Good morning, and welcome to the Faeth Therapeutics virtual event. At this time, all attendees are in a listen-only mode. A live question-and-answer session will follow the formal presentations. To our covering analysts, please use the raise hand feature to be added to the queue. As a reminder, this call is being recorded, and a replay will be available on the company website after the event. I will now turn the call over to Anand Parikh, CEO and Co-Founder of Faeth Therapeutics. Please go ahead, Anand.
Good morning. I am Anand Parikh, CEO and Co-Founder of Faeth. Thank you for joining us for this important milestone in Faeth's history. Today, we are very pleased to present phase II data for PIKTOR in advanced endometrial cancer. Before we start, today's presentation includes forward-looking statements. Please see this slide and our SEC filings for the full risk factors. Here is the agenda for the next 30 minutes. I will share the headline results and frame the opportunity for PIKTOR, both broadly and in endometrial cancer. Dr. Debbie Chirnomas, our Chief Medical Officer, will cover the disease, the trial design, efficacy, and safety. Then Dr. David Starks, the Principal Investigator on PIK-201, will join for a guided Q&A on what these results mean for patients in the clinic.
I will then conclude the prepared remarks with a review of the data and upcoming company milestones, and then we will open for questions.
Let me start with high-level takeaways. At Faeth Therapeutics, we are developing multi-node inhibition of crucial cancer pathways, beginning with PI3K/AKT/mTOR, or the PAM pathway. Today, we are announcing a significant leap forward for our first program, PIKTOR, in endometrial cancer. First, PIKTOR is now the leading oral PAM pathway inhibitor to show evidence of durable activity in endometrial cancer, the deadliest of all gynecological cancers. Second, efficacy. PIK-201 delivered a 33% confirmed overall response rate and a disease control rate of 83% in all evaluable patients. Among patients with PIK3CA mutations, with or without concurrent PTEN loss, the response rate was 44% and DCR 81%. In all patients, median PFS, a Kaplan-Meier estimate, is seven point four months. This is nearly double what would be expected from standard of care chemotherapy rechallenge and is as good or better than second-line options, including ADCs and pembrolizumab lenvatinib.
This is despite a more heavily pretreated population and a still maturing dataset. Third, tolerability. Treatment-related discontinuations were just 5%. The two toxicities that have held this entire drug class back, hyperglycemia and stomatitis, were 12% and 21%. At grade three, one patient each. Other agents in this class routinely require anti-diabetic drugs or steroid mouthwash prophylaxis. We use neither, and in a patient population that is about as metabolically challenging as it gets. Finally, phase III. Plans are now underway for a pivotal trial, and we recently completed a Type B meeting with the FDA. We also believe PIK-201 de-risks our aspirations to test PIKTOR in breast cancer, for which the phase I-B PIK-101 trial is ongoing. Why do we believe endometrial cancer is the perfect proving ground for our multi-node approach?
Endometrial cancer has the highest incidence of PAM alterations, but there's never been an FDA-approved treatment for the PAM axis. In the bar chart to the left, you can start to understand why. Only a small percentage of patients carry an isolated single PIK3CA mutation, which could, in theory, be treated with a single-node PI3 kinase inhibitor. However, PI3 kinase is involved in a majority of endometrial cancer patients, but most carry concurrent pathway mutations downstream of PIK3CA, which generally cannot be addressed by single-node inhibitors. We believe multi-node inhibition is the solution for all of these endometrial cancer patients. Full suppression of the pathway and elimination of the escape routes, that's how we designed PIKTOR.
As you can see from the figure on the right, PIKTOR consists of two drugs, serabelisib, an alpha-selective PI3 kinase inhibitor, and sapanisertib, an mTORC1 and two inhibitor, dosed in combination to fully disable the PAM pathway. With this slide, I want to quickly highlight that we are targeting large markets, starting with presenting data for endometrial cancer this year and breast cancer next year. Based on the clinical evidence to date, we believe that PIKTOR has potential in other indications as well. But today, the focus is on endometrial cancer with PIK-201. With that, I'll hand over the reins to Dr. Debbie Chirnomas. Debbie is a friend, a wonderful oncologist, and our Chief Medical Officer. She joined us from Arvinas, where she led oncology clinical development, and before that, she held clinical development roles at Gamida Cell and Pfizer, and she was on faculty at Yale.
Debbie has run PIK-201 from the start. Debbie, over to you.
Thank you, Anand, and good morning, everyone. I'm Debbie Chirnomas, Chief Medical Officer at Faeth. Thank you for joining us. Over the next several minutes, I'll cover four topics: why the PAM pathway matters in endometrial cancer, how we designed PIK-201, and the efficacy and safety top-line results. These data are still maturing, and I'll be clear about what is still developing. Next slide, please. Endometrial cancer is the most common gynecologic cancer in the U.S., with about 68,000 cases a year. Unlike most cancers, over the last decade, the incidence is up 26% and mortality is up 36%. It is now the deadliest gynecologic cancer for women with metastatic disease. Five-year survival is only about 20%-25%, and there are no approved targeted therapies. Chemotherapy is still the backbone, with very limited second-line options.
It's also a deeply metabolic disease tied to obesity and diabetes, which is exactly why our approach is so compelling. The biology speaks for itself. 80%-90% of these tumors carry a PAM pathway alteration, with no approved agent targeting that pathway. We will touch base on why that might be a little bit later. This is a large, growing, underserved population where we think we can make a real difference. Next slide. Endometrial cancer can be divided into two main groups. About 80% are endometrioid endometrial cancer, hormone-dependent, estrogen-driven, ER/PR positive, and the PAM pathway is altered in over 80% of cases. That's the population we are targeting. The other 20%, serous and clear cell, tend to be not estrogen-driven, often are P53 mutated, and rarely carry PAM alterations. By focusing on endometrioid, we go exactly where the biology and our mechanism line up.
