not only was the ORR and CBR higher than in those that were HPV negative, but the enrichment by TIRI takes the ORR from 13% to 18%, and more importantly, the CBR from 26% to 45%.
Again, this is an improvement in durability, and in particular, it's encouraging as this represents a potential enrichment factor as we seek to move through the development pathways. In terms of the safety in the second-line head and neck squamous cell cohort, this again was consistent with the safety profile seen across cohorts, with the most common AEs related to any treatment being fatigue, infusion-related reactions, and diarrhea. The safety was overall acceptable and manageable, which in this context of emerging clinical trials is, of course, a very important point. I'll now move on to our upper GI adenocarcinoma cohort. This was a relapsed metastatic population, including gastric cancer, gastroesophageal junction, and esophageal adenocarcinoma, which, of course, is all the same adenocarcinoma histology.
Patients were HER2 negative with tumors with a lower mutational burden, and all must have received prior chemo with a platinum and 5-FU, with or without a prior PD-1. We enrolled 40 patients across the two active doses of 300 or 700 mg of tagmokitug in combination with toripalimab. Again, roughly evenly balanced between the two doses, and again with safety as primary and additional efficacy measures as secondary endpoint. This was a multi-regional cohort with 60% of patients from the U.S., and the predominant anatomical site was gastric, representing around 60% of the population, followed by GEJ and then esophageal adenocarcinoma. About a third of the patients were PD-1 naive. The waterfall plot here shows the overall activity in the response evaluable population, with the 700 mg dose in blue. 300 mg in green.
In our target go-forward dose of 700 mg, we saw four confirmed PRs, resulting in an overall response rate of 23.5%, three of whom were refractory to a prior PD-1, and a CBR rate of just under 30%, both suggesting that tagmokitug with toripalimab can rescue PD-1 resistance in this population. As you can see in the legend below the waterfall plot, tumor shrinkage was observed in both PD-L1 high and low tumors and was observed across all three anatomical subtypes, including two PRs in patients with EAC. Again, the latter represents activity in esophageal carcinomas. Six patients from the response-evaluable population still continue on treatment, suggesting that there may be continued potential to improve on this interim data. The swimmer plot, again, shows very clear dose response in the upper GI adeno cohort as well, with 300 mg on top in green and 700 mg bottom in blue.
All responders have thus far been at the 700 mg target dose. As you can see, the durability is also more marked in the high dose, with several patients continuing past six months of treatment. This, again, speaks to the potential for durable benefit in this upper GI adeno cohort. As a reminder, the current standard of care for second-line upper GI adenos remains ramucirumab and paclitaxel, and so a chemo-free doublet would be a very valuable option for patients in this setting. In terms of the safety profile, again, the profile here was consistent with the safety across all cohorts, with the most common AEs that are related being infusion-related reactions, pyrexia, and lymphopenia. There were no grade five tagmokitug-related events at either dose. Overall, the safety, again, was acceptable and manageable. Let me end now with our colorectal cancer cohort.
Here we looked at a very late-line relapse metastatic population who had exhausted all approved prior standard therapies, including, for example, oxaliplatin, irinotecan-based chemo, fluoropyrimidine, or others. This was essentially a fourth-line and beyond population with a focus on patients without liver mets. The main goal of this cohort was to determine whether we could see activity in this late-line setting that may then allow us to move into earlier lines of therapy in colorectal carcinoma. We enrolled 20 patients as a single-arm cohort with 700 mg of tagmokitug in combination with toripalimab. The primary endpoint was safety, with additional efficacy measured as secondary endpoint. This is also a multi-regional cohort, with approximately 60% of the enrollment coming from the U.S.. What you see here are the waterfall and spider plots for the response-evaluable population.
First, on the waterfall plot on the left, we did see tumor shrinkage in this very late-line population, with just over half of the response-evaluable population showing some degree of tumor shrinkage, with one patient achieving a confirmed PR, representing a confirmed ORR of 6% and a CBR of 12%. In addition, we did have several patients with tumor shrinkage approaching, but not quite reaching, the criteria for a partial response. Additionally, we saw molecular response with ctDNA decline and CEA decreases, as you can see in the legend below the waterfall plot, broadly but not universally correlating with tumor shrinkage. The spider plot on the right shows the durability in this very late-line population, with three patients being treated past 24 weeks, two of whom are still continuing on treatment, which again is not trivial in this very late-line population.
