Coherus Oncology, Inc. (CHRS) Earnings Call Transcript & Summary

Good day, and thank you for standing by. Welcome to the Interim Tagmokitug Clinical Data Webcast. [Operator Instructions] 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, Hadi. 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 Cohere's 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. And now 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 Tagmokitug 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&A. . Joining me today is Dr. Rosh Dias, the company's Chief Medical Officer; as well as is Dr. Theresa Lavallee, the company's Chief Scientific and Development Officer. Later on, we'll be joined by Dr. Doug Atkins from Wash U, our Head and Neck specialist; and Dr. Dan Sang from the School Medicine who will comment on the GI data. Let me talk a little bit about the pipeline and just make 1 brief statement. I direct you to the bottom of the slide, where we talk about our Tagmokitug program, which we shown discussed today. I will, however, indicate to you that Tagmokitug is showing clear dose-dependent activity, both with respect to response and duration. We expect to have a data disclosure for Tagmokitug in January of 2027. Now our cancer focuses on overcoming immune resistance, because it is there that the battle for extended patient survival is booked and either 1 or lost. Appropriately, patient survival is generally the approval link for regulators. So while our therapeutic focus includes the shorter-term reduction in tumor size or IRR, as it is 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. And you can see this clearly here, nearly doubling the 6-year survival of nasal pharyngeal 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. So today, we report on our efforts to overcome a core part of cancer immune resistance. immune response mediation activity of Treg cells in the mucosal system, extending top to bottom from head and neck through the GI bag 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 is a particularly challenging study. Tagmokitug has demonstrated clinical activity across all of these. And as you will see today, these multiple solid tumor types with over 120 patients treated. I summarize our findings to date here for you and 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 bio-resistant populations, thereby demonstrating the ability to reverse and rescue T cells. With these studies, we saw broad pan-tumor activity at Tagmokitug 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. Now the esophageal studies have shown particular prompts with the confirmed overall response rate of 75% in all comers, that is inclusive of PDL-1 on high and low and 100% in PDL-1 positive patients with a in first-line esophageal. Dr. Dias will address this momentarily. The clinical benefit in first line and second line esophageal patients with PDL-negative tumors was also of note. And as I indicated, we now will proceed with an integrated development plan forward in both first and second line, which Dr. Lavellee will further talk about. We plan to expand cohorts to add more patients and add more longer follow-up and the leverage FDA designations as we discussed with them the path forward and the additional cohort creations. And with that, I'll hand the call over to Dr. Dias to discuss the specific results in first line Rosh?