While the subject of today's call is our endometrial program, I do want to highlight that the same crosstalk, as you can see on the right, between the PAM pathway and estrogen signaling that we also see in breast cancer. Therefore, we believe these data incrementally de-risk our ongoing development of PIKTOR in breast cancer. Next slide. This is a quick overview of the treatment landscape for advanced endometrial cancer. First-line therapy consists of carbo/Taxol plus immunotherapy. That's pretty much it. In second line, the only approved therapies include pembrolizumab plus lenvatinib and single-agent chemotherapy, like paclitaxel. Luckily for patients, ADCs are coming, but they are not here yet. It's important to remember that even though the ADCs, there are quite a few of them, the TOPO- 1 payload may unfortunately limit them to only one ADC.
If you look on the bottom, if you include the recent phase III data from TroFuse-005 that read out at ESMO, the benchmark for second-line therapy is a median PFS of seven months. That includes pembrolizumab plus lenvatinib at seven point three months and sacituzumab tirumotecan at seven point two months, compared with three point eight months for weekly paclitaxel. We are studying PIKTOR in the second line and beyond setting, and as ADCs move earlier, we believe an oral targeted option could offer physicians a meaningful alternative. Next slide. PIK-201 is an open-label, single-arm phase II conducted in partnership with GOG. We enrolled patients with advanced endometrioid endometrial cancer and a PAM pathway alteration who had progressed after platinum chemotherapy and a checkpoint inhibitor. Patients received sapanisertib three milligrams and serabelisib 200 milligrams once daily, three days on and four days off, alongside standard weekly paclitaxel.
We are reporting on 42 patients who have been treated on study. The primary endpoint is overall response rate, and key secondary endpoints include PFS, CBR, DOR, and overall survival. Next slide. Here are the demographic data. The median age was 65. Over a third of participants had more than two prior lines of therapy, and 12% had four prior lines. All patients had at least one prior taxane, and 38% had more than two. 98% had prior immunotherapy, and 10% had a prior ADC. Nearly half the patients had diabetes or pre-diabetes, and the median BMI is 29, indicating that most patients were overweight or obese, and 76% had distant metastases. These are heavily pre-treated patients, and approximately a third of whom, based on publicly available criteria, would not have been eligible for TroFuse-005. Next slide.
Here is the waterfall plot showing the best percent change in the 36 RECIST evaluable patients. As of the October 30 data cut, the confirmed objective response rate is 33%, or 12 of 36 patients. We also had a single patient with an unconfirmed partial response that had clinical progression prior to the next scan. The disease control rate is 83%. The black diamonds denote patients who are still on study. Seven patients with stable disease remain on treatment, and these patients could deepen their response over time, as we have seen in several of our current responders. Next slide. Here's the same waterfall plot split by PIK3CA status. Patients with a PIK3CA mutation are shown on the left and have an overall response rate of 44%. Patients with wild type are shown on the right.
We see confirmed responses in both groups, which is what you would expect with multi-node inhibition. These are small numbers, so we'll continue to follow, and we're just showing today the breadth of activity, which may be relevant for breast cancer, in which primarily there are PIK3CA-only mutations. Next slide. Here is the swimmer plot showing the duration of treatment for all 42 patients. The 36 efficacy evaluable patients are shown in green. The six patients who are not efficacy evaluable are in maroon at the bottom of the plot. The green arrowheads mark the 16 patients who remain on treatment at the time of the data cut. Several patients have been on study well beyond a year, and median duration of response has not been reached. Later, Dr. Starks will describe a patient whose disease converted from stable disease to a partial response after 20 months on therapy.
That is the very top line. We have seen late conversions of this kind in other patients, which may be consistent with PIKTOR's mechanism of action. Next slide. The spider plot shows the change in target lesion over time for each of the 36 evaluable patients. Below the - 30% dashed line means the tumor shrinkage met the threshold for a response. Two things to note. The responses are deep. Several patients' tumors shrank by more than a half, and in two patients, the target lesions disappeared completely. Responses last. Many patients are on study well beyond a year. Look at the line running all the way out to the far right. That is the patient we'll describe later. Her disease was stable for well over a year and then crossed into a partial response at about 20 months. She is still on treatment.
Most patients with stable disease, the yellow lines, stayed below the baseline. Next slide. Progression-free survival is a key endpoint in this setting. In the 42 safety evaluable patients, the Kaplan-Meier estimate of median PFS is seven point four Months. The lower bound of the 95% confidence interval is five point three months, and the upper bound can't yet be estimated because the data are still maturing. 62% of patients were progression-free at six months. These are preliminary estimates, and the curve is still maturing. The tick marks represent patients who remain on study. As a reminder, the median PFS with single-agent paclitaxel in this setting has been about three point three to three point eight months. Next slide. Circulating tumor DNA, or ctDNA, may provide an early indication of treatment activity. This approach has not yet been established in endometrial cancer, and therefore, this is an exploratory activity.
17 patients are shown here with paired ctDNA samples at baseline and at the start of cycle two. Tumor fraction decreased in 13 of the 17 patients, and by 50% or more in 12. In the patient David Starks will discuss, the ctDNA became undetectable by cycle two, though the radiographic response emerged many months afterward. This pattern is consistent with early target engagement, and we will continue to follow. Turning to safety, this slide shows the treatment-related adverse events in all 42 patients, irrespective of attribution to individual study drugs, including paclitaxel. The most frequent events were nausea, fatigue, and diarrhea, most of them grade one or two. Neutropenia was the most frequent grade three or higher event at 26%, and there were no cases of febrile neutropenia. PIKTOR is given in combination with paclitaxel, and these rates reflect that triplet combination.