Activity in this population supports moving to earlier lines, which was our original intent in exploring the fourth-line plus setting. Finally, in terms of safety for this CRC cohort, again, this was consistent with the safety profile across cohorts, with the most common related AEs being fatigue, rash, and anemia. Overall, again, safety was acceptable and manageable, with tagmokitug-related grade three-plus events seen in 10% of patients, with no grade four or five tagmokitug-related events. Before we move on to our panel discussion, let me just summarize a couple of points. We're pretty encouraged overall, as you heard, by the data that we've outlined over the past two minutes, which has shown clinical activity across the cohort and, importantly, an expected and manageable safety profile in combination with toripalimab and also in combination with chemotherapy.
The ability to combine with chemo gives us the ability to move into earlier lines of therapy, where it's well known that immunotherapy is more active. Whilst this is interim data, the ESCC data offers a clear potential for continued development in a tumor type that is hugely underserved, with a clear unmet medical need. In first line, with strong activity, tumor shrinkage irrespective of PD-L1 status, and initial durability, this offers a development opportunity in combination with chemo. In the second-line setting in esophageal squamous cell, activity and clear dose response has been demonstrated, which allows development then as a chemo-free option. Additionally, in the GI cohort, the activity is observed in the 700 mg dose, with the 300 mg dose showing limited benefit, and that gives us confidence in the data being tagmokitug driven and also in the dose.
The enrichment of activity in HPV-positive head and neck offers a clear path to continued development in an area of relative white space. Overall, we're also encouraged by the safety profile across the program. Earlier in program, through tagmokitug monotherapy dose escalation, we showed no DLTs up to 1,200 mg and low-grade immune-related AEs, showing targeting the CCR8+ Tregs is relatively sparing of peripheral tolerance. In combination with toripalimab across over 120 patients, we've also seen no new safety signals over what is known for PD-1 inhibitors. As expected, we did see an increase in immune-related AEs, but importantly, this has been manageable and compares favorably to IO combinations such as ipi/nivo, for example, as you can see on the right panel. We've seen comparable safety across both the 300 and 700 mg doses with similar immune-related AEs.
Most of the AEs with tagmokitug and toripalimab were grade two or less and resolved with no grade five treatment-related AEs. In our first-line esophageal squamous cell cohort with tagmokitug and toripalimab in combination with chemo, again, we demonstrated a manageable safety profile, no new safety signals, and the majority of AEs were attributed to chemo. The safety profile is very similar to other phase III studies with PD-1 inhibitors and chemotherapy that led to their U.S. approvals. Overall, the most common treatment-related AEs with the tagmokitug/toripalimab doublet have been infusion-related reactions, fatigue, and rash. Let's move on to a brief panel discussion. I'm delighted to be joined by Dr. Doug Adkins, a Head and Neck oncologist from WashU School of Medicine, and Dr. Dan Feng, a GI Oncologist from the Icahn School of Medicine at Mount Sinai.
Doctors Adkins and Feng, thank you very much for joining us today to share your perspective. As mentioned, activity across GI cohorts with a particularly strong signal in ESCC that warrants further development is pretty exciting for us, and also with activity in head and neck squamous cell with enrichment in HPV-positive patients. I'd be particularly interested in your thoughts initially as clinicians treating these very hard-to-treat cancers about your impressions on the early data across cohorts and how this could fit in with clinical practice. Perhaps we can just start with esophageal squamous cell, particularly in the first-line setting, and really just discuss your initial reactions to the first-line data. I'll just remind you, as you know, we saw an overall response rate of 75% in the evaluable population, which then goes up to 89% if we include additional scans since the October 14th cut.
Maybe I can open it up to Dr. Feng. Dr. Feng, maybe some initial reactions to the esophageal data, starting with first line.
Yeah. Thank you. I am a GI Medical Oncologist. I treat these diseases, and I am involved in a lot of the early phase drug development in this space. From my perspective, I think I want to just highlight a few things so that what my thoughts when I hear and see these data is, one, we know that esophageal squamous is actually a very bad diseases, very poor prognosis. Most of our patients, from the time they got diagnosed with advanced diseases, they have a median survival about 15- 17 months. This is also a disease that we do not have effective options past the first line.
