Q2 2023 Xilio Therapeutics Inc Earnings Call

Participants

Katarina Luptakova

Martin H. Huber; President and Head of R&D; Xilio Therapeutics, Inc.

Rene Russo; CEO & Director; Xilio Therapeutics, Inc.

Stacey J. Davis; Chief Business Officer; Xilio Therapeutics, Inc.

Uli Bialucha; Chief Scientific Officer; Xilio Therapeutics, Inc.

Diwakar Davar

Presentation

Operator

Good afternoon, and welcome to the Xilio Therapeutics Virtual Program Spotlight. (Operator Instructions) As a reminder, this program is being recorded and a replay will be made available on the Xilio Therapeutics website following the conclusion of today's event.
At this time, I would now like to turn the call over to your host, Stacey Davis, Chief Business Officer at Xilio.

Stacey J. Davis

Thank you. Good day, everyone. Welcome to the Xilio Therapeutics Virtual Spotlight event focused on XTX101, a novel Fc-enhanced tumor-activated anti-CTLA-4. Thank you for joining us today. This is Stacey Davis, I'm a Chief Business Officer, and I'll be moderating today's call.
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 Factors section of SEC filings. In addition, any forward-looking statements made on this call represents 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.
Today's agenda: In today's program, we will be covering four main areas of discussion. First, a deep dive into the CTLA-4 blockade biology and the opportunity associated with TREG Depletion. Second, Xilio's XTX101 molecule, which is a novel Fc-enhanced Tumor-Activated Anti-CTLA-4. Third, Monotherapy data for XTX101 from the ongoing Phase I clinical trial in an associated patient case. And lastly, our development plans for XTX101 in combination with an anti-PD-L1 and advanced microsatellite stable colorectal cancer, commonly referred to as MSS CRC.
After the formal presentation, there will also be a Q&A session. During the presentation, you are invited to submit questions via the chat function to be addressed during the Q&A.
Today on our call, we are joined by Dr. Diwakar Davar, who is Associate Professor of Medicine and Clinical Director melanoma and skin cancer program, UPMC Hillman Cancer Center. He specializes in the management of advanced melanoma and the development of early phase studies to test novel immunotherapy approaches to treat advanced cancers. Dr. Davar is also an investigator in the ongoing Phase I clinical trial of XTX101.
From the Xilio leadership team, we are joined by Rene Russo, Chief Executive Officer; Uli Bialucha, our Chief Scientific Officer; Katarina Luptakova, our SVP of Medical; and Marty Huber, President and Head of Research and Development.
I'd now like to turn it over to Rene Russo to kick off today's discussion.

Rene Russo

Thank you, Stacey. Good day, everyone, and thank you for joining our call today. It's clear that advancements in the field of immuno-oncology, or IO have had a truly transformational impact for certain patients with advanced cancers. However, the treatment potential for many exciting IO targets have been limited by systemic immune-related toxicity for patients.
At Xilio, we are seeking to change this paradigm by developing medicines that utilize the tumor's own dysregulated biology against itself to trick tumors into activating their own treatments locally within the tumor, while simultaneously sparing healthy tissues and cells from unintended side effects. And we call this approach tumor-selective activation.
Our tumor activated molecules are designed to make cancer therapies more effective by concentrating and focusing their power exactly where you want it inside the tumor microenvironment. And at the same time, making them better tolerated by now allowing the active cancer medicine to distribute all over the body and attack healthy cells. The way we go about this, this goal of geographic precision is through our proprietary technology that we call GPS or Geographically Precise Solutions. We use this novel approach to build tumor-activated molecules, including monoclonal antibodies, cytokines and multifunctional biologics that are designed to localize the antitumor activity within the tumor microenvironment and optimize the therapeutic index for patients.
You can see here on the right, a few of our key design components of some of our molecules that make this possible.
First, we start with highly potent IO molecules and, in some cases, further boost their potency through engineering. Second, we put these molecules under very tight regulation through a protein-engineered blocking domain or masking domain seen here in orange. And that is to shut down the activity of the molecule and bring it under tight control while the molecule is circulating outside of the tumor. Third, we design the equivalent of a switch called a protease cleavage site seen here in green. That switch or site is what releases the blocking domain and turns on the molecules activity, but only once it's inside the tumor microenvironment. Using our GPS technology, we are currently advancing multiple tumor-activated IO treatments in clinical development as well as programs in preclinical development.
The focus of today's discussion is XTX101, our clinical-stage anti-CTLA-4, which is a high affinity Fc-enhanced, tumor-activated molecule. XTX101 has completed the Phase I monotherapy dose escalation, and we have selected a recommended Phase II dose. Today, we'll be reviewing encouraging initial data from this study, including antitumor activity and safety data. And earlier this week, we also announced that we've entered into a clinical collaboration with Roche to study XTX101 in combination with atezolizumab in patients with metastatic microsatellite stable colorectal cancer or MSS CRC, including patients with metastatic disease to the liver.
MSS CRC represents a population with limited treatment options and no approved IO therapies available for patients with MSS CRC today.
Our second clinical stage program, XTX202, is a tumor-activated beta-gamma engineered IL-2 molecule. Earlier this year, we opened the XTX202 Phase II monotherapy trial in patients with advanced renal cell carcinoma and advanced melanoma at an initial Phase II dose of 1.4 milligrams per kilogram. In parallel, we continue to explore higher doses in a Phase Ia dose escalation, where we're currently dosing patients at 4.0 milligrams per kilogram.
In early November, we plan to share initial clinical data for XTX202, including safety PK/PD and antitumor activity data.
Our third clinical stage program is XTX301. This is a tumor-activated IL-12. We initiated a Phase I dose escalation in the second quarter of this year, and we anticipate sharing preliminary safety data for this program in the fourth quarter of this year.
And then finally, I'd like to take a minute to mention our preclinical program, which is a multifunctional tumor-activated PD-1 IL-2 molecule. Our goal with this molecule is to deliver a synergistic combination of a full dose PD-1 and a full dose IL-2 directly targeted to the right immune cells within the tumor microenvironment. A key feature of our approach is that the IL-2 component is designed to remain inactive until it is unmasked locally in the tumor microenvironment using our tumor activation technology.
Earlier this year, we presented exciting preclinical data from this program at AACR, demonstrating the potential of tumor-activated synergistic effects, specifically enhancing tumor reactive antigen-specific T-cells. Furthermore, we presented preclinical data showing minimal peripheral activity and superior exposure compared to unmasked multi-functional molecules. We see great potential for leveraging our platform and capabilities to enable more multifunctional molecules of this nature. And we look forward to sharing more about this specific program in the future.
Now let me turn it over to Dr. Davar.