The liver enzyme elevations are shown in the box on the right. Among the elevations that investigators attributed to PIKTOR alone, ALT grade one or two was elevated in 7% of patients, and 7% had grade three or higher. For AST, the rates were 2% for grade one and two , and 7% for grade three or higher. There are no Hy's Law cases and no drug-related deaths. This slide places PIKTOR alongside relevant comparators in the endometrial and breast cancer space. These comparisons come from different trials with different patient populations, study designs, and adverse event definitions, so they only provide context and not a head-to-head comparison, but more of a landscape of the adverse event profiles across these diseases.
In the center of the chart are the safety data of the most recent phase III results in second-line endometrial cancer, lenvatinib plus pembrolizumab and sac-TMT, which is TroFuse-005. All the way on the right are the PAM pathway drugs, two of which are approved in breast cancer, capivasertib and gedatolisib. We are showing these as a way to provide context for PAM pathway drugs, given that there are none in the endometrial space, and that is mostly because of tolerability. Along the PAM pathway-related safety events, hyperglycemia occurred in 12% of patients, at the lower end of the range shown. Stomatitis occurred in 21%, and our patients do not receive prophylactic steroid mouthwash. The discontinuation rate for treatment-related adverse events was 5%.
Historically, hyperglycemia has limited the use of PAM inhibitors, and single-node PI3K-alpha drugs report roughly 40%-70% hyperglycemia, usually in trials that excluded patients with poorly controlled diabetes. In PIK-201, we enrolled patients with a hemoglobin A1C of up to eight and a fasting glucose with a limit of 160. Nearly half of our patients had diabetes or pre-diabetes. We deliberately used these broad eligibility criteria so that the trial would reflect the real-world patient population. As mentioned earlier, with all of that, we saw hyperglycemia in 12% of patients, with a grade three event in one patient. Here we look at the rates of stomatitis in both PAM pathway inhibitors in breast cancer and in an ADC study in endometrial cancer. Both GDC-0077 and sac-TMT used steroid mouthwash prophylaxis and reported rates of over 50% all grade and 10% or more grade three stomatitis.
In PIK-201, we did not use steroid mouthwash prophylaxis, and we have seen one case of grade three stomatitis. Next slide. Here is how our PIK-201 data compare relative to paclitaxel re-challenge, which is a standard of care treatment in the advanced endometrial cancer setting. These contemporary data give us confidence that we can succeed in a randomized trial against a control arm that would likely include standard of care paclitaxel re-challenge. As you can see, our preliminary median PFS was seven point four months compared to paclitaxel three point eight months in TroFuse, and in an [audio distortion] study, three point three months. Next slide. Looking at early phase studies in cross-trial comparison, the PIK-201 phase II data look encouraging relative to ADCs and other PAM pathway inhibitors. We are seeing response rates and durability in the same range as the ADCs, with a completely orthogonal mechanism of action.
Patients with advanced endometrial cancer desperately need new treatment options beyond the ADCs. We believe PIKTOR could offer a meaningful differentiated option. Next slide. To summarize, PIKTOR plus paclitaxel showed a 33% confirmed objective response with a median PFS of seven point four months in a heavily pre-treated population. Responses were seen across all molecular subgroups examined, and specifically in the PIK3CA altered and wild-type tumors. PAM-related adverse events that have historically limited this class, particularly in the endometrial cancer space, include hyperglycemia and stomatitis, both of which occurred at low rates in our study, even though nearly half of our patients had diabetes or pre-diabetes at baseline. Few patients discontinued for adverse events, and there were no treatment-related deaths.
PIKTOR is an oral regimen with a completely different mechanism of action from the ADCs in development, in a disease with no approved PAM pathway agents, even though it is the most commonly altered pathway in this cancer. As I stated at the beginning, these data are still maturing. Many patients remain on treatment, and we have seen late responses, and median duration has not yet been reached. Next slide. It is now my pleasure to introduce Dr. David Starks. Next slide. Dr. Starks is a gynecologic oncologist at Avera Cancer Institute in Sioux Falls, South Dakota. He is the Director of Research at Avera and the Associate Professor of Medicine at the University of South Dakota. He is the Principal Investigator on PIK-201. He was also the lead author of the phase I dose escalation study of this regimen.
Dr. Starks trained at Michigan, Case Western, and the Cleveland Clinic. David, thank you for joining us.
Thank you. It's a pleasure to be here.
Can you walk us through your history with PIKTOR? You were actually the one with the initial idea to combine PIKTOR with paclitaxel, and you served as the first author on the dose escalation study publication. What was the rationale for combining these three drugs?
Sure. Our initial involvement was in collaboration with Takeda, who had the PIKTOR combination at the time. They had preclinical data in both cell line and mouse models demonstrating the additive effect of the combination of the oral agents compared to either alone. We had internal translational data suggesting that combining PIKTOR with weekly Taxol could re-sensitize resistant tumors to a taxane, and this was allowing for a significant increase in anti-tumor effects. We started a single-site investigator-initiated trial. It was a phase I dose escalation study evaluating PIKTOR and Taxol in solid tumors. This study took place prior to immunotherapy being adopted as a frontline therapy. We enrolled 19 heavily pre-treated patients and demonstrated an overall response rate of 47%, which included three complete responses, all in the heavily pre-treated endometrial cancer patient cohorts.
This led to an interest in pursuing this combination for our endometrial cancer patients, and that was the genesis of the current study.
Can you tell us a little bit more about the unmet need in endometrial cancer, particularly in patients who have relapsed or have refractory disease after treatment with chemotherapy and IO?
