Good morning, everyone, and welcome to Leap Therapeutics TRX518 Clinical Perspectives conference call. Following the presentation, there'll be an opportunity for questions. Please be advised that this call is being recorded at the company's request. At this time, I'll now turn the call over to Mary Jenkins of Argot Partners. Please begin.
Thank you, Nicole. Welcome, and thank you for joining us today for Leap Therapeutics TRX518 Clinical Perspectives conference call and webcast. I'm Mary Jenkins with Argot Partners. With me today are Dr. Christopher Mirabelli, Chairman, President, and CEO, Douglas Onsi, Chief Financial Officer, and Dr. Cynthia Sirard, an Oncologist and Vice President of Clinical Research and Development. This call is being accompanied by a slide deck. I'll ask you to please turn to our forward-looking statements on slide two. Before we begin, I would like to remind you that any statements made during this call that are not historical are considered to be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995.
Actual results may differ materially from those indicated by these statements as a result of various important factors, including those discussed in the Risk Factors section in the company's most recent quarterly report on Form 10-Q, as well as other reports filed with the SEC. Any forward-looking statements represent our views as of today, December 17th, 2018 only. A replay of this call will be available on the company's website, www.leaptx.com, following this call. Now please advance to slide four. I'm pleased to turn the call over to Dr. Cynthia Sirard, Leap's Vice President of Clinical and Research Development.
Thank you for your attendance today. We would like to build upon the TRX518 clinical experience to date, including an update on some of the monotherapy patients where we've demonstrated safety and tolerability with benefit in about 55% of the patients who are heavily pre-treated. In addition to building upon the monotherapy data, we will also present some data in combination with anti-PD-1 therapy, including nivolumab and pembrolizumab, where we've had a confirmed complete response with a patient with esophageal squamous cancer. In addition, a confirmed partial response in a patient who had seen prior anti-PD-1 therapy and was able to re-respond to a PD-1 plus GITR agonist combination therapy. In addition, we'll describe some data in combination with gemcitabine, where we've demonstrated meaningful clinical benefit in patients with heavily pre-treated malignancies, including patients with pancreatic or biliary tract cancer.
I will let the two speakers go into much more detail as it relates to all of these patients, and I would like to introduce those speakers at this time. We will be hearing from Dr. Jason Luke, an assistant professor of medicine at University of Chicago, as well as Dr. Todd Bauer, who is at Tennessee Oncology and Sarah Cannon Research Institute. With that, we'll turn the call over.
Hello, this is Jason Luke from the University of Chicago. Thank you for the invitation to speak today on the clinical development of TRX518, an anti-GITR antibody as an immunotherapeutic for cancer being developed in combination with other immuno-oncology agents as well as chemotherapy. Today, I'm going to discuss the data as developed to date around the clinical development of this molecule in combination with both pembrolizumab and nivolumab and what appears to be some early interesting data that really could act as a springboard to bring this development program forward. Before I begin, it's important to point out my disclosures, which are listed here. From there, we'll move on to discussion of GITR as a therapeutic target and TRX518 as a monoclonal antibody directed towards that target.
GITR, sometimes called the tumor necrosis factor receptor superfamily member 18, for those who are checking, is a very interesting immuno-oncology target. It was originally discovered in the context of T-regulatory cells, in animal models, with a thought that perhaps similar to FOXP3, it may be a diagnostic marker. Subsequent to that, it's now been identified as a marker that's turned on in the context of T-cell activation and therefore has become increasingly of interest as a potential means to boost T-cell activation, perhaps in the context of cancer immunotherapy to drive subsequent therapeutic effect. I think this is a very important point when we think about the clinical utility of developing an anti-GITR antibody, and especially TRX518, is that there's a potentially dichotomous mechanism of action.
You can see on this slide that TRX518 has the potential both to deplete Tregs via stimulation of GITR in that population. Importantly, it also has the potential to stimulate T effector cells to be even more powerful. Here I would note some specific engineering that's relevant to the TRX518 molecule, which is the aglycosylation of the antibody. We don't have time to get into the details of antibody engineering here, but suffice it to say that aglycosylation is an important feature in that it limits the antibody-dependent cell cytotoxicity, or ADCC, properties of an antibody. This is a complexity I think that's important as we think about the whole field of agonistic antibodies for cancer immunotherapy, where many of them have retained ADCC and perhaps not been as effective as we have hoped.