Thank you, Denny, and good afternoon, everyone. So today, I'll put the data from our program. As a reminder, this is an ongoing program with continued data And so what I'll be presenting will be the interim data from the program. We'll present data from our GI program in 4 tumor settings, starting with esophageal squamous cell carcinoma in both first line with chemotherapy and in second line and our esophageal squamous cell cohort will be the main focus in our development presentation due to the strong activity we are 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 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 6 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 end point. Let me now start 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 included with PD-L1 positive and negative tumors. Enrollment is ongoing and at the data cutoff date, 10 patients have been dosed and 8 patients are evaluable. We investigated our planned go-forward dose of 700 milligrams of Tagmokitug in combination with toripalimab and with the U.S. standard of care chemotherapy. That is cisplatin with safety as a primary endpoint and additional efficacy secondary end points. In terms of regional accrual, this was a multiregional 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. Whilst the data set needs expanding. As you can see, tumor shrinkage was observed in of evaluable patients. And as you can see from the legend below the waterfall plot showing PD-L1 status, the tumor shrinkage importantly, was at the irrespective PD-L1 data, so not only for PD-L1 positions 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-1. In terms of best overall response of the 8 evaluable patients, 1 patient had a confirmed complete response. And additionally, 5 patients had a confirmed partial response of whom 2 patients continue on treatment as marked by the vertical arrows overall representing a 75% confirmed overall loss rate. For the 2 remaining evaluable patients on the far left of the waterfall, 1 had an unconfirmed PR. So meaning at the time of data cutoff, they had just see a single scan and are waiting for the next scan confirmed. And the other patient had tumor shrinkage, not quite leading the criteria for a confirmed PR that shows durability beyond 6 months and continued on treatment. These 2 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% OR in this population. Since our data cutoff date of October 14, there has been some further improvement in activity with no attrition. We verified 2 additional scans that reflect the volume. Firstly, the second from left patient with a PD-L1 negative unconfirmed PR has been confirmed. And 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 14 date, the ORR in the evaluable population would go from 75% to 89%, and an ORR in PD-L1 positive patients will be maintained at 100%. 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 39% ORR in PD-L1 positive patients. And so we do remain very encouraged by the interim activity demonstrated here. But as we stress durability and long-term stable disease is very important. We look forward to these data continue to mature. And while these compelling data need to mature the durability, this does want cohort expansion to a larger data set up to 30 or 40 patients. This slide shows and represents 6 CT scans from this cohort, and this is from the patient who had a complete response. Let me just orient you. This is an actual CT scan looking at a cross-section of the upper esophageus showing an esophageal map on the top panel and a supraclavicular node on the bottom. With on the left and the follow-up scan on the right after almost 8 months. The participant had a PD-L1 positive MFS tumor. Looking from baseline on the left to follow up slide 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 falloff scan on the right. There's also a 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 that response has also extended beyond target lesions. All nontarget lesions had disappeared after 8 cycles and no new lesions have appeared, representing a very deep response in this patient. Despite a here represents the 8 evaluable patients, and this reflects the speed and the durability of the response. Again, all participants demonstrated tumor shrinkage. We've all seen 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 of 4 patients still remain on therapy as noted by the red arrows on the end of the relevant patient line. Secondly, 2 patients have demonstrated activity for close to 8 months with the patient that is in stable disease still continuing on treatment. And note again that this is a patient who is PD-L1 negative, again, reflecting activity irrespective of PD-L1 data. So 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. So this, as you know, is a tumor setting where 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 milligrams of Tagmo in combination with Tory and with 10 patients in each dose level. Again, safety is the primary endpoint with efficacy a secondary endpoint and 17 of 20 patients have been dosed thus far. This is also multiregional 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 a 300-milligram dose of Tagmo with 700 milligrams in blue, of course, both in combination with toripalimab. On the measures below, you see best overall response prior PD-L1 status and time since last PD-1. And as you can see, of the 8 evaluable patients, all but 2 had a best overall response of either stable disease or partial response with 1 patient having a confirmed partial response relating to a confirmed ORR of 16.7% in the 700-milligram dose add an additional patient having an unconfirmed PR with treatment still ongoing. With the confirmed PR was in a patient whose tumor was PD-L1 positive, whereas the unconfirmed PR was in the patients 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 6 months, was 33.3% in the 700-milligram target dose, representing potential for this doublet as a chemo-free regimen in this tumor setting. The 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 Tagmo dose response. As you can see, there is a very clear dose response in this randomized cohort. The 700 milligrams Tagmo with in blue shows benefit, whereas the 300-milligram dose in green is not sufficient. At the 700-milligram Tagmo dose, we saw both the confirmed and the unconcerned PR and also what's pretty striking is the long-term stable disease, showing durability of activity in this dose level. Of note, 2 patients are still continuing treatment close to 8 months, including 1 patient with a PD-L1 negative tumor -- whilst the data set is small and still maturing, the current median PFS of 5.5 months is encouraging and with 6 patients in this cohort still continuing on treatment several of whom are either in stable disease or uncomPR 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 across our comparisons, the current standard of care provides a median PFS of between 2 and 4 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 tag motory doublet is very consistent with the overall integrated safety that I'll outline later in the first line. So I think the discontinuation rate is around 40%. But of course, this is in combination with chemotherapy, and it's also very similar to the overall discontinuation rate reported, for example, in CheckMate-648 in the same setting. Across both lines of therapy, there were no Grade 5 Tagmo-related events. The most common is related to any study drug have shown and the safety profile for both esophageal squamous cell cohort supports continued development. Let me now hand over to Theresa to talk about the integrated plan moving forward to the