Diwakar Davar

Next slide. So CTLA-4 is a very exciting target in cancer and cancer immunotherapy. CTLA-4, which stands for cytotoxic T-lymphocyte associated protein 4, also known as a CD152 protein receptor essentially is the negative counter regulatory counterpart of CD28. CTLA-4 was actually first identified in 1991 by the labs of Tak Mak and Arlene Sharpe, who published their data independently. And what they identified was that this was a key receptor that formed part of the immunoglobulin receptor superfamily, and it was actually the second receptor for the T-cell costimulatory ligand B7.
So essentially, what we now know about CTLA-4 is that CTLA-4 along with CD28 represent a unique spectrum by which the immune system is able to tune immune responses following T-cell recognition. It's constitutively expressed by TREGs. But also very importantly, it can be up regulated by other T-cell subsets, particularly CD4 T helper cells upon activation, which is particularly critical in the context of cancer.
The way it works is that it competes with CD28 for binding to CD80 and 86, the aforementioned ligands. But given its greater binding affinity for the ligands, CTLA-4 effectively diminishes signaling and mediates immune expression. Now CTLA-4 will also mediate immune suppression through other means, including the removal of CD80, CD86 on APCs via trans-endocytosis and other mechanisms, and it's important to clarify that the mechanisms by which it elucidates and mediates immune suppression and not completely elucidated at this point in time.
Now very importantly, CTLA-4 blockade preclinically is being shown to be associated with antitumor immunity with the development of immunological memory. And the development of these agents is essentially what led to the Nobel prize being awarded to Jim Allison.
Next slide, please. Now in the context of cancer immunotherapy, the promise of this blockade was really heralded by the use of monoclonal antibodies, again, as mentioned by Jim Allison, that demonstrated that effective blockade preclinically resulted in antitumor activity as well as immunological memory.
The first advances in the context of cancer happened more than a decade ago when the CTLA-4 blocking antibody, ipilimumab known then as MDX-010 of Medarex-010 was developed by Medarex and it produced durable responses in a small fraction of extensively pretreated melanoma patients. This was demonstrated both as a single agent and also in combination with peptide vaccines in pivotal NCI trials, and I show you an example of such a responder highlighted in a paper by almost a decade ago in 2014 by Steve Rosenberg's group. And what you can see is what we now noted the hallmark of cancer immunotherapy, which is you see an effect upon both regression of lung lesions, multiple lung lesions. And very interestingly enough, even though this was not demonstrated until relatively recently, a regression of an untreated brain met in panel E&F.
This led to subsequent dose finding trials that confirmed that multiple doses were effective, particularly doses 3 and 10 milligrams per kilogram and identified two schedules that were taken into subsequent clinical trials. And this 022 trial demonstrated single-agent response rates of about 4% to 10% and also an irAE rate of about 5% to 18%. So very interestingly enough, the promise of CTLA-4 blockade heralded some very important principles of cancer immunotherapy that include the fact that unlike with checkpoint inhibitors, PD-1 checkpoint inhibitor therapy, the schedule and the dose actually does matter.
This is a drug -- this is a checkpoint and this is a drug for which there is dose-dependent efficacy and there's also different schedules that potentially may be efficacious. And that's why identifying dose and schedule is very, very important with CTLA-4 blockade. Next slide, please.
The early developments of CTLA-4 and the single-agent responses that were seen in the previously mentioned 022 trials led to 2 pivotal Phase III trials. The first was essentially a Phase III trial of ipilimumab plus minus gp100 vaccine in pretreated melanoma patients. And this was conducted by Steve Hodi and his colleagues had published more than a decade ago in 2011. And in this pivotal paper, essentially, what Dr. Hodi and his colleague showed was that the response rate to -- in heavily pretreated melanoma patients was 11%. But most importantly, even though the responses were 11%, up to 1/4 of patients, 5 to 1/4 of patients, 22% of patients who were treated with ipilimumab who are live more than 2 years later.
So firstly, not everybody who had a radiographic shrinkage counted towards the benefit indicating that there was a proportion of patients who did not have cancer regression, at least its cancer regression as we knew it in 2011, but who also had evidence of benefit because they did not pass away. This subsequently led to a Phase III trial in PD-1 and CTLA-4 -- and previously treatment-naive melanoma patients, what is known as the 024 study, and in that 024 study, ipilimumab at 10 milligrams per kilogram was studied in combination with dacarbazine and demonstrated a response rate of about 20% with about 47% of patients with the combination being alive and well at approximately two years.
And in this pivotal Phase III trials, what we learned was that, one, both EP3 and EP10 are active, both EP3 and EP10 produce responses, but despite differences in schedules and differences in doses, we see a durable tail to the curve, and this is what led to both the FDA approval for ipilimumab in advanced melanoma, but also some key principles that have guided immunotherapy drug development over the last decade being notably being that rate. Not all radiographic responses result in cancer shrinkage, but there are proportional patients who benefit, who do not have radiographic responses. And two, at least in the context of CTLA-4 development, drug and -- dose and schedule do matter. Next slide, please.
What we have learned since then are some important preclinical aspects of the biology of CTLA-4 that were not known when the drug went into clinic. And the reason for that is probably to do with some unique human specific factors that were not identified in preclinical models. And that starts with -- it has always been thought that given the expression of CTLA-4and TREGs constitutively, the TREG depletion is very important for the efficacy of the drug. And therefore, Fc-mediated TREG depletion that is ADCC via an Fc-IgG1 backbone is critical to the function of CTLA-4 antibodies. And this was known preclinically.
What we then realized was that there may be in addition to TREG depletion, an additional role for the Fc-Fc Gamma interaction in terms of improving APC function via receptor clustering. And this data came out of several pivotal papers, including by the Agenus Group in the cancer cell paper in 2018, but also in another paper in the same addition of cancer cell by Sergio Quezada, who's actually Jim Allison's post doc, demonstrating that Fc-Fc Gamma interactions were very important to the efficacy of ipilimumab or Fc-active CTLA-4s.
Now very interestingly, in the same paper, Dr. Quezada and colleagues demonstrated that the clinical efficacy of ipilimumab was associated with particularly single nucleotide polymorphisms on CD16 that is Fc Gamma, high affinity that were known to have higher binding affinity and increased ADCC. And this is the high affinity polymorphism. Now that -- all of that led to the development of Fc-enhanced CTLA-4 molecules such as the Agenus 1181 molecule known as 1181 or balstilimab that specifically binds to not just high but also low affinity Fc Gamma and demonstrates clinical activity in cold tumors. And as you can see here, what we know about the Agenus 1181 data is that there is this rather remarkable signal of efficacy in microsatellite stable colorectal cancer, but very interestingly, complete absence of any efficacy in liver metastases, an important biological factor that is of significant importance to patients.
Now as it turns out, the deep durable response as seen come at a cost and that cost is side effect. So the Agenus data, while exciting, has to be taken in light of the fact that the drug is associated with a very significant incidence of at least 30% Grade 2 or greater immune later adverse events, particularly colonic inflammation that sometimes can result in a therapeutic cessation of the drug, because of the need of how severe the side effect is.
So overall, what we have now come with CTLA-4 is we've basically completed the immunotherapy revolution. We started with -- this was the drug that actually kick started the IO revolution with the deep, durable responses that were seen in a very, very select subset of melanoma patients. But now with improved understanding of how the biology works in humans we have ways in which we can potentially improve upon the efficacy of the drug as well as the toxicity of the drug through some novel mechanisms. And potentially, the tumor microenvironment, selective activation of this agent would be very exciting because it could potentially overcome some of the aforementioned limitations of other Fc-enhanced CTLA-4 agents.
So thank you, and I will turn it over to our folks.