I think I would say that if you're an endometrial cancer patient, there's both bad news and good news. The bad news, as we heard, was that this is the fourth most common cancer in women, and sadly, the incidence and mortality is increasing. The good news is, compared to when we conducted our phase I study, there was a dearth of treatment options at that time. There's been an explosion of interest in studying much-needed new treatments for these patients. Clearly, we have excellent first-line options with frontline immunotherapy, especially for endometrial cancer patients who are dMMR. But with IO moving to the frontline for those patients who are pMMR, those patients who fail to respond to first-line therapy or develop recurrence, management options quickly become constrained. The five-year OS, as we heard, for advanced or recurrent disease is 20%.
Obviously, the data from TroFuse-005 is very exciting and will offer a tool for management of recurrent disease, and there are other ADCs being evaluated in this space as well. I think it is important to say that we are not curing patients with ADCs, and with the interest in moving ADCs into earlier settings, I think there remains a substantial opening for novel treatments in the recurrent setting.
What are some of the challenges that patients with advanced endometrial cancer face with respect to their comorbidities? Can you speak a little bit about sort of how healthy or not they are?
Sure. At baseline, these endometrial cancer patients are a challenging population to treat and manage. These patients are obese and have associated obesity-related conditions like type 2 diabetes, chronic hypertension, and heart disease. As an example, there was an old study called the ASTEC study, which was designed to study the role of pelvic lymph node dissection and surgical staging. But one of the things that they noted, of the patients who died on that study, 50% of the deaths were related to patient comorbidities and not to their cancer. Added onto this unhealthy patient population is the reality that these patients are heavily pretreated and now have a depleted bone marrow and diminished reserves for dealing with common treatment-related side effects such as nausea, vomiting, and diarrhea, which can quickly lead to dehydration and acute kidney injury, as just one example.
Any study that has patients like this enrolled is going to have to aggressively support these patients to minimize toxicity and help them maintain a reasonable quality of life.
Can you walk us through your experience with PIKTOR in the PIK-201 trial? Do the responses tend to occur shortly after treatment, or do they tend to deepen? Any thoughts on why that might be?
We've enrolled eight patients to the study so far. Six patients are still on active treatment. One of the patients, as we'll talk about, is approaching almost two years of treatment, and we have several that are approaching the one-year milestone. We have seen both early responses as well as delayed responses, and I think that that may be indicative of the mechanism of this combination, along with taxane. I would note that side effects have been manageable, and overall, the PIKTOR-Taxol combination is well tolerated. I think it's important to say that patients do not stay on a therapy for one to two years if they are miserable and have a poor quality of life. So, I think that the duration of treatment in some of the patients we are seeing is a testament to the tolerability of this regimen.
Thank you, David. Maybe we can move now to hearing a little bit more about your patients. Why don't you tell us about this first patient?
Yes. This was a patient that's been alluded to previously. This is a 53-year-old female. She initially had a stage IIIA endometrial cancer, and she had no favorable markers for immunotherapy. She was initially diagnosed in 2018, at the time of surgery. This was followed by treatment with carbo/Taxol and whole pelvic radiation therapy. Because this was 2018, IO was not frontline standard management at this time. She developed a recurrence in 2024 in a previously radiated nodal bed, which is a poor prognostic finding, as these tumors are more difficult to treat since you can't re-radiate them, and the tumor environment has poor vascularization, making it harder to deliver drug to the tumor. This recurrence was PET and biopsy confirmed. The patient was treated at this point with carbo/Taxol and immunotherapy, with persistence of the disease at the end of the treatment.
She was started on PIKTOR-Taxol and has been on study now for almost two years with stable disease, although she had a recent conversion to a partial response as evaluated by RECIST. Of note, and as was kind of referred to before, this patient's ctDNA became negative at the start of cycle number two, and a subsequent PET scan, which was obtained for clinical indications, is negative for disease activity in the involved nodal bed. In fact, as an aside, the radiologist who was doing her most recent read commented to me that this node is dead and probably has been for a while, but per RECIST, she is currently only a PR. The patient has overall found the current regimen to be well tolerated after some initial issues with fatigue, diarrhea, and nausea, early on in the treatment course, but now these are all very well controlled.
In her own words, quote, "I'm on cruise control," and she has been for almost two years.
Thank you. Maybe we can talk a little bit about your second patient that you wanted to share with us.
Yes. Patient number two is a 60-year-old woman. She initially had stage IVB disease at the time of presentation and had such a significant tumor burden that she was not operable or able to be taken to surgery, which would usually be the standard management. She was treated upfront with carbo/Taxol and immunotherapy in a neoadjuvant fashion, with the hope of shrinking her disease and rendering her operable. Of note, she had favorable markers for immunotherapy response, with her tumor demonstrating both MSI-high and TMB-high features. She responded well enough to treatment that she was able to go to surgery, although on her final pathology, residual disease was still found on her gynecologic organs as well as the surrounding tissues from the pelvis, including her colon.
She was subsequently treated with whole pelvic radiation therapy to try and control the pelvis and continued on immunotherapy maintenance, but she progressed three months after completion of her radiation therapy. The aggressive nature of the tumor, I think, is quite clear. She started on everolimus and letrozole and had disease control for about seven months, but ultimately progressed in her chest and her upper abdomen with omental implants. She was then started on the PIKTOR-Taxol combination. We have representative images on these slides. On the top, we can see in the abdomen one of the representative upper abdomen omental lesions before, and then completely resolved as we go to the right. Similarly in the chest, we can see one of the chest lesions close to the heart, and then we can see that it has resolved on the right as well.