Thanks, Rosh. We recognize we need more mature follow-up and clearly more patients. but the signal to date is compelling. And 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 approvals 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. So we see that, that objective is possible in these data sets. . So let's move on to the benchmarks. So shown on the left in gray in the first-line setting, you see the 3 approved PD-1 inhibitors plus QR therapy in the United States, showing an overall response rate of about 50% to 60%. While toripalimab through the JUPITER 6 study is approved in China and Europe, it is not recognized by the U.S. FDA because it uses a different chemotherapy that's not used in U.S. medical practice, it did not include U.S. patients, the program incorporates U.S. standard of care in 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. So the only standard of care therapy is chemotherapy. It was the lack of benefit that made them revise the labels. Here, we're seeing activity. So 75%, 100% are big numbers, but always you would expect with more follow-up is attrition. We were pleased to see if the first look where we increase -- have another partial responder confirmed and a new evaluable patient as a part of response. We maintained 100% and improved the 75% to 89%. So in the second-line setting, Rosh showed you that swimmers plot, when those patients are so sick, they can't swallow, they are malnutrition, they've gone through first-line chemo when they fail, they fail fast. And the under-dose Tagmokitug dose with toripalimab we see only 1 patient made it past 6 weeks on study treatment. In the 700-milligram dose, we see a number of patients on past 3 weeks, 8 months is the chemotherapy median overall survival so that's why we focus on the clinical benefit rate because with long-term stable disease is meaningful. So what we show you here is that adding Tagmokitug to toripalimab improved on PD-1 treatment have in PD-1 naive patients and in less inflamed patient tumors, such as PD-L1 negative. And in the second line setting, we've shown activity in PD-1 resistant. So Tagmokitug can add to PD-1 in all settings. Next slide. Shown here on the right-hand side of the slide is the data that we've talked about for JUPITER 6 with toripalimab in chemotherapy from the China study, where we see activity irrespective of PD-L1 status, as shown by the ratio being the So why do we think that is true? We see this due to potency, toripalimab is a higher binding affinity and a unique efficate. So when used in combination with with chemotherapy, the less inflating tumor can have activation of antitumor immunity due to this potency. That is not true in the absence of chemotherapy. So in the second line setting where IO alone is showing activity in PD-L1 negative patients. That can be attributed to Timo, bringing in best remodeling of the tumor microenvironment and overcoming a less inland tumor. So exactly the objective of what we wanted with depleting Tregs from the tumor and remodeling the tumor microenvironment. Next slide. So how do we take this forward, we said, expand the patient data set to 30 to 40 patients to more mature follow-up. And engaged with FDA about favorable regulatory strategies. So with this compelling activity, what we see is 2 drugs, 2 approvals or 2 drugs, 2 indications that it can really change the treatment landscape in ESCC for a best-in-disease opportunity. So bringing in the opportunity to take 2 studies with randomized controlled trials and looking at accelerated approval endpoints with surrogate 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 Private FrontRunner where they're encouraging development in earlier lines of therapy and if we're 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 1.5 years later, got full approval based on the OS data. So next slide, please. The immediate next steps or meet with FDA and align on the go-forward dose. We've shown you the 700-milligram 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 rate sensitive. So the lower dose is able to overcome in a highly inflamed tumor to bring antitumor community 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-milligram dose level. Consistently giving us confidence in the 700-milligram dose as the go-forward dose. So we also want to call your attention to the far right portion of this slide, where we talk about the full And that 50% of the spend, 50% of the risk is also under CMC components. Given the biosimilar heritage of Porters, we feel confident we can put together a robust and quality CMC package for a BLA submission. And 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 2 drug approvals would add complexity. In Europe, toripalimab is approved in first-line esophageal famous cell carcinoma. Project Orbis is 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 to pay approved in this indication could be leveraged to increase getting the -- decreasing the complexity and 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 5 different indications or lines of therapy. And 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 a high unmet need in both settings. We believe there is a highly efficient development path. And as Theresa outlined, 1 with the potential for accelerated approval leveraging various FDA indications. There are multiple path to market, and there is a broad patient population given the ability to address full PD-L1 positive in PD-L1 negative with no selection. It's also potentially a global program. As Theresa indicated, toripalimab is approved in Europe for esophageal irrespective PD-L1 status which creates the opportunity for, we believe, great 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 the very promising data. Here in the U.S., there's approximately 5,000 to 7,000 patients to be addressed across these lines of therapy as we will be using 2 novel agents, Coherus. This translates to an economic opportunity of about $1.5 billion and a rare indication which is very suitable for our commercialization pets. With that now, I'll 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