Uli Bialucha

Thank you, Dr. Davar. That's a great segue for us into moving to discuss the design of XTX101. We can go to the next slide.
What we're looking at here is a structural representation of our antibody molecule, XTX101. On the left-hand side, we are showing the molecule in its inactive masked state and on the right-hand side is the active unmasked state. I'll note upfront, the antibody that we're using here is a novel CTLA-4 antibody, it is not ipilimumab. We selected this antibody specifically for high affinity, and it is a CTLA-4 blocking antibody.
When activated, XTX101 has about tenfold higher affinity for CTLA-4 compared to ipilimumab. Now once we selected the unmasked antibody as our lead, we next use our platform to discover a unique and customized mask highlighted to you in orange. This peptide mask blocks the antigen binding region of the molecule and prevents it from interacting with its target CTLA-4. We then use a combination of computational as well as structural biology approaches to optimize how we connect that mask to the rest of the antibody, an incorporated a cleavage element here shown in green. This cleavage element is what tumor-associated proteases act upon for activation of the molecule.
Now the final feature that distinguishes this molecule from ipilimumab in other first-generation CTLA-4 antibodies, is that we incorporated mutations in the Fc region of the antibody that enhance the affinity of the molecule for activating Fc gamma receptors, thereby enabling the antibody to elicit enhanced antibody-dependent cell-mediated cytotoxicity or ADCC. In the context of XTX101, the enhanced ADCC drives potent TREG depletion as this cell type features elevated levels of CTLA-4 expression, particularly in the tumor microenvironment. I'll note that the work that has gone into optimizing the cleavage side for XTX101 was quite extensive, and that's probably where we leveraged most of our unique expertise.
What we wanted to do is dial in the right selectivity for tumor-associated proteases, but also the right degree of specificity and efficiency of cleavage. So we designed the molecule to be at steady stage about 90% masked and around 10% activated. And we did that with CTLA-4 biology in mind. With the understanding that we want some activity in tumor draining the lymph nodes as well as peripheral lymph nodes to facilitate efficient T-cell priming.
Now on the right-hand side, you'll see the active state of the molecule. The masks have been released following proteolytic cleavage of the linker and the antibody is now able to do 2 things. One, it will bind CTLA-4 with high affinity and will block the checkpoint. And then two, the antibody will drive potent ADCC against TREGs, which express CTLA-4 at high levels in the tumor microenvironment.
So to sum this up, the masking approach is designed to minimize activity of XTX101 outside of the tumor microenvironment and improved tolerability. And then once activated by tumor-associated proteases, the two mechanisms of action, potent blockade of CTLA-4 and TREG depletion combined to enable antitumor activity.
Next, I would like to show you some preclinical data for XTX101. On the left-hand panel here in the upper graph, we are focusing on antitumor activity with XTX101, and we are comparing that to activity with ipilimumab in the lower graph. In response to a single dose of XTX101 at the low dose level of 0.3 milligrams per kilogram, we saw robust antitumor activity, including complete regressions in a subset of the animals.
Now we also saw activity with ipilimumab in this model, but at least 3 milligrams per kilogram, so a tenfold higher dose of Ipi were needed to drive a similar level of activity to that of XTX101. This is a key preclinical demonstration of the 10x improvement in potency with XTX101.
In the middle panel, we are focusing on the mechanism of action and what is happening in the tumor. Specifically, we're looking at tumor-infiltrating immune cell changes in response to treatment. The top panel here shows CD8 cells, and you can see that XTX101 at this time point was very effective in inducing an influx of CD8 positive T cells, which are known to be key mediators of antitumor immunity.
In the bottom middle panel, we see that XTX101 treatment resulted in a decrease of immune suppressive regulatory T cells or TREGs, consistent with the ADCC enhancement built into XTX101. We also see that ipilimumab in contrast did not deplete TREGs. It's important actually to take the two together, the increase in CD8s and the depletion in TREGs. This essentially results in a robust increase in CD8 to TREG ratio and is exactly the pharmacology you would want to see with XTX101.
Now on the right-hand side here, we actually have an opportunity to make a replica of the Agenus molecule AGEN1181. And we profiled XTX101 against the AGEN1181 as well as ipilimumab and ran ADCC assay as shown in the top right graph. As expected, ipilimumab did not signal in the ADCC assay, whereas the Agenus molecule did show robust ADCC as an Fc-enhanced molecule would be expected to. Importantly, XTX101 matched the level of activity of the Agenus molecule in this assay when activated. However, what we have seen from AGEN1181 and as noted by Dr. Davar in the clinic, there is a toxicity profile that is consistent with what we would be expected from a systemic (inaudible) classical T cell activation assay. Here, both the Agenus molecule and unmasked XTX101 compared favorably relative to ipilimumab which demonstrates the robust checkpoint blocking function of XTX101 in this model system once activated.
I'll now turn it over to Katarina Luptakova, to walk you through the clinical data from our Phase I clinical trial of XTX101.

