Good afternoon, and thank you for joining Xilio Investor Conference Call. At this time, all participants are in listen mode only. Following management's remarks, we will hold a question-and-answer session. At that time, lines will be open for you. If anyone should require operator assistance, please press star, then zero on your touch-tone telephone. I would now like to turn the call over to Scott Young, VP of Investor Relations from Xilio Therapeutics. Please go ahead, Scott.
Good afternoon, everyone. Welcome to the Xilio Therapeutics Investor Conference Call. Today, we will review clinical data from the phase I-C dose-escalation trial of Vilastobart, also known as XTX101, in combination with atezolizumab in patients with advanced solid tumors. Vilastobart is our tumor-activated, Fc-enhanced, high-affinity-binding anti-CTLA-4, and these data are being presented in a late-breaker poster presentation tomorrow at the Society for Immunotherapy of Cancer annual meeting, also known as SITC. Before we get started, I'd like to remind everyone that the statements we make on this conference call will include forward-looking statements.
Actual events or results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties, and other factors, including those set forth in the risk factor section of our SEC filings, including our most recent Form 10-Q and any other filings that we have made or may make with the SEC in the future. In addition, any forward-looking statements made on this call represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update or revise any forward-looking statements. Following the completion of this call, a replay will be available on Xilio's Investor Relations website, which can be found at ir.xilio-tx.com. Today, we are joined by Dr.
Aparna Parikh, Director of Colorectal Medical Oncology and Medical Director at the Young Adult Colorectal Cancer Center at the Massachusetts General Hospital. Dr. Parikh is a renowned expert in gastrointestinal cancers. She serves on the NCCN Guideline Committee for Colorectal Cancer, is internationally recognized for her pioneering work in liquid biopsy, and is an investigator in our ongoing phase II trial for Vilastobart and atezolizumab in MSS colorectal cancer. From the Xilio leadership team, I'm joined by René Russo, our President and Chief Executive Officer, and Katarina Luptakova, our Chief Medical Officer. In addition, Uli Bialucha, our Chief Scientific Officer, and Chris Frankenfield, our Chief Financial and Operating Officer, will join us for the Q&A portion of the call.
In today's program, we will be covering three main areas of discussion: an overview of Xilio's platform, technology, and pipeline progress, a review of the growing unmet medical need in colorectal cancer with microsatellite stable colorectal cancer, commonly referred to as MSS-CRC, representing the vast majority of colorectal cancer cases, and an overview of initial phase 1C clinical data for Velastigard, our tumor-activated anti-CTLA-4, in combination with atezolizumab in patients with advanced solid tumors. With that, I'm pleased to turn the call over to René Russo, President and Chief Executive Officer.
Thank you, Scott, and thank you all for joining us today. Before we begin, I'd like to provide an overview of Xilio's technology and pipeline. The field of immuno-oncology has had a transformational impact for some patients with advanced cancers, and we believe it remains the key to unlocking the potential for long-term durable cures for patients. However, many new and promising IO targets are associated with systemic immune-related toxicity, causing collateral damage to patients' normal healthy tissues and cells. At Xilio, we believe there is a smarter way to deliver these potent IO medicines, to focus and concentrate the activity of our medicines inside the tumor while protecting healthy tissues and cells from unwanted side effects. We call this approach tumor selective activation. Our tumor-activated molecules work by leveraging dysregulated MMPs in solid tumors.
MMPs, or matrix metalloproteinases, are expressed throughout the body but are under tight control of inhibitors in healthy tissue. In the microenvironment of a solid tumor, MMP activity becomes dysregulated and enhanced and allows the tumor to grow, invade surrounding tissue, and metastasize. Our tumor activation technology harnesses this high activity of tumor MMPs to turn on our molecules selectively once inside the tumor. Importantly, our molecules are designed to be activated across a wide range of solid tumor types without the need for biomarkers. Xilio's tumor-activated design approach has been successfully applied across diverse molecular structures and administered now in over 200 patients in the clinic. Each molecule is individually designed with a unique protein-engineered masking domain, seen here in orange, that shuts down the activity when the molecule is circulating outside of the tumor in peripheral blood and healthy tissues.