For me, in looking at the front-line data you have with toripalimab plus tagmokitug plus chemo, I was very impressed with the high response rate because you show the data that close to 90% for all comer and 100% for the PD-L1 positive patients. I think that it is worth noting that also that the benefits are also seen in the patient with PD-L1 CPS less than one, or we call them PD-L1 negative patients. This is way better than what has been reported in the clinical trial and what we have seen in our everyday clinical practice. In the second-line setting, the combo without chemotherapies also has shown really impressive activities because this is a space that we really rely on single-agent chemo therapies. For patients who were previously treated with PD-L1 or PD-1 antibodies, there is really no great options from these for chemo.
A lot of the patients are heavily pre-treated when they get to this point. I think it is worth noting that the combo actually had two response. I know one is unconfirmed among all the six patients and including patients who have PD-L1 negative status. I was encouraged by the data in the front line and the second line setting in the esophageal squamous cell carcinoma.
Thanks, Dr. Feng. You alluded to the fact that we saw activity irrespective of PD-L1 status in the first line setting, in particular. What are your thoughts on how this could fit in with the treatment paradigm? As we have said previously, the PD-1s are not approved in the PD-L1 negative space.
Yeah. I think that this combination definitely has activities, so that is in the PD-L1 negative patient population. I think if we are going to look into further clinical studies, we should definitely include those patients, and this provides a great option for those patients.
Thank you for your perspective. The other point that we were discussing was second-line esophageal, where, as you quite rightly said, these patients are very advanced, and typically have a very poor performance status. What are your thoughts on the potential for a chemo-free option in this setting in particular?
Well, a lot of times in this patient population, we were using single-agent chemotherapies, right? I think the chemo-free option is quite attractive for the patient in this population, and also especially for the patient who is PD-L1 negative.
Yeah, absolutely. Dr. Adkins, did you have any comments on the esophageal data that you saw today?
Yes, I agree with Dan. I think the data showing activity in PD-L1 zero patients is particularly interesting and applicable to patient care for which we don't have a good immunotherapy approach.
What were your initial reactions to the overall response rate that you saw in terms of tumor shrinkage across all of the patients?
It does seem to be more favorable than comparators in the literature.
Thank you, Dr. Adkins. Maybe we can move on briefly to head and neck. You saw the data there with activity overall, but more enriched in the HPV positive patients. I'd be very interested in your thoughts, Dr. Adkins, on what is the competitive environment or what is the unmet need really in the HPV positive space, and of course, any reactions that you had to the data that you've seen in the head and neck space.
There are two striking findings that I observed in review of this data with the tagmokitug and toripalimab. Number one was the interesting observation of the apparent sensitivity of HPV positive disease to this combination. Number two was the durability of CBR. The current data that my review of the context of literature shows that for patients with HPV positive PD-1 platinum-refractory disease, current drugs result in, at best, a 10% progression-free survival at four months. When I reviewed the data for tagmokitug and toripalimab, it looks like that number is close to 40%, which is very striking. Although the response rates are relatively low, the durability of clinical benefit rate is striking. The fact that it's demonstrated in HPV positive disease is a very unique data set.
Generally, most of the registrational pathway drugs that are being pursued in recurrent metastatic head neck cancer are focused on HPV negative disease. The number of EGFR bifunctionals are, for the most part, targeting HPV negative disease. There's very little going on in drug development for the HPV positive population, and that represents about 30% of patients with recurrent metastatic disease. There's a clear unmet need for looking at strategies to target HPV positive disease. It looks like tagmokitug and toripalimab might be that combination worthy of pursuing.
Thank you, Dr. Adkins. One of the other things that we think about with HPV positive patients, of course, these patients tend to have a better performance status. Often they tend to be working as well. I think that may also be a potential opportunity for these patients. What are your thoughts on the safety profile, again, in the context of the emerging therapeutics?
I do think it's, in my experience, the combination has been quite tolerable. Many patients have had limited side effects, and the side effects that I've observed that you've shown in your slides, infusion reactions or diarrhea or transaminitis, have been mild and manageable with appropriate therapy. In terms of impact on quality of life, I found it, compared to chemotherapy, far better quality of life on this combination. I do think there's a good rationale for a favorable adverse event profile.
Thank you, Dr. Adkins. Very helpful to get your perspective on that. Maybe we can get some initial thoughts, Dr. Feng, from you on the upper GI adeno cohorts and the colorectal as well. As a reminder, I think a couple of the things that I said was that we saw very clear dose differentiation in terms of activity with the upper GI adeno cohort. Also remember that we had those two additional patients with EAC within that cohort, also perhaps forming a little bit of a package here, really, in terms of being able to plant a flag in a real area of unmet medical need in esophageal. What are your initial reactions to the upper GI adeno data that you've seen before we move on to colorectal?