Thank you, Denny. So 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 the trial, where with TAGNA-monotherapy, we showed clear tumor remodeling to a more state with depletion of the intratumoral CCR8 positive Tregs and an influx of CD8 as you can see in the immunofluorescent slide on the top left panel and clear antitumor activity with the addition of tori on the bottom left panel with a PR in a fourth line patient whose chemo was refractory to a prior PD-1 taxane and TJI. The current cohort I'll report on is interim data on the second line specific population. So 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 which 23 very evaluable with 300 or 700 milligrams of Tagmo in combination with tori with a roughly equal split between the 2 doses. Again, safety was the primary endpoint with additional efficacy measures as secondary end points. As we communicated on our last earnings call that we have seen activity both in terms of response, well as duration with enrichment of activity in HPV-positive patients. And you can see this in the water plot here. The waterfall shows HPV-positive evaluable patients with both doses, 300 milligrams in green and 700 milligrams in blue in combination with toripalimab. The majority of the patients with HPV-positive disease are shown here did have activity reaching criteria for either a partial response or stable disease at active doses, suggesting that Tagmo is able to rescue PD-1 distance at both of these levels. In this HPV-positive population, there were 3 confirmed PRs and 1 additional unconfirmed PR with activity in both PD-L1 positive and PD-L1 low patients resulting in an ORR of 13% and a CR of 26%. The viewability in particular, was encouraging with several patients in the second-line HPV-positive population out past 6 months of treatment. We also saw patients 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 and 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 population. This suggests the potential for further study in this HPV positive population, importantly with this as a chemo-free regimen, which represents a revive white space in terms of key development opportunity for patient benefit. The other area of potential enrichment that we've seen is the baseline immune context. The tumor immune regulatory index, or TIRI, is a tumor-derived PCR containing biomarker scores, 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 theory further enriches both ORR as well as CBR in 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, enrich proactivity 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 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 the potential enrichment factor as we seek to move through the development pathway. 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 testable and manageable, which in this context of emerging clinical trials is, of course, a very important point. I'll 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 low acute mutational burden and all must have received prior chemo with the platinum and with or without a prior PD-1. We enrolled 40 patients across the 2 active doses of 300 or 700 milligrams of Tagmo in combination with tori, again, roughly evenly balanced between the 2 doses. And again, with a primary and additional efficacy measures as secondary endpoints. This was a multiregional cohort with 60% of patients in the U.S. And the predominant anatomical cycle is gastric representing around 60% of the population, followed by GEK and then esophageal adenocarcinoma and about 1/3 of the patients were PD-1 naive. The waterfall plot here shows the overall activity in the response evaluable population with the 700-milligram dose in blue and 300 milligrams in green. In our target, go-forward dose of 700 milligrams, we saw 4 confirmed PRs, resulting in an overall response rate of 23.5%, 3 of whom were refractory to prior PD-1 and a CBR rate of just under 30%, both suggesting that Tagmo and tori can rescue PD-1 resistance in this population. As you can see in the legend below the waterall plot, tumor shrinkage was observed in both PD-L1 high and low tumors and was observed across all 3 anatomical subsides, including 2 PRs in patients with VAT. So again, the latter represents activity in the esophageal carcinomas. Six patients for the response evaluable population still continue on treatment, suggesting that there may be continued potential to improve on this interim data. The swimmers plot again shows very clear dose response in the upper GI adeno cohort as well with 300 milligrams on top in green and 700 milligrams bottom in blue. All responders have thus far been at the 700-milligram target dose. And as you can see, the durability is also marked in the high dose with several patients continuing past 6 months of treatment. This again speaks to the potential for durable benefit in its APA GI adeno cohort. As a reminder, the 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 