Once inside the tumor, MMPs activate the protease cleavage site, seen here in green, which releases the masking domain and turns on the molecule's activity. We're currently advancing two tumor-activated IO molecules in clinical development, as well as several preclinical programs. Vilastobart, the focus of our call today, is our tumor-activated FC-enhanced anti-CTLA-4, currently advancing in a phase II clinical trial in combination with atezolizumab in patients with colorectal cancer, specifically MSS-CRC, including in patients with metastatic disease in the liver. As previously announced, this phase II trial is part of a co-funded clinical collaboration with Roche. Our second clinical stage program is XTX-301, our tumor-activated IL-12, which is currently in phase I dose escalation. This program is part of an exclusive license and collaboration agreement with Gilead, which we entered into earlier this year.
Next in our pipeline is our bispecific tumor-activated PD-1 /IL-2 molecule, XTX501, which is currently undergoing initial IND-enabling work. Finally, I'd like to mention our new tumor-activated cell engager programs, which are advancing in discovery, utilizing our clinically validated tumor activation technology. A few reminders about the design of the Velastigard molecule and what we've shown to date in the clinic. Vilastobart is a tumor-activated, high-affinity, FC-enhanced anti-CTLA-4 antibody. Preclinically, Vilastobart is tenfold more potent than ipilimumab and features Fc mutations for enhanced effector function and improved T cell priming, as well as depletion of immunosuppressive regulatory T cells. In the clinic, Vilastobart has shown to be over 70% activated in patient biopsies, with less than 15% of the active molecule in peripheral circulation.
Consistent with this tumor-activated design, Vilastobart demonstrated minimal immune-related adverse events and was well tolerated in phase I monotherapy studies, including with long-term administration greater than one year. Importantly, Vilastobart demonstrated monotherapy anti-tumor activity, including a deep and durable confirmed PR in a PD-L1 negative non-small cell lung cancer patient with complete resolution of liver metastases, which are known to be difficult to treat even with potent IO combinations. Vilastobart is currently in phase II development for advanced MSS colorectal cancer, including in patients with metastatic liver disease. As many of you know, MSS-CRC continues to be a growing and very urgent area of unmet medical need with limited treatment options, particularly for patients with advanced disease. I'd now like to turn it over to Dr. Parikh to discuss the current epidemiology and treatment options for MSS-CRC and how this disease is impacting patients.
Thank you so much for having me today. It's my pleasure to really speak about a tremendous problem, not only in the U.S. but globally in terms of metastatic patients with colorectal cancer. In the United States, colorectal cancer is now the second leading cause of cancer death. It is also now, as of last year, the leading cause of cancer death in men under 50. Globally, the burden is tremendous. It is the third most common cancer in terms of new cases, with nearly 2 million cases globally and 1 million cancer-related deaths from colorectal cancer across the world. Unfortunately, the main problem with colorectal cancer is that the majority of patients, 65% of patients, actually present with Stage IV disease.
Of the patients with Stage IV disease, nearly 70% of these have liver metastases, which, as we'll talk about, really is a challenge in terms of response to therapies, particularly immunotherapy. When we're looking at patients with colorectal cancer, the far majority of patients in the metastatic setting actually have no curative options. Colorectal cancer is a cancer that's a little bit unique in the metastatic space, where there are patients that do have curative options, including local therapies such as surgery, radiation. Again, the majority of patients are not on the curative path and have multifocal disease. Unfortunately, though the landscape is changing in terms of targeted therapies, the majority of patients are not only microsatellite stable, 95% of patients, but the majority of patients also do not have targetable, actionable alterations. Currently, there is a tremendous unmet need.