Yeah. In this space, I think the few things that I really noticed from the data are, one, as you pointed out, it's the 700 mg that really make a big differences, and that's the true effective doses for patient in this population. Two is that I think that in the second line setting, while we did not really see, I mean, the response rate is somewhat comparable, if not superior, to the current standard of care chemo plus ramucirumab options. I think that I definitely would appreciate the toxicity profile, at least I've seen in my own experiences and also from your own data for these patient population, because this is also a population, a lot of them also, again, very heavily pre-treated because we now use FLOT in the locally advanced settings.
Two is I think that we just unfortunately haven't had the mature PFS data yet, but I'm hoping based on the trend we've seen right now, I look forward to see the PFS data because I think in your experiences and also in your preliminary data, this suggests that duo IO not only is attractive option for patients who are heavily pre-treated with chemo, but also can potentially have much more durable response. The last thing that I do want, I think I want to note that is that I think the responses in PD-L1 pre-treated patients, the vast majority of your patients are understood in your cohorts are treated with PD-L1 or PD-1 before. Actually, I think the first three out of the four patient responders were actually treated before.
I think that the signal, the efficacy we've seen in patients who were previously treated with PD-L1, that's also I think for me, that's actually really worth noting. That's exciting.
That's awesome. Thank you for, again, your commentary there. Colorectal, as I said in our comments, the whole intention here was to start in the late-line setting, see if we can see activity in a very hard-to-treat population, and then maybe think about progressing early in the treatment paradigm. What do you think of the data in terms of support of that strategy for colorectal?
Well, we've seen the combination activities, even though it's very limited signals in the advanced settings. Personally, I think that in my experience, a lot of the colorectal patients have gone through two, three years of more therapy until they get on the clinical trials. The efficacy of IO in that patient population was really poor. I think that with the preliminary, with the limited clinical activities even, in the advanced setting, I actually personally think that there is potential more activities in the earlier-line setting before the patient has gone through years of the chemotherapies. I think that colorectal is a space that there's a lot of changes over time. I do think that at earlier-line, potentially we can see more IO activities.
Your safety profile actually in the esophageal cancer, as well as your own safety data on the duo and the tagmokitug plus the toripalimab, I think that supports us to move into the earlier line to combine with chemotherapies.
Very helpful. I know we've taken up quite a little bit of your time. As a company, we're very proud of being able to explore therapeutics in areas of real unmet medical need. Perhaps I could just end with by asking your final comments, particularly on the esophageal space, where we do believe there's low competitive density in terms of the developmental environment married together with a real unmet medical need. Perhaps I can just ask for some final comments, both in the first line setting in terms of development, in combination with chemotherapy for this doublet, and also in second line as a chemo-free option as the doublet itself. Perhaps, Doug, we can start with you and then some final thoughts after that from Dr. Feng.
Rosh, this is for esophageal, you said?
Yes. First line as well as second line. In terms of the unmet medical need, perhaps the lack of the competitive options within this space and the potential for the four-drug combination, so tagmokitug/toripalimab in combination with chemo in the first line and as a chemo-free option in the second line for tagmokitug/toripalimab.
Well, combining tagmokitug/toripalimab with chemo is a tolerable regimen, and it is important that adding drugs to the chemo is a tolerable combination. I think that those two agents are clearly tolerable and safe to combine with chemotherapy. The initial activity, particularly in PD-L1 zero disease, is very promising and also in patients who have PD-1 refractory disease is very promising. So in both the first line and the second line plus settings, the rationale looks very favorable to proceed forward with those combinations.
Thank you, Dr. Adkins. Dr. Feng, any final thoughts on esophageal squamous cell and the data that you have seen?
I think the ESCC really represents a field that with a lot of unmet needs. As I pointed out earlier, I think the overall prognosis is still very poor with these diseases. We lost majority of the patient within the first year and a half. For me, a lot of times, the esophageal cancer, when recurring locally, can cause a lot of difficult trouble eating and rapid decline in the patient's nutritional status and functional status. I think there's a huge need to improve the response rate in the front line setting and also in the second line setting because we really don't have a very good option in there. This is a landscape that's also changing, too.