Katarina Luptakova

Thank you, Uli. The Phase I trial is a multicenter open-label study designed to evaluate the safety and tolerability of XTX101 as monotherapy in patients with advanced solid tumors and to determine the recommended dose and schedule of XTX101 for Phase II.
Part 1A was the monotherapy dose escalation that is now completed with patients ongoing and in follow-up. Part 1B is the monotherapy dose expansion designed to collect three and on-treatment tumor samples in order to assess the pharmacodynamic profile of XTX101. Part 1B is ongoing at the recommended Phase II dose of 150 milligrams every 6 weeks.
To date, 29 patients have been enrolled and treated in the XTX101 study across Part 1A and 1B. Note, we are including 27 patients in this data update as two patients are still too early to include for safety data at the time of August 3 data cutoff.
The patient population reflects a typical first-in-human oncology population with a median age of 67 and a heavily pretreated population with a range of up to 12 prior lines of therapy and a median on 4 prior lines. In fact, for most patients enrolled in the study, the choice has been between seeking end-of-life care in hospice, or enrollment in a clinical study. Almost half of the patients previously received immunotherapy, and the remaining patients typically have tumor types that would not be considered for IO treatment as per standard of care.
The tumor types treated in the study include a range of various histology as expected for an oncology Phase I study. Of note, in the most recent 6 months, our investigators increasingly started enrolling patients with colorectal cancer.
In terms of patient disposition, the predominant reason for treatment discontinuation was progression of the underlying disease including content withdrawals as patients move to hospice and investigator decisions where patient exhibited clinical progression. Only four patients discontinued treatment due to a treatment-related adverse event, and in all four cases, this was related to an infusion reaction, which importantly all occurred on a once every 3-week dosing schedule.
On the next slide, we are looking at an overview of our dose escalation schema, using an accelerated study design, transitioning to a standard [3 plus 3] dose escalation evaluating ascending doses of XTX101 with threefold dose escalation between each dose level. We used flat dosing because this molecule is expected to have antibody-like volume of distribution and body weight dosing is not necessary. I'd like to remind you there is some accumulation of the activated molecule which was intentional in the design process, as Uli mentioned earlier. Knowing this, we expected to see a certain amount of systemic activity and at higher doses toxicity. For this reason, we designed the study to boost the dose levels in order to understand the maximum tolerated dose.
The second point I would like to point out is that we took into account our target dose based on the preclinical data, 60 milligrams every 3 weeks was intended to give us the exposure of the tumor that was on par with ipilimumab at 10 milligrams per kilogram. So those were the two key anchor points in the study design. One dose limiting toxicity of colitis was reported at 60-milligram. This event was confounded by preexisting GI condition with the patient experiencing diarrhea at baseline before treatment. At a threefold higher dose of 180 milligrams once every 3 weeks, two DLTs of grade 3 colitis were noted.
At this point, we sought to optimize the dose and schedule to preserve the higher Cmax seen with the 180-milligram dose while matching the AUC exposure of the 60 milligrams once every 3-week target dose. With this in mind, we evaluated dosing XTX101 at 150 milligrams once every 6 weeks where no DLTs were reported among five patients treated in the dose escalation portion of the study.
As you will see in more detail in the next slide, we did not observe infusion reactions nor colitis in the patients treated at 150 milligrams once every 6 weeks. We are now reviewing the summary of related adverse events in 27 patients treated in either Part 1A or Part 1B. First, it's very important to note that we have not observed any Grade 4 or 5 treatment-related adverse events at any dose. At the once every 3-week dosing, GI immune-related adverse events occurred in approximately 1/3 of patients with 4 patients having grade 3 diarrhea or colitis. Of note, these Grade 3 adverse events were driven primarily by the highest dose of 180 milligrams once every 3 weeks, which was well beyond our target dose of 60 milligrams once every 3 weeks.
In contrast, in patients treated at the RP2D of 150 milligrams once every 6 weeks, only one related Grade 3 GI event was observed, which was diarrhea occurring after the second dose. One case of grade 3 dermatitis which rapidly resolved with steroids was also observed at the RP2D.
The remaining safety profile for patients treated with the once every 3-week schedule was unremarkable with the exception of the Grade 3 infusion reactions, which all occurred during either the second or third infusion. Importantly, no infusion reactions of any grade have been reported to date in the once every 6 weeks schedule.
Finally, the infusion reactions did result in before treatment discontinuation at the once every 3-week schedule. However, no discontinuation due to treatment-related adverse events have been observed at the RP2D at this time.
Data on the best overall response are presented here as the percentage change in the sum of diameters in the target lesions from baseline. This waterfall plot is showing the evaluable patients who had at least one post-baseline scan as of the data cut off. Three patients had a reduction in the sum of their tumor measurements. One patient with squamous cell carcinoma of the skin had a stable disease with a maximum reduction of 5%. A second non-small cell lung cancer patient had a reduction of 7%, and one patient had a confirmed partial response with a reduction of 52% and this patient was continuing on treatment at the time of data cutoff.
This spider plot displays the change in measurements over time to evaluate the duration of effect. The blue line shows the tumor measurement for the patient I mentioned with squamous cell carcinoma of the skin, who was treated at 60 milligrams once every 3-week dose and maintain stable disease for 24 weeks. The lowest black line shows a slight tumor reduction for the patient with non-small cell lung cancer. This patient receives XTX101 at the 180-milligram once every 3-week dose and had to discontinue treatment due to an infusion reaction during the third dose. Last but certainly not least, the orange line at the bottom is the non-small cell lung cancer patient who was treated at 150 milligrams once every 6 weeks and achieved a confirmed partial response.
At this point, I would like to turn it over to Marty to share more of the details related to this patient.