Refractory treatment options include a combination of chemotherapy plus or minus different approaches to targeting VEGF with TKIs and bevacizumab, for example. But what we see with these approaches is some survival benefit, but albeit a quite small survival benefit on the order of kind of a three-ish month improvement and response rates that are in the single digits, almost 0% responses with these therapies. So if you take a step back and then look at the therapeutic development space of immunotherapy, which has obviously been transformational in many tumor types and in the rare MSI high group in colorectal cancer, in MSS patients, we have just, unfortunately, not seen efficacy to date. Many combinations of different IO approaches, CTLA-4 PD-1, various VEGF IO combinations have not had activity. The signals of activity that we have been seeing are in patients without liver metastases.
Though that is encouraging and fantastic for those patients to potentially have an option with immunotherapy strategies, remember that's only about a third of the patients. We really need approaches to think about how to tackle this multifocal disease, particularly for patients with liver metastasis, knowing that this is still the lion's share of the patients that are MSS and have liver metastases.
Thank you, Dr. Parikh. I'll now turn it over to our Chief Medical Officer, Katarina Luptakova, to walk you through the clinical data from the phase I-C dose escalation trials for Vilastobart, our tumor-activated anti-CTLA-4, in combination with atezolizumab in patients with advanced solid tumors.
Thank you, Rene, and thank you, Dr. Parikh, for that overview. As you have heard from Dr. Parikh, patients with MSS colorectal cancer are in urgent need of novel therapies. And Xilio is developing Vilastobart in this patient population. Before initiating the phase II combination study in metastatic MSS-CRC, we evaluated the combination of Vilastobart and atezolizumab in phase I-C dose escalation. Based on the safety observed in phase I-C, in the third quarter of this year, we initiated enrollment in phase II for Vilastobart at 100 mg every six weeks in combination with atezolizumab at 1,200 mg every three weeks. In parallel, we are continuing to evaluate Vilastobart at a dose level of 150 mg every six weeks in the ongoing phase I-C trial in combination with atezolizumab.
I'll now turn to our initial data from the combination dose escalation, phase I-C, which will be presented in our late-breaking poster at SITC tomorrow. On this slide, you see the study design on the left and patient demographics for the phase I-C combination dose escalation trial to the right. Phase I monotherapy consisted of parts 1A and 1B. We previously reported data for these portions of the study at ESMO IO last year, which demonstrated evidence of monotherapy anti-tumor activity and a safety profile that we believe is clearly differentiated from systemically active FC-enhanced anti-CTLA-4 agents. For the phase I-C, a total of 17 patients were enrolled in the combination dose escalation. Notably, these were very heavily pretreated patients, with almost half receiving four or more prior lines of therapy.
While patients with all solid tumors were eligible for enrollment, the histologies more heavily represented include some of the immunologically coldest tumors led by MSS-CRC. As of the data cut-out of October 7, there were seven patients still ongoing on treatment. Only two patients discontinued treatment due to the adverse events, and only one of these was related to treatment. Let's now turn to the safety data. Consistent with what we've seen previously with monotherapy, the combination was generally well tolerated, with a safety profile that we believe is clearly differentiated from a systemically active, potent FC-enhanced anti-CTLA-4 agent in combination. There were no grade 4 or 5 treatment-related adverse events. Only three patients experienced grade 3 treatment-related adverse events. One patient had a transient grade 3 ALT elevation related to atezolizumab. One patient experienced a transient grade 3 ALT and alkali elevation.
One patient experienced a grade 3 colitis and diarrhea. The last two events were considered DLTs related to the combination therapy and have since resolved. The incidence of immune-related adverse events was low, with only one patient experiencing colitis, with no endocrine and limited skin-related adverse events. The most common non-immune-related adverse events were infusion reactions, and these included low-grade, reversible, and manageable events. Based on this initial safety profile, we selected the dose level for Vilastobart at 100 mg every six weeks as the initial RP2D, while we are continuing to evaluate the 150 mg dose level in the ongoing Phase I-C.