fusion-related reactions, pyrexia and There were no grade 5 Tagmo-related events at either dose. And overall, the safety again was acceptable and manageable. And let me end now with our colorectal cancer cohort. Here, we look at the very late line relapsed metastatic population who had exhausted all approved prior standard therapies, including, for example, oxaliplatin irinotecan-based chemo, a fluorocarimidine or others. So this is essentially a fourth line and beyond population with a focus on patients without liver mets. The main goal of cohort was to determine whether we see activity in this late-line setting that may then allow us to move into earlier lines of therapy in collector carcinoma. We enrolled 20 patients as a single arm cohort with 700 milligrams of Tagmo in combination with tori and again, the primary endpoint of safety with additional efficacy measures expected end points. This is also multiregional cohorts 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 1 patient achieving a confirmed PR, representing a confirmed ORR of 6% and a CBR of 12%. And in addition, we did have several patients with tumor shrinkage approaching but not quite reaching the criteria for a partial response. Additionally, we saw a molecular response with C2 DNA 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 3 patients being treated past 24 weeks, 2 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. And finally, in terms of safety CRD cohort, again, it was consistent with the safety profile across cohorts with the most common related as in fatigue, rash and anemia. Overall, again, safety was acceptable and manageable with Tagmo related Grade 3 plus events seen in 100 patients with no grade 4 or 5 Tagmo-related events. So before we move on to our panel discussion, let me just summarize a couple of points. So we're pretty encouraged overall, as you heard, by the we've outlined over the past 2 minutes, which has shown clinical activity across the cohorts and importantly, an expected and manageable safety profile in combination with tori and also in combination with chemotherapy. The ability to combine with chemo gives us the ability to move into earlier lines of therapies where it's well known that immunotherapy is more active. Whilst this is interim data, the ESC 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 a clear dose response have been demonstrated, which allows development then as a chemo-free option. Additionally, in the cohort, the activity is observed in the 700-milligram dose with the 300-milligram dose showing limited benefit, and that gives us confidence in the data being Tagmo-driven and also in the dose and 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 all by a safety profile across the program. earlier in program through a monotherapy dose escalation, we showed no DLTs up to 1,200 milligrams and low-grade immune-related AEs, showing targeting the TCRA-positive rates is relatively sparing of tolerance. In combination with tori 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 compare favorably to IO-IO combinations such as for example, as you can see on the right panel. We've seen comparable safety across both the 300 and 700-milligram doses with similar immune-related AEs. Most of the AEs with Tagma and Tori were grade 2 or less and resolved with no grade 5 treatment-related AEs. And in our esophageal squamous cell cohort with Tagmo and tori in combination with chemo, again, we demonstrated a manageable safety profile, no new safety signals and the majority of AEs were attributed chemo. The safety profile is very similar to other Phase III studies with PD-1 inhibitors and chemotherapy that led to their U.S. approval. Overall, the most common treatment-related AEs where the Tagmo-tori doublets have been infusion-related reactions, fatigue and rash. So let's move on to a brief panel discussion. I'm delighted to be joined by Dr. Doug Adkins head and neck oncologist from School of Medicine; and Dr. Dan Sang, a GI oncologist from the School of Medicine at Mount Sinai. Dr. Adkins and Dr. Sang, thank you very much for joining us today to share our perspective. As mentioned, activity across GI cohorts with a particularly strong signal in ESG further development is pretty exciting for us. And also with head and neck squamous cell with enrichment in HPV-positive patients. I'd be particularly interested in your thoughts initially as clinic is treating you very hard to treat cancers about your impression on the early data across cohorts and how this could fit in with clinical practice, so perhaps we can just start with esophageal squamous cell, particularly in the first line setting again and really just discuss your initial reactions to the first-line data. And 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 So maybe I can open it up to Dr. Sang, maybe some initial reactions to the esophageal data, starting with first line.