Martin H. Huber

Thank you, Katarina. I'm pleased to share more information on this patient, which represents our best observed response to date. Here, we have a 66-year-old female patient with metastatic non-small cell lung cancer as the primary lesion. And as you can see, metastasis to the liver. The patient's molecular profiling was unremarkable. In addition, there was no PD-L1 staining in the tumor.
She had previously been treated with chemotherapy, which resulted in a response, which then progressed after approximately four months. She was then enrolled in the XTX101 Phase I dose escalation at dose level 5, which is 150 milligrams every 6 weeks. To date, she has received 7 doses of XTX101 at the recommended Phase II dose and a response was last assessed at the 36-week time point. The only treatment-related adverse events on XTX101 have been Grade 1 fatigue. The patient developed clear evidence of antitumor activity at week 9 in both the lung and liver lesions. Here, you can see the CT images of the chest at 2 different levels, capturing the lung tumor.
In the upper row, this captures the upper portion of the lesion and as you can see, we are going across the chest approximately at the level where the trachea splits into two main bronchi. And going from left to right, you see a decrease in the tumor size from baseline through weeks 9 and 18.
In the lower cut, which represents the main portion of the tumor, which is measured for RECIST response assessments, you can also appreciate that the tumor becomes smaller at week 9 and 18, but most importantly, you noticed at week 9, significant cavitation likely indicating necrosis in the center of the tumor. This is not reflected in standard tumor measurements by RECIST. These lesions continued to decrease through both week 27 and week 36 scans, and this has resulted in a confirmed partial response.
If we look at the next slide, however, this is where we really got excited. This is the liver lesions for the patient. And as mentioned previously, liver metastases are not very responsive to IO treatment. This patient was noticed to have multiple liver lesions as highlighted by the orange circles here.
One of them, the largest one on the posterior lobe of the liver was 23 millimeters at baseline and that's that large circle lesion on the lower image. The others are smaller and then there were multiple lesions under 10 millimeters, which are nontarget lesions.
Notably, both the target lesion and all nontarget lesions were described as absent in the follow-up scans at week 9 and week 18. The lesions have disappeared. As of week 27 and week 36 scans, the hepatic lesions have not returned. So we've seen a complete reduction of the hepatic metastasis, which just was a very striking in a setting of monotherapy with an anti-CTLA-4 in a PD-L1 negative lung cancer patient.
The next question then is this being driven by tumor-specific activity or by systemic activity. This patient's case is supporting that XTX101 masking has been effective. There was a lack of peripheral activity as evidenced by the pharmacodynamic data. There were minimal changes in the peripheral CD8, CD4 and TREGs on treatment. At the same time, the clinical data support that there's tumor-specific activation as evidenced by the clear tumor response in this patient.
These figures show the PD data from the peripheral blood in this patient that was concorded with the partial response. The best way to look at this is full change. If you had a systemically active anti-CTLA-4 present, you would expect to see at least two to threefold changes in several of these markers. For example, you would expect CD8 T cell counts as well as the subset of proliferating CD8 T cells as measured by [Q67], to increase more than twofold.
As you can see here, pretreatment is shown in black, which is baseline. On treatment shown in orange at cycle 4, day 7. In all of the values assessed, there is a less than twofold change throughout with minimal changes observed in any of the markers. This is consistent with the observation and we also were not seeing any immune-related adverse events in the periphery in this patient.
I'd now like to change gears and talk about more where we're headed with XTX101. In the United States, colorectal cancer ranked second as a cause of cancer-related mortality and (inaudible) is the leading cause of cancer-related death had been under the age of 50. More than 150,000 patients are diagnosed annually and unfortunately, approximately 60% of these are not candidates for surgical resection due to the presence of metastatic disease. Chemotherapy and radiotherapy are used, but primarily as palliation in the metastatic setting.
Recent advances in IO treatment with anti-PD-1 have shown great promise, but that is limited to the less than 5% of patients whose metastatic colorectal cancer is MSI high, which is primarily associated with Lynch syndrome. Over 95% of the patients with metastatic colorectal cancer are classified as having microsatellite stable disease or MSS CRC. This is a clear example of a cold tumor characterized by weak immunogenicity and limited immune cells. Unfortunately, previous efforts to bring checkpoint inhibitors these patients have shown little to no efficacy with previous studies yielding a 0% to 5% objective response rate.