There are other drugs currently in development, but I think a pure IO combination provides an attractive option for these heavily pre-treated patients, as well as for patients who really need durable disease control.
Wonderful. Dr. Adkins, Dr. Feng, thank you so much for your perspective. It's been invaluable. Really do appreciate it. I'm going to hand over to Denny again, just to close, and then we'll open it up for Q and A. Denny?
Thank you, Rosh. Let me just briefly summarize where we land on this. Once again, we think that the first and second line offer a very unique, highly integrated, synergistic development opportunity. As you just heard from our KOLs, a significant opportunity. These patients are just tragically underserved. We have differentiated activity. We're building on the existing track record of toripalimab in esophageal, irrespective of PD-L1 status. We have approval in Europe already, where it's doing very well commercially. We're able to avail ourselves to a number of FDA designations to facilitate a very efficient, rapid development plan such as orphan, breakthrough status, Fast Track, and so on. We like the size of the U.S. opportunity. We think it fits very well with our commercial footprint so far and the rare diseases that we have gone after.
We believe also that there's a very strong opportunity for ex-U.S. partnering, giving the data we've shown, the dose responses that we've shown in tagmokitug, a clear impact on survivability and durability. I would just say that there's also the opportunity now for us to go forward with some additional combinations. As you know, we do have a study starting with J&J and metastatic prostate. We're going to get that going here just shortly and be able to tell you about that sometime, I think, in the first quarter, early second quarter. But I think that this data really opens up a lot of opportunities for tagmokitug and so on. With that, we will close. We will thank you for listening in today and look forward to seeing you at the meetings.
Very good. Thank you. Heidi, w hy don't we go ahead and start the Q and A?
Thank you. We will now begin the question and answer session. As a reminder, if you wish to ask a question, you will need to press star one one on your telephone and wait for your name to be announced. Please limit yourself to one question and one follow-up question. To withdraw your question, please press star one one again. We will take our first question, and the question comes from the line of Paul Jeng from Guggenheim. Please go ahead. Your line is open.
Hey, thanks for taking the question and for providing this very comprehensive update today. My first question, can you just comment on any early PFS trends you're seeing in frontline esophageal? Obviously, the durability of response and how that translates to survival will be pretty critical from a regulatory perspective. So just curious on anything you're seeing that gives you confidence even at this early stage. Then I have a follow-up.
Thank you, Paul, for the question. We talked a little bit about the need for this data to mature. It actually is way too early in terms of the esophageal first line specifically, to really talk about median PFS. We will be obviously following. We will give you updates as they arise. What I can say is that for the evaluable data set, the CBR, which perhaps is at this stage in the absence of a median PFS, perhaps the most informative, we are seeing about an 87% or thereabouts CBR rate. I think that bodes pretty positively right now, but again, we have to see median PFS mature and the patients stay on therapy for a little bit longer.
Great. My second question is on the regulatory path in esophageal. It was great to see the plan for an interim ORR analysis that is contemplated in the phase III. I think otherwise these studies could tend to take three-plus years to read out to OS. My question is, what do you view as the bar for response rate to get an accelerated approval in the frontline setting? Likewise, how confident are you that a positive response rate interim is also possible in second line based on what you have seen? Thank you.
Yeah, great question, Paul. I think at this time, what we would need to do is really meet with the regulators. Clearly, if there was an attrition in the signal we are seeing, that would be definitive. As we get more mature follow-up and more patient data set, we can answer that sufficiently. There are two aspects. We have shown improvement in response, but also opened up a patient population that is underserved by immunotherapy. A key point with regulators is with chemotherapy having a 30% response rate in PD-L1 negative, what is required to really show significant improvement? We will evolve those numbers. In the second-line setting, I do think the duration of benefit CBR rate would be a discussion we would have. You have seen that we have started to include ctDNA.
Those analyses are ongoing for the esophageal cohort, and we talk with the FDA about complementing the data sets with molecular response as well.
Thank you, Paul.
Okay, thank you very much.
We will take our next question. Your next question comes from Jay Olson from Oppenheimer. Please go ahead. Your line is open.
Oh, hey, everybody. Congrats on all the impressive progress, and thank you so much for providing this informative update. Can you talk about the timeline to enroll additional first-line and second-line ESCC patients to enable a regulatory discussion for next steps? If you expect to provide updates on durability for these reported patients sometime maybe next year? Then I had a follow-up if I could, please.