Despite enrolling a heavily pretreated patient population with immunologically cold, non-inflamed tumors, we were excited to observe evidence of anti-tumor activity in multiple patients, which included patients with non-small cell lung cancer, colorectal cancer patients without liver metastases, and most remarkably, patients with such difficult-to-treat tumors as ampullary carcinoma and MSS-CRC with liver metastases. The tumor reductions were typically rapid and observed at the time of first disease assessment with an imaging scan at nine weeks. Specifically, looking at the patient with MSS colorectal cancer with a liver metastatic lesion, this patient experienced a significant tumor reduction at the time of the first scan. The response was sustained and deepened over time to become a partial response at 27 weeks.
The first response observed in the trial was a patient with ampullary carcinoma, which is a rare tumor arising from the connection between the pancreatic biliary duct and duodenum, and it's considered to be a cold tumor akin to pancreatic cancer, which is typically very difficult to treat. This patient was a 76-year-old man treated previously with two prior lines of chemotherapy. After initiating treatment with Vilastobart and atezolizumab, the investigator observed a signal indicative of a clinical response based on the serum tumor marker CA 19-9, which is very specific to pancreatic and biliary malignancies. This marker was elevated at 700 when the study treatment started and decreased from 700 to 41 after six weeks of treatment. Consistent with the meaningful decrease in the serum tumor marker, imaging showed a 32% decrease in the sum of diameters of the target lesions at the time of first scan.
In fact, the numerical change in the diameter of the target lesions in one dimension only does not do justice to the magnitude of decrease in the overall tumor volume, which can be clearly seen on the CT scan imaging. You can see the largest target lesion at the time of the baseline scan on the left-hand side and a marked decrease in the overall tumor volume and flattening of the lesion at the first scan eight weeks after starting therapy. The second response observed in phase I-C was in a patient with MSS colorectal cancer. This is a 69-year-old female who underwent five prior lines of therapy, including combination chemotherapy, anti-VEGF, and EGFR agents. After initiating treatment with Vilastobart and atezolizumab, the patient had a 28% tumor reduction at the time of the first scan.
At 27 weeks, the response deepened to a partial response with a 33% reduction in the sum of target lesions. Importantly, this included a complete resolution of a metastatic liver lesion, and the patient is now awaiting a confirmatory scan. Let's take a closer look at the changes in the liver lesion in this patient on the CT scan. What is most exciting is that the target metastatic lesion in the liver was getting progressively smaller at each imaging until it fully resolved by week 27. This is particularly meaningful as liver metastases are notoriously difficult to treat in patients with MSS-CRC, and most immunotherapy combinations to date have not shown efficacy in this setting, where the unmet need is the highest. I will now turn back to Dr. Parikh to give us her view on the data.
Thanks again, and looking forward to the presentation at SITC tomorrow. To start, I will say certainly encouraging data. I think we all recognize that this is still a limited sample size with a small number of patients. As an investigator that has been in the colorectal space now for kind of over a decade and has lived through many immunotherapy approaches, every time we start to see some signals of efficacy, not only in this patient with CRC that has liver metastasis, but ampullary cancer, I think certainly piques interest. As noted before, we really have seen kind of tremendous limitations in activity to date in patients with liver metastasis, and certainly ampullary PDAC, even without liver metastasis, limited activity. Certainly encouraging data. I think the other notable piece that has stood out in terms of the toxicity profile, I think, is certainly encouraging.
Being an investigator in the trial, we have seen, as noted, the infusion reactions, some but very manageable. And certainly the colitis that we've seen with other prior CTLA-4 inhibitors and FC-enhanced CTLA-4 inhibitors, at least in the patients treated to date, seems to be meaningfully lower, which is important because this can be a limiting side effect, not only sometimes requiring steroids, but potentially other immunosuppressive agents to curtail the colitis if it becomes severe. So I think to date, very encouraging small data, but certainly excited by this to see where this goes, not only in terms of the efficacy signal, but hopefully a promising safety profile as well that is to hold.