Overall, the patient has found the regimen to be well tolerated. She is a pre-diabetic and has maintained tight glucose control with diet management. Nausea, diarrhea, and peripheral neuropathy have also been manageable. She is another patient who has had a long treatment duration while still maintaining a reasonable quality of life.
Thank you, David. These are really encouraging stories. I will now hand it back over to Anand for closing remarks.
Thank you, Debbie, and thank you, Dr. Starks. To recap, we believe PIKTOR is now the first oral PAM pathway inhibitor to show evidence of potentially durable activity in advanced recurrent endometrial cancer, the deadliest of all gynecological cancers. Therapeutically, it is important to note that PIKTOR is in a lane of its own. Nearly every other late-stage program in this disease is a TOPO- 1 ADC. That is one mechanism, one payload class, and based on ADC exclusion criteria and prior physician experience, the belief is that TOPO- 1 ADCs, like those in development in endometrial cancer, can only be given to a patient once. We have heard from many oncologists who want a targeted option they can reach for instead.
Finally, with ADCs expected to move into earlier treatment settings, we believe there is a real value proposition for PIKTOR as an orthogonal mechanism of action, or alternatively, given our largely non-overlapping toxicity profile and distinct mechanism of action, potentially even combining with ADCs in the future. I will close with milestones. 2026 was a pivotal year for Faeth. We became a public company, initiated our PIK-101 trial in breast cancer, and today we presented top-line results from our PIK-201 trial in endometrial cancer. We are already working hard to ensure 2027 will be just as productive. In the first half of next year, we plan on providing you with regulatory guidance as to our plans for a pivotal trial in endometrial cancer, and we will also plan on presenting a mature PIK-201 dataset at a medical meeting in 2027.
Later in the year, we expect to report breast cancer data from our PIK-101 trial and begin study startup activities for our phase III study in endometrial cancer. Next slide. This is my last slide, which is a summary of our plans to de-risk PIKTOR development in a stepwise fashion, with the ultimate goal of unlocking the potential of PAM in multiple tumor types. We began with endometrial cancer, and our goal when we set out on the PIK-201 journey was to convince ourselves that the therapy was clinically active. We have done that today, and the ramifications go well beyond endometrial cancer. With these data in hand, we plan to prepare for a registrational trial next year. As for breast cancer, we expect to have data from PIK-101 by year-end 2027, and then expand into other indications where we already have clinical data.
Our goal is to finally unlock the promise of this pathway, which my co-founder, Lew Cantley, discovered many years ago, and across a variety of tumor types. This is an exciting moment for Faeth, and I want to thank the patients, the investigators, and our fearless employees who helped make this a reality. Thank you. Let's open it up for questions.
Thank you, Anand, and to all of our speakers. At this time, we will be conducting a live Q&A session. To our covering analysts, please use the raise hand feature to be added to the queue. Please hold for a brief moment while we pull for questions. Our first question comes from Tara Bancroft with TD Cowen. Please go ahead, Tara.
Hi. Good morning, and congrats on these great data. I guess I will ask maybe on safety. So grade three stomatitis looks fantastic, but I am curious if you would consider doing a prophylactic mouthwash to reduce the lower grade events even further. Just curious what you are hearing, like feedback on that, and how it compares to single-node inhibitors, or also on the GI tox and how impactful that is to patients, if at all, especially since hyperglycemia is typically the rate-limiting or the limiting AE. Yeah, just more on that would be great. Thank you.
Thanks, Tara. We appreciate the question. On stomatitis, I think we have a best-in-class profile, and I want to reiterate that that mouthwash is quite challenging for patients. It is four times a day dexamethasone mouthwash, cannot eat for an hour before or afterwards. At this time, given the low-grade nature of the stomatitis, we do not think there is any need for a prophylaxis, and we have not had a single discontinuation due to stomatitis. In terms of other AEs, I think a good thing to note is that we are on the background of paclitaxel, which obviously has its own toxicity profile, particularly with regards to some of the AEs that you noted. But overall, given the low rate of discontinuation, we think this is a really tolerable regimen. Dr. Starks, Debbie, anything you want to add?
I think the only thing that I would add from our site, nausea and vomiting has been very well controlled. I think we have made sure, I think just because we've had a little bit more experience coming from the phase I as well, I think we've just been very aggressive about making sure that patients are compliant with taking anti-emetics, particularly around the period of time that they're taking their oral drugs. I would say that we found it to be very, very manageable.
Great. Thank you.
Thank you.
Thank you, Tara. Our next question comes from Li Watsek from Cantor. Please go ahead, Li.
Hey, guys. Thanks for taking our question. Wanted to add our congrats as well. This one is for Dr. Starks. I wonder if you can just comment on the safety profiles of ADCs such as sacituzumab versus PIKTOR. Which one do you perceive is perhaps more tolerable for patients given some of the comorbidities that you discussed on the call? If you can touch on the stomatitis rates observed in the study, that would be great.
Certainly. Our site wasn't involved in the TroFuse-005 study, so I've only kind of the same information that you've probably seen in the reading. I mean, I can comment in general to antibody-drug conjugates. I mean, each of them sort of has their own unique kind of toxicity profile. I think it's just a safer way of delivering chemotherapy, but I mean, certain ones have ocular toxicity, some have problems with GI toxicity or nausea. I would say that I think the PIKTOR combination appears to be very well tolerated. I think side effects that have been kind of discussed earlier are manageable. Again, I think compared to some of the ADC trials that we are referencing, I think this is a sicker population. In some ways, I think compared to TroFuse-005, this is also a more heavily pre-treated population.