Yes. Thank you, Jay, for the question. I will answer the first part of that, and maybe Theresa can chime in a little bit on timing of any FDA discussions that we can have. Importantly, I think there are a couple of important metrics, right? We have talked about overall response rate as well as CBR and durability. Remember, the esophageal cohorts have not as yet completed accrual. They are close, but they have not as yet completed accrual. Step 1, we will be waiting for the remaining few patients to enroll and dose and then see what the durability is then. I think that is the most important point. The point about when we can expand, I think this data does support expansion into an additional population to around 30- 40 subjects or patients. I think that is the next immediate step.
I think the question will be how much durability do we wait for before we start the expansion? I think sometime around the second or third quarter of next year, we could move into an expansion, pending further FDA discussions. But I will let Theresa comment on a little bit more on timing of FDA discussions.
Yeah. Immediate next steps are to align on the dose. The meeting package is being finalized now, so we plan that for the first quarter of next year. You always have your development plan in there in a discussion with FDA. To have a robust discussion with them, we would need a minimum of 30 patients, to talk about other favorable regulatory strategies and how to design the magnitude of the benefit. But clearly saying toripalimab already has orphan drug designation in the U.S. for esophageal cancer. Engaging FDA, even through programs like that for tagmokitug is our strategy. Talk often, talk frequently, and really partner with them on our development strategy.
Great. Thank you. I appreciate that strategy there. If I could ask a follow-up. Given that toripalimab is approved in first-line ESCC in Europe, and now you have clear efficacy signals for tagmokitug plus toripalimab in ESCC, would you consider taking another look at filing toripalimab in ESCC with the FDA?
Yeah, I would love that. I don't think 10 patients is going to be enough. The issue with the data from JUPITER-06 is the chemotherapy comparator in that study comes out at above 50%. The applicability to U.S. medical practice, they have a pretty strong argument. We will continue in discussions with the European group on their experiences and leverage everything we can to have those conversations as early as possible.
Okay, great. Maybe if I could ask one more question. In second-line ESCC, how are you thinking about the patient population for your registrational study? Any differences on PD-L1 status or prior ICI exposure? Would all patients need prior ICI exposure?
Yeah, I think that's the beauty of this, right? We would take all comers, so PD-1 refractory, clearly an unmet medical need. In fact, if you read the FDA comments on the most recent approval in the second-line setting, tislelizumab, they actually comment that they don't even think it's going to be used much because most patients will have PD-1 in the frontline setting. But having that option to treat all comers, PD-1 refractory, PD-1 naive, and irrespective of PD-L1. The other thing to remember is KEYNOTE-181, the pembro approval in the second-line setting only got approved in PD-L1 high, CPS greater than 10. So I think this really opens up an IO treatment for these patients that they aren't eligible for today. So super exciting.
Thank you for your questions, Jay.
Thank you.
Operator, ready for the next question.
Of course, we will take our next question, and the question comes from Mike Nedelcovych from TD Cowen. Please go ahead. Your line is open.
Hi, thank you for the questions. I have two. My first relates to your potential commercial strategy. How does your thinking about potential commercialization in the U.S. versus ex-U.S. and partnering strategies play into your thinking about the development path for tagmokitug? That is my first question. My second question relates to the competitive landscape. I know data are sparse, so comparing your data set to others is very difficult at this point. Are there any data sets you could point to that would help us understand how tagmokitug with these new data fit into the competitive landscape? I think gastric cancer may offer the best opportunity there. Thank you.
Yeah. Thanks for that, Mike. I will take the first part about partnering and commercial, then I will let Dr. LaVallee take the second part. Obviously, there is an advantage of having toripalimab approved in Europe for esophageal, irrespective of PD-L1 status. I think there is a reasonable opportunity of partnering with someone in Europe and the read-through to the clinical development and so forth. Similarly, in Asia, there is a very high incidence, of course, of esophageal as well as gastric cancer in Asia. One of the things that we will do is take this data and begin talking to some parties there.
With respect to the development plan, I think ultimately, I think we could reasonably expect to see perhaps 50% or 60% of the patients in Asia, 30%-ish, maybe 40% of the patients in the U.S., and maybe 10%, 20% -ish of the patients in Europe. We have had a longstanding strategy of globalization of these products because we do have global rights, both to tagmokitug and casdozokitug. I think that addresses that very well.