Based on these data, we estimate that there are approximately 85,000 patients in the U.S. alone with stage IV metastatic MSS CRC who are currently not candidates for approved IO agents. In recent studies showing responses in patients with metastatic MSS CRC with Fc-enhanced CTLA-4 as outlined earlier in this presentation, combined with the PD-1 treatment, the population with a clear benefit has been restricted to patients without hepatic metastases, which is the most common site of metastatic disease in these patients. Therefore, approximately 60,000 patients in the U.S. who have MSS CRC and presence of liver metastases are currently not candidates for IO treatment even with the investigational Fc-enhanced anti-CTLA-4 agents.
As Rene mentioned at the top of the call, our next step with XTX101 will be to study it in combination with atezolizumab in patients with MSS CRC. Our approach is to determine the potential for XTX101 plus atezolizumab in these patients without any current IO options will start with the dose escalation cohort shown here as Part 1C.
To expedite study initiation, the Part 1C was added as an amendment to the ongoing Phase I trial. In combination dose escalation, we will be allowing patients with a range of solid tumors to enable rapid dose escalation. However, as was noted earlier, we are seeing an enrichment for colorectal cancer patients already in the ongoing Phase I. So we anticipate seeing a fair number of these patients in the study.
Assuming that we have an acceptable toxicity profile for the combination at the initial dose will explore XTX101 at higher doses, subject to the results of dose escalation, we plan to initiate a Phase II study of XTX101 in combination with atezolizumab in patients with MSS CRC. A key advantage of performing a proof-of-concept study in patients with MSS CRC is that a randomized trial is not required to isolate the contribution of XTX101. Given that this has an established response rate for anti-PD-L1s of less than 5% and an ORR of 20% or greater for the combination will be statistically significant, clinically meaningful in these patients, showing the contribution of XTX101. Importantly, we intend to include patients both with and without hepatic metastasis based on the early antitumor activity observed in our patient with non-small cell lung cancer. Our current goal is to activate this combination dose escalation by the fourth quarter of 2023.
Now let me recap what we have discussed. The totality of safety, efficacy, PK and PD data presented for XTX101 supports continued development of this mass tumor-activated and Fc-enhanced anti-CTLA-4 molecule. With the completion of enrollment of Phase I monotherapy dose escalation, the recommended Phase II dose has been established as 150 milligrams once every 6 weeks.
At this dose and schedule, a favorable safety profile was observed with only one incident of reversible grade 3 diarrhea and one instance of reversible grade 3 dermatitis. Importantly, at the recommended Phase II dose of 150 milligrams every 6 weeks, we have not observed other immune-related adverse events typically associated with anti-CTLA-4 therapy. Further, with the once every 6-week schedule, no infusion reactions were observed.
At this dose level, a Cmax was reached that adjusted for potency would be twice as high as the Cmax of ipilimumab at 10 milligrams per kilogram. The antitumor activity observed in the patient with non-small cell lung cancer is notable for activity in both the primary lung lesion as well as in the liver metastasis.
In summary, at 150 milligrams every 6 weeks, the clinical performance of XTX101 to date is consistent with our target profile criteria and what's really exciting for us as a company is that it also represents the first clinical validation of our platform, both in terms of safety and efficacy. Stacey?

Question and Answer Session

Stacey J. Davis

Thank you, Marty, for sharing that compelling overview of the patient case and the aspiration that we have to bring XTX101 to patients with such great unmet need in MSS CRC. As a brief acknowledgment, we would like to thank the patients, family of caregivers and investigators and study site staff for the commitment to this trial as well as to all of our Xilio employees.
Now we're going to turn it over to the Q&A portion of the program. (Operator Instructions) The first question, Marty, is going to be directed to you to go a little bit deeper into the clinical trial design.
Can you share some additional color on your plans for the XTX101 combination study? How are you thinking about starting dose? Are you planning on starting the combination with the RP2D?

Martin H. Huber

Thank you, Stacey. As we move forward with the study, this is a novel combination. And so we are taking a fairly standard approach is that you have to assume there may be some interaction from a toxicity point of view. So we will start the initial dose level with a 50% reduction. So we'll go to 1/2 of the recommended Phase II dose that we saw with monotherapy. So that will be 75 milligrams every 6 weeks.
Then based on the safety data for the combination observed at the first dose level, we then plan to reescalate to the higher dose. Importantly, even if we end up with the first dose level, the -- being the recommended Phase II dose, we do anticipate this would be sufficient to move forward in a combination study as the Cmax for XTX101 at 75 milligrams is similar to the Cmax (inaudible) at 10 milligrams per kilogram when adjusted for the 10x increase in potency. So we think there's still the opportunity to have a highly potent tumor selective anti-CTLA-4 combined with an anti-PD-L1.