Thank you, Dr. Parikh. We're also encouraged by the initial results of the phase I-C combination dose escalation trial, which demonstrate Vilastobart‘s potentially differentiated safety as well as early anti-tumor activity in combination with atezolizumab in immunotherapy-resistant tumors, including in an MSS-CRC patient with complete resolution of a target metastatic lesion. Importantly, as you said, we believe this activity in liver metastases that we've now seen both in the monotherapy setting and combination therapy setting for Vilastobart are particularly meaningful, given the high unmet need for MSS-CRC patients with liver metastases and the lack of efficacy of other IO combinations in these patients to date.
We'll continue to advance Vilastobart in the ongoing phase II combination proof of concept study in MSS-CRC, and we look forward to reporting initial phase II results in the first 20 patients later this year and plan to provide additional data for the first 40 patients in Q1 of 2025. Thank you all for your time. We'll now open the line for questions.
At this time, I would like to remind everyone, in order to ask a question, press star, then the number one on your telephone keypad. We will pause for just a moment to compile the Q&A roster. Your first question comes from the line of Michael Ulz with Morgan Stanley. Please go ahead.
Hi, this is Rohit from Mike. Thanks for taking our questions. Just in terms of the dose selection, some of the efficacy shown here is with the 150 mg for six weeks for Vilastobart. So just wanted to see what gives you confidence in moving forward to 100 mg in the phase II trial? Thank you.
Hi, Rohit. Thank you for the question. Yeah, so I think taking a step back, just keeping in mind, historically, when you're combining IO agents, what we often see is a significant dose reduction in both agents, sometimes as much as threefold, and in the case of ipilimumab, often from 3 mg/kg to 1 mg/kg in combination with PD-1. In contrast, for the initial RP2D for Vilastobart in combination with atezolizumab, we selected 100 mg, which is about 1/3 , 33% reduction from the monotherapy dose of 150, so a minimal reduction, and we're giving the full monotherapy dose of atezolizumab at 1,200 mg, so that's number one. I think, importantly, number two, keeping in mind that the Vilastobart potency that we demonstrated preclinically is 10x that of ipilimumab.
Our initial target dose going into the clinic has always been about 1 mg/kg or somewhere in the range of around 60 mg-70 mg. That would give us exposures equivalent to ipilimumab at 10 mg/kg . We're well above that at 100, and we believe this is a biologically active dose given the preclinical data we've seen to date. That said, though, we are continuing to advance the 150 mg dose level in combination with atezolizumab in phase I-C in parallel with the phase II. If that dose clears, we will then have the option to bring a second dose into phase II, which could give us a jumpstart on the Project Optimus requirements.
Thank you. Your next question comes from the line of Marc Frahm with TD Cowen. Please go ahead.
Thanks for taking my questions. Maybe first on the patient who had the unconfirmed response in ampullary carcinoma, can you just explain why they decided to discontinue after that scan? Because as you pointed out, the tumor shrinkage seems pretty interesting, as well as the CA 19-9 was quite profound. And then maybe for the physician, Dr. Parikh, just as we get, you noted it's an interesting but kind of early and small data set right now, but as we get a larger data set, what are you looking for to confirm that this really is an interesting program you want to keep working with?
Thanks, Marc. So yeah, I'll talk a little bit about what we know in the ampullary carcinoma patient. We agree it was a pretty remarkable response after one cycle, including the biomarkers and that tumor reduction. We'd only be speculating as to why any patient withdraws consent from a study. We've obviously worked closely with the site on this. What we could tell you is that it is a 76-year-old patient that had this opportunity to join the study and was referred from their local oncologist to a tertiary care center where our investigator was. And our understanding is that this was a great distance away from where the patient lived and required the travel back and forth, which was extensive. That we think could have contributed to their reason to withdraw because they stopped treatment with the investigator and decided to go back to treatment with their local oncologist.
I'll also mention, though, that this patient did experience the grade 3 colitis. This AE was reported as resolved while the patient was still enrolled in the study, but we can't really speculate as to why the patient withdrew. But it is unfortunate, as it would have been great to see this patient continue on therapy.