Our patients have had more lines of therapy than the majority of patients who are on TroFuse-005. I think when you're kind of It's a little bit like comparing apples and oranges, but I do think that we're seeing that this is very, very tolerable. I'll kind of go back to my other point. I mean, you have patients on for one to two years. People are not going to stick on something if they're miserable for that length of time, even if they're having cancer control. I do think that that is a testament to the fact that this is very, very manageable, and patients can have a very decent quality of life. I think, again, we kind of alluded to stomatitis and hyperglycemia for these patients were low.
I think ultimately, as Anand was kind of saying, I think if you do have a patient who develops kind of a grade one, grade two stomatitis, you can talk about then bringing in mouthwash for management. But I think doing it as more of a symptom management rather than prevention has worked very well for us.
Thanks, Li. Next question.
Thank you, Li. Our next question comes from Andrew Berens with Leerink. Please go ahead, Andy. Andrew, you may be on mute. All right, it looks like Andrew's having some technical difficulties, so we'll take the next question from Alethia Young with William Blair. Please go ahead, Alethia.
Hey, guys. Thanks for taking my question. Congrats on these data. They're quite interesting. I wanted to ask maybe two. One around, why do you think you've seen in some cases with stable disease response converts later? Is there anything you're kind of seeing with those tumors early on, like in transformation, and do you think anything about kind of the mechanism of targeting the PAM pathway? My next question is just maybe perhaps for the company and also for Dr. Starks just in general. Just thinking about these data and trying to read into how we should think about the upcoming breast cancer readout, what do you think kind of the core takeaways are when you're kind of heading into a full kind of oral, maybe set up more in breast than here with paclitaxel? Thanks.
Thanks, Alethia. In terms of the activity that we've seen and the translation to breast cancer, maybe I'll take that one and leave the other question for Dr. Starks and Debbie. In terms of the read-through to breast cancer, I think we're really excited. We look at a patient population in endometrial cancer that has a five-year survival rate of about 20%, which is far below what breast cancer patients typically see at about 50%. We think both for that reason and the fact that it's going to be a less comorbid population, that what we see here should not only translate, but potentially could be improved upon quite significantly in breast cancer. Remember also, we won't have the background of paclitaxel to work with.
We'll be working with different combination agents like CDK, fulvestrant, oral SERD, which I think generally are even better tolerated than paclitaxel. I'll leave the other half of your question, why we're seeing late responses, to maybe Debbie. Any thoughts, or Dr. Starks?
Yeah, I'll start, and then if David has anything to add, that would be great. Essentially, it boils down to the fact that the PI3K pathway is cytostatic. It's really related to cell growth. You have an opportunity for cells to be kind of kept in stasis, if you will, or kept stable, and allow the re-sensitization to taxane to take effect and work together. I think depending on the patient and their tumor and their tumor burden, that may end up taking a while. The other thing that perhaps Dr. Starks can comment on is sometimes the physical resolution of a lesion takes a little longer and shows up later, and we saw that in his patient who's been on for quite a while. David, I don't know if you want to add anything.
No, not too much more to add than that. Yes, I think especially that lesion in a radiated field, with the nodal area being dead, it's just harder for the body to resorb. Probably what we may end up seeing with that patient ultimately is that may continue to shrink a little bit, and then we'll see it get calcified, but never maybe fully resolve.
Thank you, Alethia. We'll now return to Andrew Berens with Leerink for the next question. Please go ahead, Andrew.
Hi. Can you hear me now?
Yes.
Great. Thanks for giving me a second shot at this. Congrats on the progress. Wondering if you can give us some color on the scientific rationale for combining PIKTOR and a TOPO-1 based ADC, and how you're thinking about different combination partners strategically, given this rapidly evolving space. I know you've provided some of this already, but can we get a little more color on mucositis? How long does it last, and how does it seem to compare to that seen with mTOR agents like everolimus?
Yeah, on the combination, or potential combination with TOPO- 1 ADCs, I think one thing that's really important to remember is that TOPO- 1 ADCs can generally only be given once, right? So, every patient that sac-TMT gets is a patient that Puxi-Sam or IMMU-132 will never see, because of TOPO- 1 exposure. We think that we can help ADCs, which are really targeted chemo. Since we've demonstrated tolerability with paclitaxel, we think, due to the lack of overlapping toxicity, we can really potentially help an ADC distinguish itself. Many of these ADCs are clustered around six to seven months PFS, and very similar response rates.
We think particularly as they move forward into first line, given there should be no reason that we would cause some resistance to an ADC, we think we can really help drag them over the line, and help them distinguish themselves. How we think about that strategic partnership is something that we'll talk about in the future maybe, but I can say that we will likely have some preclinical combination data at AACR on that particular topic. For the stomatitis resolution question, Debbie, do you want to take that?
Yes. Basically, all the cases were mild. There was one grade three patient who received treatment, but only two patients received treatment at all. Basically, most patients had only one episode. So, they were mild, resolved, and have not seen a lot of repeat, which is why David reiterated that using prophylaxis is not yet really indicated.
Great. Thank you.
Thank you, Andrew. Our next question comes from Jay Olson with Oppenheimer. Please go ahead, Jay.
Oh, hey. Congrats on these impressive results, especially in difficult-to-treat patients with such high unmet needs. We are curious about the 44% confirmed ORR in PIK3CA mutant patients. Combined with best-in-class tolerability, where could a pathway-directed regimen fit potentially in the frontline setting? Then maybe for Dr. Starks, what would make you favor that particular sequence in a patient with a known PAM alteration? Thank you.
Thanks, Jay. The PIK3CA subset did have a higher ORR, and we think that makes sense given the mechanism of action. It is important to remember that 80% of all endometrial patients have PTEN loss, so that PIK3CA activity is on the background of still significant PTEN loss. We think that investigators, or I should say physicians, when given the option, are really going to reach for a targeted therapy first, and that is a lot of the feedback that we have heard. It may be a case where in first line or in second line, physicians are going to reach for patients who have a PIK3CA mutation, which is approximately 50% of the patients. Then they'll reach for our regimen first, the ADC afterwards, and then for patients who don't, maybe they choose to go ADC first and then our regimen afterwards.