Stacey J. Davis

All right. Marty, we got a couple of follow-up components here.
One additional challenge for novel combinations is always establishing contribution of components. How are you thinking about understanding the role of XTX101 in the combination with atezolizumab and how are you going a meaningful answer without a randomized Phase II study?

Martin H. Huber

Yes. I think that's really one of the strengths of looking at MSS colorectal. If we were looking at another tumor type like lung cancer, where the anti-PD-1, anti-PD-L1 or anti-PD-1 would have monotherapy activity, you would have to think in terms of a randomized trial. But in this setting, where the anti-PD-L1 has very limited activity at best, less than 5%. The sample size necessary to just a single arm see that a 20% response rate or higher is meaningful is roughly 40 or 50 patients. And if you see that, it's clear that's the contribution of the 101 because you would not expect to see that with either agent in monotherapy.

Stacey J. Davis

Great. There's one more portion of this from Marc Frahm at TD Cowen.
What portion of patients in the Phase IC dose escalation study do you expect will actually be MSS CRC patients?

Martin H. Huber

It's hard to give a precise number. But I think if you look at what's happened in 1B, the last -- the majority of the last patients enrolled have all been MSS CRC. We think there's interest in this population, especially in the patients with hepatic metastasis who are not eligible for some of the other studies out there. So while we can't give an exact number, we think there will be a clear enrichment.

Stacey J. Davis

Great. And in terms of -- this is a question for Michael Ulz from Morgan Stanley.
Given the response in the PD-L1 negative, lung cancer patients. What are we thinking about as far as lung as an opportunity?

Martin H. Huber

I'm going to give a quick answer, and then I'm going to turn it over to Uli to think -- talk a little bit broader how we're looking at the wider tumor types. With regards to lung cancer, that is obviously, an area of interest for us. I think the challenge there is that we would need to probably look at more of a randomized trial, et cetera, to get the clear proof of concept, but that is something that we would see as an opportunity during via a collaboration. Uli?

Uli Bialucha

Yes. Thanks, Marty. I think the only piece I would add here is that with the tolerability profile that we've seen so far and the fact that our molecule is Fc-enhanced to elicit those two mechanisms of action that I spoke about, the potent checkpoint blockade and TREG depletion, I think there's a clear expectation that TREG biology matters in other tumor types. And we can -- we've done some internal work to actually understand where those signatures are present. And I would say that there is ample opportunity, non-small cell lung cancer, for sure, has been mentioned. We also believe that head and neck and some other indications could be of high interest for the molecule.

Stacey J. Davis

Thanks, Uli. And I think we want to build on this question a little bit more.
Dr. Davar, given what you shared with us earlier about CTLA-4 blockade and the profile that we've talked about with 101, we obviously just touched on lung cancer, and we're advancing in MSS CRC. What are other tumor types or indications that you think would be interesting or important to explore with XTX101 in combination with PD-1 or PD-L1?

Diwakar Davar

Okay. So thank you for the question, Stacey. I think the obvious points that were discussed were obviously of patient populations where in CTLA-4 already has got an established efficacy profile, but wherein that efficacy profile could be improved, right? So for example, we know that PD-1 CTLA-4 is efficacious in melanoma, cutaneous melanoma. But again, CTLA-4 has a single-agent response rate of about 15%. The combination PD-1/CTLA-4 has an efficacy rate of about 55% in frontline metastatic melanoma.
But in the perioperative space, there is no established standard beyond PD-1 monotherapy. And even then it's not FDA approved, it's just on NCCN. So if you have a very effective PD-1/CTLA-4 molecule, particularly where the CTLA-4 has got clearly efficacy and has reduced toxicity, suddenly studying that in the perioperative setting in melanoma opens a whole new vista being able to move the drug earlier into the life cycle of the patient, wherein the patients are PD-1 -- certainly PD-1 naive, right?
The other areas -- so beyond the data in which -- where in PD-1/CTLA-4 is already FDA approved, so non-small cell lung cancer, I'd say kidney cancer, you can very easily start seeing that in many of these settings. PD-1/CTLA-4 with a novel CTLA-4 that has got a greater efficacy bar could certainly improve upon the efficacy of PD-1 in this space.
And it is important to keep in mind that in many of these diseases, for example, certainly in renal cell carcinoma, it is certainly thought that the CTLA-4 efficacy was lower than expected. Now why that might be the case? We don't quite know, but it's certainly possible that this is -- these are diseases melanoma, kidney cancer, microsatellite high colorectal cancer, wherein it's going to be very advantageous to try to stack.
But one of the very important things that I think Marty brought up is also the idea that you really want to be getting patients who are PD-1 naive. And therefore, the standard dogma of drug development, which is to go as late as possible and then move the drug forward is really being appended right now wherein you can really do these smaller niche trials and studying the drug in a perioperative landscape to try to get a signal in a PD-1 naive patient population. And really, that potentially is very efficacious because there is no CTLA-4 inhibitor outside of melanoma -- ipilimumab melanoma that is approved in the adjuvant landscape.
So you did have a PD-1/CTLA-4 combination and you study that in a perioperative setting, your control arm would be something that you do not have to compare the standard of care could be easy to beat if there is provocative data for the combination. So I think short answer is lots of exciting data, the areas that I would be thinking would be very interesting would be areas where CTLA-4 is already in the frontline setting, but could be extended in the perioperative setting, in the PD-1 naive setting, and that will be melanoma, non-small cell lung cancer, and certainly, potentially tumor types like head and neck carcinoma, wherein there are certainly signals for PD-1 and the perioperative setting are very hot in all of these areas.