Secondarily, I think that we're getting some very good experience in these more rare cancers. Nasopharyngeal cancer has about 2,000 patients in the U.S., incidence per year. This is about 6,000, so it is about three times as large. I think a lot of the approaches, the infrastructure and so on, and ways of addressing the market should be very similar. I wouldn't contemplate that we'd have to expand our footprint in order to do so. I think we fit in quite well, particularly since you're also promoting toripalimab at the same time, right? So you have NPC plus esophageal. I think that makes a lot of sense. Overall, I think it's a pretty good fit. Theresa, do you want to talk about the—
Yeah. Hopefully, I understand your question right, Mike. I'm going to answer it, and if you need a follow-up, let me know. From a competitive landscape, first in esophageal, like all tumor types today, ADCs are showing some activity. The data in the frontline study that Rosh shared with you, showing that we can combine and enhance activity with chemotherapy, really lends itself to think about combinations there. So continue to add novel combinations, and ADCs is a combination that I think makes a lot of sense for tagmokitug. Additionally, in gastric cancer, I think that's what you asked specifically about, in the second-line setting, these data are still maturing. The current data sets do not exceed the standard of care benchmark. If it improves, we'll have a different conversation, but it clearly shows activity in the disease.
Here again, ADCs are an important regimen as well as VEGF, another well-known mechanism to combine with Treg depletion. So looking at novel combination strategies now that we've shown a baseline for activity. Thirdly, the analysis for the CCR8 TIRI scores across the various tumor types is still ongoing. So if we have any enrichment strategy to move forward with, we would explore that.
Hmm. Thank you—
Thank you.
—very much. We are ready for the next question, operator.
We will take our next question. The question comes from Brian Cheng from JP Morgan. Please go ahead. Your line is open.
Hey, guys. Thanks for taking our questions. Maybe just first, when we look at toripalimab plus chemo performance back in the JUPITER-06 study, I believe in the supplemental, the investigator-assessed response rate was about 72%. Here, I think you are reporting 75% from N of eight at the time of cutoff. How confident are you that the contribution of tagmokitug here is indeed clinically meaningful? Will you be able to need to as you run later stage studies? Then I have a follow-up. Thank you.
Well, thanks for your question, Brian. Dr. LaVallee, you want to address that?
Yeah, Brian, thanks, and as always very detailed, so we appreciate that. So at this stage, like I said, for the JUPITER-06, you're right, it's 72.4% for toripalimab plus chemo in the JUPITER-06 study. The chemo is 58%, so exceeding the benchmarks. That's why we said the relevant U.S. benchmarks for comparison here, we believe, is the three approved U.S. studies in the U.S.. The data that we have to give us confidence that tagmokitug is bringing some of the activity is seeing the activity in the second-line setting. So toripalimab does not have differential activity in the absence of something to stimulate the immune system, like chemotherapy. So tagmokitug has potentiated PD-1 in a less inflamed tumor. So we'll need to build out the dataset in the PD-L1 low. Clearly, we need more patients, more follow-up.
We have two patients in the PD-L1 low, so happy to see that depth of response and that durability of response, and we'll continue to build that dataset out.
Thank you, Brian.
Got it.
I'll just add, Brian, let me just add one more thing. You talked about JUPITER-06, so one thing, I know you know this, but I'll remind you, of course. JUPITER-06 was a China-only study, whereas our study is multi-regional, and I think that's also an important point. The second point to your comment about the addition of tagmokitug is, I think it's important to look at that question with the totality of the cohort. So we're seeing not only in second-line esophageal, where there's two arms, we're also seeing in second-line upper GI adenos that very clear dose differentiation in terms of the addition of tagmokitug to toripalimab at the higher dose as well.
Great. Thanks for the color. Maybe just a quick one. Just looking at the swimmer's plot that you presented during your webinar here. It seems that a lot of the patients have dropped off before you reach 20 weeks of treatment. Even though they have shown really nice partial responses at the week 12 endpoint. What are the reasons for them dropping off treatments?
Which tumor type are you talking about? Are you talking about second-line esophageal or—
Well—
—maybe just clarify that.
—yeah, front-line ESCC. I mean, second line—
Okay.
—ESCC, you also have one patient that already dropped off out of the—
Yeah.
—two responders, right?