I'll take the next question. In terms of response rate, just to refresh a little bit, and I think OS expectations. So remember, for refractory CRC, the response rates with the current standard of care agents are in, again, the single-digit ranges, 0%-3% at best. So from my end, if a response rate still holds, as we see data in 2025 at around 20% in the liver metastasis patient population and continues to be seen in the non-liver metastasis patient population, I would be very excited by that and encouraged. So yeah, 20%, just to clarify, yeah, 20% in patients with liver metastasis, and I think overall as well. Yeah.
Great. Thank you.
Your next question comes from the line of Laura Prendergast with Raymond James. Please go ahead.
Hey, guys. Thanks for taking the questions, and looking forward to seeing the phase II data soon. So clearly, most of these patients are incredibly sick, heavily pretreated. I'm curious if the patients who had stable disease, before they discontinued, were there any quality of life improvements, specifically as it relates to their symptom burden? And then just generally, if you can comment more broadly on reasoning for some of the discontinuations that we saw, especially in those stable disease patients. And then a third question, any baseline differences between the MSS colorectal patients being enrolled in the phase I-C versus what we should expect in the phase II?
Thanks, Laura. Yeah, let's start with the last one. I think we do expect the phase II trial to be less heavily pretreated patients, slightly earlier in therapy than we do see typically in the phase I-C, and the phase II will be all MSS-CRC, including with and without liver metastasis, where the phase I-C did allow other cold tumor types. Do you want to add anything to that, Katarina, on differences in the population for phase II?
I think, Rene, you have covered it well. Typically, a phase I patient population is typically more heavily pretreated patients who exhausted all available options, and they are referred to a phase I clinic as opposed to phase II patient population seen typically with a gastrointestinal oncologist, and you would expect a little bit less heavily pretreated patient population.
Yeah. Thank you. And then I think, Laura, just to clarify, I think you're asking about patients that had stable disease in the trial but then discontinued.
Yes. Just generally color around why those patients discontinued. It seems like a lot withdrew consent. Just a nature of how sick these patients were, and then also just any quality of life improvements that you saw in these patients who didn't have a response, but yeah.
Yeah. So I think we covered a little bit in the beginning that the discontinuation first of all, I think discontinuations in phase I are common. They're late-line patients. There's been withdrawals of consent and investigator decision. We don't always know what's actually behind that, and we'll continue to query that database through the end of the trial to learn more. There was only one discontinuation due to an adverse event, but many of these other discontinuations where the investigator or the patient decided to withdraw were in the setting of progressive disease. So let me turn it over to Katarina to see if there's anything you'd like to add.
Thank you. And sometimes if there's a clinical disease progression not documented by full RECIST measurements, that's typically then collected as investigator decision for discontinuation of treatment. And I think there was a question about quality of life. So being early in development, we don't have a formal quality of life questionnaire. It's certainly something we would be bringing on in next stages of development. I think anecdotally, obviously, patients who do have response to treatment, they do typically feel better. I'm just thinking if we didn't have a patient with lung metastasis, or there was one that had a non-PR who, for example, felt better because the cough resolved. So certainly, we can see signals like these.
Thanks, Katarina.
This is Dr. Parikh again. I wanted to just clarify my point a little bit around promising development paths here. I think keeping in mind that the probably competitor in this space right now is Agenus, which is going after the non-liver metastasis patient population, and I think the benchmark there is around that 20% benchmark for the non-liver metastasis patient population, and so I think it at least has to be that, at least with the current data, but the toxicity profile is being looked at in Agenus with different dosing strategies from the phase II, and we'll see that data hopefully sometime this next year.
And so I think potentially still an opportunity, even if the signal holds in the non-liver metastasis patient population, if there is a toxicity advantage, even with a lower potentially dosing strategy with Agenus, if that efficacy holds in the phase II and ultimately the dose they take forward in phase III. But then I think, again, if you focus in on just the liver metastasis patient population, if you continue to see overall upper teens of a response rate in that, I think it's fantastic.
Thank you. Thank you, Dr. Parikh. Laura, did we answer your question?
Yes, you did. I appreciate it. Thank you.
Thanks so much.