Again, as I noted earlier, unlike the ADCs, we think we're going to see all of these patients at one point or another, whether in first line or in second line. David, anything you want to add?
I mean, I think it's a really interesting question. I think you're kind of anticipating some of the things that we've been thinking about. I do think first line right now is dominated by IO, but I think maybe what you're alluding to, if you're a dMMR patient and you don't get a checkpoint inhibitor, I think that's borderline malpractice. But dMMR patients are not the majority of the patients who are going to be getting immunotherapy upfront. You've got the pMMR population, and I think that's the population that people are trying to address. So to your question, I think if we had a pMMR patient and you saw that they had an aberration in the PAM pathway, this could be something you would think about in the front line. But I mean, I think, again, we'd have to conduct a study to demonstrate efficacy in upfront treatment.
I do think, based on where some of this seems like it's going, that could become a very reasonable option. And I think the further we could put combination chemotherapy, IO for certain patients into second line, I think that would be a win.
Great. Thank you.
Thank you, Jay. Our next question comes from Jack Allen with Baird. Please go ahead, Jack.
Great. Thanks for taking the questions, and congrats on the data. I wanted to ask about the go-forward plan here. Any additional color you can provide as it relates to your thoughts on the design of the phase III study? What kind of patient population could you look at there? I know you looked at patients with two to four lines of prior therapy, which is a little bit more severe pretreatment as compared to what was studied in TroFuse-005. How are you thinking about potentially pursuing a more targeted patient population in the phase III trial?
Yeah. So we had our FDA end of phase II meeting November 3rd, actually. Still awaiting meeting minutes, but I think we have alignment generally on a potential go-forward plan, and we'll look forward to making an explicit announcement on that in the first half of next year, and hopefully initiating a registrational trial in 2027. We think that trial would have a chemo comparator arm with PIKTOR in an all-comers population. We obviously have to await the formal meeting minutes, but that's an exciting regimen. Debbie, anything you want to add there?
No, we are really looking forward to seeing if this can provide efficacy in a broader population and getting it out there.
Thank you, Jack. Our next question comes from Sean McCutcheon with Raymond James. Please go ahead, Sean.
Hi, guys. Congrats on the strong durability signal here. Can you maybe speak a bit more to the patients that were deemed non-responsive, evaluable in the dataset, and whether these patients would have been eligible for a subsequent phase III trial, maybe to the point of Jack's question? Then understanding the fraught nature of over-interpreting a PFS curve from a single-arm study, can you speak to the maturity of the PFS curve, sources of censoring, and the lower bound confidence? Currently, it looks like the lower bound sits right at the upper bound for the TroFuse-005 control arm, which looks promising. It would be good to get a sense for how the curve could evolve with longer-term follow-up. Thanks.
Yeah. Thanks, Sean. I am happy to hand that over to Debbie, but I think generally, we feel pretty good about the data, having seen that patients who have been on study for even longer, that the PFS estimates look very consistent within that group, gives us confidence the data will hold. Then in terms of the disposition of the patients who are not efficacy evaluable, I will hand it over to Debbie.
Thanks. Just regarding the KM curve stability, I would say that we are confident that we are in a stable place, although, of course, it could change. We are also encouraged by the 62% six-month landmark analysis, which gives us, again, some confidence, and the number of patients that we still have on therapy that we know will contribute. Regarding the patients who were unevaluable, three of them were rapid progressors. I do not think they would have been eligible for other studies, going to your question about phase III. Three patients had non-AE-related reasons for coming off, meaning one patient had a significant morbidity from her diabetes and needed a toe amputation that was somehow scheduled not correctly and needed to come off to really deal with that. Other patients have logistic or other issues. Those are difficult to know whether they would be eligible.
I think the fact that almost half of our patients have diabetes or pre-diabetes means that their ability to be fit for future trials will continue to be a challenge. I am glad that we can accommodate and treat, again, a real-world population.
Thank you, Sean. Our next question comes from Geoffrey Meacham with Citi. Please go ahead, Geoffrey.
Great. Thank you. Thanks for the question, and congrats on some great data. I wanted to get into the diabetic question. In this trial, and then in the breast study too, you guys have a population that is either diabetic or pre-diabetic. I guess the question is there a trend in efficacy between those patients and non-diabetics? Can you tie any of that into the mechanism or the risk of resistance, or even trends on the safety tolerability side as well? Maybe help us with kind of how you consider that as a factor looking to either the breast study going forward or a phase III design. Thank you.
Thanks, Geoff. Generally, if you look at our inclusion criteria, no contemporary PAM agent has taken patients this sick in terms of diabetes, with half of the patients being either diabetic or pre-diabetic. I am not sure we have ever seen that. We feel that showing a best-in-class tolerability profile on a variety of different counts, but particularly hyperglycemia, given the context of that population, really gives us a lot of confidence as we move forward into breast cancer, where patients do not have the same insulin-resistant profile. We are really excited about what it shows, and particularly as we go across tumor types and populations, we want this to be a treatment for everyone. I think this shows that it really can address the American and global population where they are. Yeah.
Great. Thank you. Our next question comes from Jonathan [audio distortion] in Needham. Please go ahead, Jonathan.
Hey, guys. This is Jonathan on for Gil. I wanted to add my congratulations on the data. Just a quick one from me. When we are thinking about the landscape for endometrial cancer, Debbie, I know you gave a comp with Len plus Pembro, but given that Pembro has moved to frontline, and ADCs are vying for the frontline, really, what do you think the landscape is going to look like, given that PIKTOR might be the only thing really in the second line?