Stacey J. Davis

Thank you. There's one more thread to pull on here, Dr. Davar, which is if you thought beyond combinations with PD-1 or PD-L1, are there other molecules or other MOAs that you think would be interesting or important to study with XTX101?

Diwakar Davar

Yes, absolutely. I think that firstly, checkpoint is we're really at the very early aspect trying to unpack all of these potential combinations, right? When you start thinking of what the biology of CTLA-4 is doing, really, you're priming. You're reducing TREGs and you're priming.
So there are two sort of main areas that you think could be potentially efficacious. The first is to combine it with an agent wherein priming is important. So for example, if you've got a CD3 bispecific, that's a T cell bi-engager. These are drugs from companies like Immunocore. The drug would be (inaudible), which is the first CD3 bispecific that is FDA approved in this case for uveal melanoma.
Now the drug has got very minimal single-agent efficacy tends to be associated with improvement in overall survival and ctDNA reduction and suddenly better than the comparator, which is chemotherapy. But single agent efficacy of the drug certainly could be improved is modest. And this is an area where potentially a combination will be very exciting.
The other class of drugs beyond the CD3 bispecifics where you could potentially see some mechanisms of action very interesting would be to combine it with agents that are known to have synergistic effect upon TREG depletion. So for example, looking at agents that are either administered in cold tumors, such as uveal melanoma into the liver directly or agents such as oncolytic viruses that are being used to prime cold tumors, such as intrahepatic administered RP3 from Replimune. These are all agents that were in a priming agent that works on TREG depletion but also CD4 priming could be very important to augment the efficacy of these novel agents. So I think the [test] classes certainly CD3 bispecifics and also agents that are involved in oncolytic viruses and agents that involve in APC priming such as TLR agonists.

Stacey J. Davis

Thank you. The next question is going to go in a slightly different direction, and this is going to be directed to Rene.
If we take a step back and look at the long-term opportunity for XTX101, how are you thinking about the collaboration with Roche and how does this fit in with our overall partnering strategy?

Rene Russo

Thanks, Stacey. So I think, first off, we want to express how excited we are to have this collaboration with the Roche team. And if you think about everything that's just been discussed here today, it's clear that the unmet need in MSS CRC is significant and that a combination of XTX101 with atezolizumab really represents new potential for these patients that we feel is extremely important to explore. Particularly in the sub group with liver metastases.
But beyond that, as we just heard from Dr. Davar, there are numerous additional tumor types and additional mechanisms and molecules that likely makes sense to combine with XTX101. And what we think the best way to approach this to be able to explore all of these different applications where XTX101 may have an important role to play, will be through collaborations. So we're very excited about this first collaboration with Roche, and we will be actively exploring areas where additional collaborative programs make sense for the molecule.

Stacey J. Davis

Thank you. And I think we have time for just one more question, and we're going to direct this one to Uli.
Uli, there's a lot of activity and excitement about progress in the CTLA-4 space overall. Can you help us understand how you're thinking about XTX101 in the terms of the competitive landscape versus other molecules that are in development?

Uli Bialucha

Yes. I think great question. I think if you go back to where the field started with ipilimumab, the two big things that we learned were, first, that increased dose demonstrated improved efficacy. But secondly -- but the higher doses, such as 10-milligram per kilogram are not really tolerable. So I think we've consistently seen a [dissenting] toxicity that's associated with the first generation that is still a limitation. But I think as the field is advanced, there are molecules now in development that clearly aim to improve upon that, mostly on potency through, for instance, the Fc enhancement. And I think one example there would include molecules like Agenus molecule that we spoke about earlier.
But with these types of unmasked molecules, they're still systemically active. So we would expect that toxicity could still be a challenge, particularly with molecules as they getting studied in ever larger study cohorts. And on the other side, more addressing the toxicity associated with those first-generation molecules, there are various approaches to conditional activation that are currently being explored.
In some cases, people are trying to use conditional activation via pH-sensitive switch. But at least from what we've seen to date there, data on the molecules using that approach they've not really achieved an optimal outcome.
And so the other cases where we have molecules that are trying to use the protease mediated switch, I think that is starting to look more promising. There are a few in development that use that approach. One of the examples I think is one of EMS' CTLA-4 molecule that currently remains in development using CytomX technology.
And it was actually -- it's interesting, it was announced earlier this year that BMS was discontinuing two of those three molecules that were part of this arrangement, which included the masked version of ipilimumab, which, of course, lacks the TREG depleting MOA. And they also discontinued the unmatched non-fucosylated version of ipilimumab, which we would think would face toxicity challenges as an unmasked molecule.
The remaining molecule that's moving forward, I think it's [BMS-986288], which is advancing now into Phase II, it's a masked non-fucosylated version of ipilimumab. And so this molecule in some regards is really the closest in design to what we are doing with XTX101. But we have to remember that it is still ipilimumab at the core. So we believe the potency of that molecule is not really fully optimized.
So then maybe lastly, as we noted earlier, we designed XTX101 to optimize both the potency and peripheral safety, including the design criteria for low-level activated drug in the periphery, around 10%. So with the optimized Cmax that we've been talking about, we've been able to achieve through the Q6-week dosing, but we believe that in XTX101, really a molecule with best-in-class potential.

Stacey J. Davis

All right. Great. I think that's going to wrap us up for Q&A today, and I'll turn it back to the operator to close this out.

Operator

Thank you, everyone, for joining us today. As a reminder, the replay will be available on the Xilio website following the conclusion of the event. And with that, you may go ahead and disconnect your line.