Got it. Let me just summarize some of the safety data there in terms of the drop off. We have had four out of the 10 discontinuing treatment due to a treatment emergent AE. Remember that in the first-line setting, there is a four-drug combination in combination with cisplatin as well as 5-FU. Cisplatin is well known to have toxicity, in particular renal toxicity. A couple of those patients, two of the four, dropped off due to either an elevated creatinine or some form of renal tox. The other couple dropped off due to a rash. Those are the reasons. One thing that we and so obviously, a probable immune relate, the rash is probably immune related. I think that was the split in terms of the actual drop offs.
Patients do still continue treatment, in terms of we have some patients who are still on study treatment, as I mentioned. Also we have a couple more additional patients to add to this specific set. But in terms of your question on drop off, a couple due to chemotherapy-related toxicity, so cisplatin in particular, which can be mitigated, and in a future study, we can of course swap out to carbo, which does not have as much renal tox, as an example.
Okay. Thanks for the color. Thank you.
Yep. Thank you, Brian.
Thank you. We will take our next question. The question comes from Swayampakula Ramakanth from H.C. Wainwright. Please go ahead. Your line is open.
Thank you. This is RK from H.C. Wainwright. Appreciate me having an opportunity to ask you questions. Most of them have been answered. I have just a couple of them. Rosh, just to understand how you're framing clinically meaningful benefit as you're targeting in each of these settings, both first line and second line, beyond just the response rate. For example, in the first line, what duration of response PFS and improvement, especially in swallowing or nutritional status, would actually justify having tagmokitug added to the PD-1 plus chemo, especially when you account for some of the toxicities and treatment discontinuations that you just talked about? And in the second line, specifically among patients that progress beyond PD-1, what response durability and PFS would make this chemo-free therapy clinically valuable?
Yeah. Let me answer both of those questions, and thank you for the question. Your first question was on quality of life, essentially, and how this could affect quality of life. We did not measure quality-of-life measures specifically in this initial study. Obviously, it will be a future additional measure that we'll incorporate into later-stage designs. But I think it's pretty intuitive that typically, when you see a response there, quality of life will improve. So while I can't answer your question about specific metrics for level of improvement in quality-of-life measures, that's something we will be looking at in future studies. Also, I'll draw your attention to the CT scans that I showed earlier, which really shows that disappearance of that esophageal mass.
You can imagine, right, how that diminution in size or complete disappearance of an esophageal may help in terms of swallowing or in terms of nutrition status, et cetera. So that's your first question. I think your second question was in terms of what kind of metrics are we looking at in terms of durability for the second line setting. Was that your question?
Yes.
Okay. The current standard of care is pretty dire in terms of the median PFS. Again, while it's not yet mature, what we showed in the second line setting was a median PFS of around 5.5 months. The standard of care gives you somewhere between two and four, depending on what treatment regime you're talking about. So that's — Again, we need to replicate this with a larger patient number and more duration. Again, I'll remind you, we haven't completed accrual as yet. 17 of 20 patients are currently in that second line cohort. So right now, based on a small data set, admittedly with pretty wide confidence intervals, given the small patient number, it's pretty encouraging given the rough benchmarks of the current standard of care of two to four months.
Thank you. One quick follow-up. Are you prospectively going to define your go, no-go thresholds for these expanded cohorts that you're planning? Would you make that public after your discussion with the FDA?
Dr. LaVallee, would you like to take that question?
Yeah, I don't think that we would make that public. I think it's the totality of the data, as we've always said. I mean, the thing that is compelling in the second-line setting is it is a randomized study, essentially. It's nice to have that dose response so you can have confidence in the tagmokitug effect. The other thing that's challenging in the second-line setting, to your earlier questions, is the PD-1 approvals in the first-line settings are relatively recent. So data sets in the PD-1 refractory patients are nascent, so really setting that up. But it would be a randomized study with looking at comparison to chemotherapy and seeing duration landmark effects that are exceeding expectations.
Thank you. Thanks for taking my question.
Thank you for those questions, RK. Thank you.
Thank you. This concludes today's question and answer session. I will now hand back for closing remarks.
Thank you, Heidi. Thank you all for joining us today on our tagmokitug data reveal. I particularly want to thank our two advisors, our KOL clinicians, Dr. Adkins from WashU, our Head and Neck Specialist, and Dr. Dan Feng from Mount Sinai, to give the clinical perspective. Secondarily, I would just urge all of you to reach out to the company if you have any further questions about the data or our plans going forward. We'd be happy to chat, and we'll see you. Bye-bye.
This concludes today's conference call. Thank you for participating. You may now disconnect.