Yeah, Debbie, go for it.
Thanks for the great question. It is kind of a soapbox of mine. I am shocked, especially compared to the breast cancer space, at how few options patients with endometrial cancer have. I think you said it beautifully. There is virtually nothing but single-agent chemo or made-up regimens that have no proven efficacy. I think the physicians that we have been working with, including Dr. Starks and the GOG physicians, are really excited about having something else to offer patients that really has a potential to work. I think it is a fairly, unfortunately, wide-open space. Unfortunately for patients.
Thank you. Our next question comes from Silvan Tuerkcan with Citizens. Please go ahead, Silvan.
Yeah, good morning, and congratulations on this great update here in endometrial cancer. My question is, we have been getting some questions on the paclitaxel, obviously, combination here. Could you just please repeat what the expectations were for the paclitaxel monotherapy in this particular enrolled patient population? Because we know that there are some real-world retrospective studies out there, like the ECHO-EU chart review study, that they reach sometimes response rates in the 30%, the six to seven month PFS. Why is this perhaps not a good benchmark, and why is it more like the more contemporary trials that you showed here? Thanks.
Yeah, I always enjoy this question. Thanks, Silvan, for it. I think if you were to ask most endometrial cancer docs, and the discussant at ESMO talked about this and mentioned that, "Look, with chemo, we see 10%-15% response rate, three to four months PFS." And they see it consistently. You might have an individual patient, of course, that can go to six to seven months, but I think pretty consistently across all the studies, whether it is TroFuse, our own arm study, any randomized clinical study, you are going to see a very similar result. This is something that has been seen again and again and again. I do not really think there is much doubt here anymore. I do not know, Dr. Starks, how you feel about this.
No, I would agree with that. I think you really have to take into account the retrospective nature of some of the things you were discussing. I think when you look at this as a comparator arm in a lot of different endometrial trials, the results are kind of roughly the same. I think just as a clinical aside, if we tell patients we're getting down to this point, we kind of let them know, we'll say, "You're going to be on this for maybe two to three months, and then we're going to have to be switching between single agents." That just is kind of, I think, the direction that things go until the patients are going to hospice, essentially. Not much excitement around single agents.
There's some patients who may uniquely have an interesting response, but that's not what we would counsel our patients about or suggest that that would be the expectation.
Let me maybe go a little bit off script here. Dr. Starks, how confident are you that PIKTOR is adding something on top of paclitaxel?
Well, I mean, yes, I think very, very confident. Again, I think when you've had patients before who've had a taxane in frontline, and if you're getting to the single-agent treatments, a lot of times we're looking for something that is not. Especially if Taxol was kind of in their prior line, you're going to be looking at people who are going to be looking at things, other single agents, whether it's Doxil or doxorubicin, or some of the other single agents that we've seen in some of the other cancer arms. It's not the thing you're going to be most excited to use because you're expecting that there's going to be resistance.
I think when you are noting that you've got this PAM aberration, I would say at least from our side, particularly with some of our experience, we're more than enthusiastic to get our patients on this, even if Taxol was in their prior line, just because of the results that we have seen.
Thank you. Our final question comes from Jeet Mukherjee with BTIG. Please go ahead, Jeet.
Hey, good morning. Thanks for taking the question, and congrats on the impressive data. Two from me. Understanding it's perhaps early, but just any comments or trends regarding overall survival you can speak to right now? Maybe for Dr. Starks, just as it relates to hyperglycemia, can you just speak to how it's managed across the various grades, and in what circumstances does it become concerning? Thank you.
Yeah, I think on OS, we're a little bit early, but obviously the PFS trends that we've seen, especially in comparison to sacituzumab with a 62% six-month PFS compared to 51% sacituzumab with potentially a good trend for sacituzumab and Trodelvy, give us hope that we'll eventually see that, and that is something that we're tracking. Debbie, anything you want to add there?
No, I think that's right. The data are quite immature with respect to OS, so we'll be monitoring closely.
Yeah, Dr. Starks, on hyperglycemia management.
I think as we alluded to, a lot of the patients that we were letting on this study, we were allowing for a much higher hemoglobin A1C. We'd been involved with a previous PI3K agent before, and they had a hemoglobin A1C cutoff at six. I mean, we literally, we could not get any patients on that study from an endometrial population. It just was an unrealistic cutoff. Patients can't be on insulin, obviously, with this treatment regimen due to the mechanism. Metformin has been one of the drugs that we have used for management. Obviously, there's kind of a change in diabetes management in general with GLP-1 agents. We didn't have a ton of patients, at least at our site, and Debbie could maybe talk more about the entire study, but who have needed GLP-1s.
I do think that diabetic management is obviously a changing kind of paradigm as well. Obviously, I think if patients are demonstrating hyperglycemia that would be out of control, and I think the one patient that was alluded to that needed the toe amputation, maybe perhaps a more ruthless kind of screening would have prevented that patient from coming on at all. But if patients, at least on a study, are having that kind of level of poor diabetes control, they have to come off study. But I think overall, we've found, again, the hyperglycemia rates have been very low, and we have not had to do kind of excessive management or support to attain that.
Thank you for your questions, Jeet, and to all of our analysts. I will now turn it back to Anand to close out the call. Thank you.
Thank you. We are incredibly excited by this data. We think that it really demonstrates the activity of PIKTOR in endometrial cancer and augurs incredibly well for breast. I just want to say thank you to Dr. Starks, to all of our investigators who have helped us get to this point, our employees, and the patients. We are very excited about the future for Faeth, and we will look forward to sharing an update from this data in the near future as well. Thanks, everyone.