Yes. So I am a GI medical oncologist. If I treat these diseases, and I'm involved in a lot of the early stage to in this space. So from perspective, I think I want to just highlight a few things, so that put my thought when I hear and see these data is one, I mean, we know that 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 of about 15 to 17 months. So we don't -- this is also a disease that we don't have effective options past the first line. So for me in looking at the frontline data you have on the tori plus chemo, I would now for was the high response rate because you show the data they close to 90% for all comer and 100% for the PD-L1 positive patients. We think that it's worth noting that also that the benefit are also seen in the patient with PD-L1 or we call the PD-L1 negative patients. This is way better than what we have been reported in the clinical trial and what we've seen in clinical within our everyday clinical practice. In the second-line setting, the combo without chemotherapy also has shown really impressive activity. So this is a space that we really relied on single-agent chemotherapies and the for patients who are previously treated with PD-L1 or PD-1 antibodies. There's really no great option from the chemo. And these are a lot of the patients are heavily pretreated when they get to this point. So I think it's worth noting that the combo actually had 2 response. I know 1 is on confirmed among the 6 patients, including patients who have PD-L1 negative status. So I was encouraged by the data in the frontline in 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? Because as we've said previously, the PD-1s are not approved in the PD-L1 negative space. .

Yes. So I think that this combination definitely have activities, so that's in the PD-L1 negative patient population. So I think when we -- if we're going to look into further clinical studies, we will not which definitely includes those patients and this provides a great option for those patients.

Thank you for your perspective. The other point that we were discussing with second-line esophageal where, as you quite rightly said, these patients are very, 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?

So a lot of times in this patient population, we were using single-agent chemotherapies, right? So I think the chemo-free option is quite attractive for the patient in this population. So I -- and also especially for patients with PD-L1 negative.

Yes, absolutely. Dr do you have any comments on esophageal data that you saw today?

Yes. I agree with Dan. I think the data showing activity in PD-1 0 piece is particularly interesting and to patient care for which we don't have with immunotherapy approach. And 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 and the other

Thank you, Dr. Adkin. 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 you have thoughts, Dr. Adkins, 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 2 striking findings that I observed in review of this data with Tagmo and toripalimab. Number 1 was the interesting observation of the apparent sensitivity of e-positive disease to this combination. And number two, with the durability of CBR. The current data in my review of the context of shows that for patients with HPV-positive PD-1 refractory platinum-refractory disease, current drugs result and at best 10% progression-free survival at 4 months. When I reviewed the data for Tagmo and toripalimab, it looks like that, that number is close to 40%, which is very striking. So although the response rates are relatively low, the durability of clinical benefit rate is striking. And the fact that it's demonstrated in positive disease with a very unique data set. Generally, most of the registrational pathway drugs that pursued in recreate HBV case or current metastatic head and neck cancer are focused on HBV-negative disease. The number of functionals are, for the most part, targeting HPV-negative disease. There's very little going on in the the HBV-positive population. And that represents about 30% of patients with head and neck disease. So there's a clear unmet need for looking at strategies to target HPV-positive disease. It looks like Tagmo 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 more -- a better performance specs often, they tend to be working as well. So I think that may also be a a potential opportunity for these patients. What are your thoughts on the stature profile again in the context of the emerging therapeutics?

I do think it's, in my experience, the combination has been quite Many patients that had limited side effects and the side effects that you've shown in your slides and future reactions or diarrhea or had been mild and manageable with appropriate therapy. In terms of impact on quality of life, I found it compared to chemotherapy, far better quality lion this combination. So I do think there's a good rationale for a favorable profile.

Thank you, Dr. Adkins. It's 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 what 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 2 additional with EAC within that cohort also perhaps performing 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?

Yes. So we -- in this space is 1 I think my -- the few things that I really noticed on the data are, one, as you pointed out, is the 700-milligram that really make a big difference and that's a truly effective doses for patients 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 not superior to the current standard here chemo of chemo plus vanucizumab option. I think that I definitely would appreciate the toxicity profile as I have seen in my own experiences and also from your own data for the patient population also and a lot of them also get very heavily pretreated because we now use in the local setting. So is, I think that we just unfortunately haven't had the PFS data yet. And -- 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 experience is then also in your data is suggested to IO, not only it's an attractive option for patients who are heavily pretreated with chemo but also can potentially have a much more durable response. And the last thing that you wanted -- as I think I want to note that is that I think the response in PD-L1 pretreated patients. The vast majority of your patients are on the cohorts or treated with PL-1 or PD-1 before. And so -- and actually, I think the first 3 out of the 4 responders are actually having were actually treated before. So I think that the signal, the efficacy we've seen in patients who were previously treated PD-L1, that's also, I think, for me, that that's actually really worth noticing and that's exciting.

That's awesome. Thank you, again, your commentary there. Colorectal, as I said in our comments, the whole intention here was to start in the late line setting see frequency activity in a very hard-to-treat population. And then maybe I think about progressing early in the treatment paradigm. What do you think of that -- the data in terms of support of that strategy for colorectal.

Well, so we've -- we've seen the combination activities, even though very limited setting. Personally, I think that in the -- a lot of the colorectal -- in my experience, a lot of the collections have gone to use of more therapy into they get on the clinical trial. And the efficacy of IO in that patient population was really was really poor. So I think that with the with limited clinical activities in the setting doesn't mean that I actually personally think that there is potential more activity in the earlier line setting before the patient has gone through uses of chemotherapies. And I think that colorectal is a space of that. There's a lot of changes over time. And I do think that is earlier line potentially can have more more IO activities. And your safety profile actually in the esophageal cancer as well as you do your own safety data Tagmo plus tori and the time of plus the toll I think that supports us to move into earlier lines combined with chemotherapy.

Very helpful. I know we've taken up quite a little bit of your time. As a company, we are very proud of being able to explore therapeutics in areas we are unmet medical need. So perhaps I can just end with by 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. So 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 of the chemo-free option as the doublet itself. And perhaps Doug, we can start with you and then some final thoughts after that from Dr. Feng.

rsoh, this is you said?

Yes. Yes, first line as well as second line. In terms of the unmet medical need, perhaps the lack of competitive options within the space and the potential for the 4-drug combination. So Tago, tori in combination with chemo in the first line and as a chemo-free option in the second line for Tagmo-tori.

We're combining Tagmo-tori Tore, that chemo there is a tolerable regimen, and it's important that adding drugs to the chemo is a tolerable combination. And I think the agents are clearly tolerable and safe to combine with chemotherapy. But the initial activity, particularly in PD-1 so 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 setting the rational looks is very favorable to proceed forward with those combinations.

Thank you, Dr. Adkins. Dr. Feng, any final thoughts on the total call on the esophageal squamous cell data that you've seen?

I think the ESPCs really represents a few that was a lot of unmet needs. I mean as I pointed out earlier, I think the overall prognosis is still very poor with this disease with a large majority of patients within the first 1.5 years. So -- and then this is -- so for me, diseases at the lot of times that the esophageal cancer is when the locally can cause a lot of difficult trouble eating and rapid decline in the patient's nutritional status and functional status, so I think there's a huge need to improve the response rate in the frontline 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 to the other drugs development. But I think the pure I/O combination provides an attractive option for these heavily pretreated patients as well as for patients who really need doable 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 and just to close, and then we'll open it up for Q&A.

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. And it's 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, and we're doing very well commercially. And 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 rare diseases that we have gone after. We believe also that there is a very strong opportunity for ex U.S. partnering given the data we've shown, the dose responses that we've shown and Tagmo 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 back going here just shortly and be able to tell you about that for some time, I think in the first quarter, early second quarter, but I think that this data really opens up a lot opportunities for Tagmo and so on. And so with that, we will close. We will thank you for your today and look forward to seeing you at the meeting.

Good. So thank you, Hadi. Why don't we go ahead and join or start the Q&A.

[Operator Instructions] The question comes from the line of Paul Jeng from Guggenheim.

So my first question, can you just comment on any early PFS trends you're seeing in front line 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 you can at this early stage? And I have a follow-up.

Thank you, Paul, for the question. So we talked a little bit about the need for the data to mature. It actually is too early -- way too early in terms of the esophageal first line specifically to really talk about median PFS. We will be obviously following. We'll 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're seeing about an 87% or thereabout CBR rate. So I think that bodes pretty positively right now. But again, we have to see median PFS the patient's therapy for a little bit longer.