That may, in fact, be because they're having a deleterious effect on effector T cells. Here, we're hopeful that by not having an ADCC component, we're able to drive the activity of T effector cells to attack tumor cells, as is noted here, while simultaneously depleting immune inhibitory elements of the tumor microenvironment. As we move forward, we can look at the clinical development program to- date of TRX518 in combination with immune checkpoint inhibitors. It's noted that GITR agonists in pre-clinical models have been synergistic with checkpoint antibodies, and that includes both PD-1 and CTLA-4 antibodies. An initial study evaluated TRX518 as a monotherapy and now in combination with anti-PD-1, and this study is enrolling across indications where anti-PD-1 antibodies are deemed clinically appropriate as witnessed by FDA approval.
The results to date from this dose escalation study, as well as the dose expansions, will be discussed some detail here, and this has been ongoing and will move into early 2019. The patient population for these studies have been a heavily pre-treated advanced solid tumor population with many different types of immunotherapy-resistant tumors. It's notable that within the population, seven of the 14 patients to be described have previously failed a prior anti-PD-1, PD-L1 antibody. As noted, the study relies upon standards of care, and it's noted that there are cohorts within this study for the combination of TRX518 in combination with pembrolizumab, nivolumab, and with chemotherapy with gemcitabine. That cohort will be discussed later by my colleague, Dr. Bauer. Note that dose escalations have been performed for each one of these molecules and now have proceeded into dose expansion.
This slide shows TRX518 in combination with pembrolizumab or nivolumab in terms of a spider plot, as it's described, looking at individual patients with their treatment outcome out over time. On the plot, you can see on the X-axis the time for days the patients have been on study, and then the percent change in the target lesions on the left-hand side. You can note there's a confirmed complete response in a patient with esophageal carcinoma, and note that patient is ongoing now at seven months of therapy. There's a confirmed partial response in a patient with urothelial cancer who had previously had progression on an anti-PD-1 therapy. There's a patient with durable stable disease with tumor reduction and tumor volume, notably in a patient with ocular uveal melanoma, now continuing into six months of therapy.
I think these clinical vignettes are quite interesting to nominate that more is going on here beyond just anti-PD-1 alone. Notable in the field that several studies of anti-PD-1 plus a second molecule have read out over the last few years not really clearly nominating the second drug as adding a significant benefit. Here in this study, we've added patients to the study who are more likely to be refractory, and therefore, in a single arm sort of approach, we can have potentially more confidence that something useful is being done. I'm going to highlight a few of the case reports. I'll note that the patient with esophageal carcinoma is going to be discussed by Dr. Bauer, as it's actually his patient, and he knows the details even better than I do.
I'll discuss the partial response that was observed in the patient with TRX518 + nivolumab who had urothelial cancer and previously progressed on pembrolizumab. The clinical history for this patient includes that they were 75 years old and diagnosed in 2017. Patient did have a PD-L1 positive tumor at baseline but had significant disease burden, including the lungs, the lymph nodes, bones, and in the retroperitoneum. The patient underwent a radical nephrectomy, followed by pembrolizumab and appeared to have an initial treatment response, although developed acquired resistance with progressive disease. Patient accrued to this study of TRX518 in combination with nivolumab, and as was mentioned, has demonstrated a partial response that's confirmed at the end of now two and then four cycles with 39% reduction in disease burden, but eventually went on to have disease progression after six months.
On this slide, you can see clinical images of the lesions that shrank. Note that in urothelial carcinoma, it's quite common to have bulky adenopathy. You can see that the target lesions here for this patient shrank by 39% from the baseline in May of 2018 to July in 2018. These were pre and para-aortic lymph nodes. My understanding is that this patient also had an improvement in symptoms while under therapy on this clinical trial. From a translational perspective, the question becomes can we interrogate the mechanism to better understand what the impact of the therapy is? What you can see here is increased immune activity in the urothelial carcinoma tumor biopsies from the patient who demonstrated a partial response. You can see on the left-hand side, staining from pretreatment tissue for granzyme B, PD-1, and a DAPI stain.
From pretreatment to post-treatment, looking at cycle one on day 21, you can see a marked increase of CD8 T-cells with increased granzyme B in this patient. It's now well understood that there is a feed-forward cycle in the context of anti-PD-1 that you will see something similar to this. Notably, in this patient, we do observe that patient had previously progressed on a PD-1. The question then becomes, can we further isolate the activity of anti-GITR or TRX518 in the context of this pre to post-treatment biopsy? On this slide, we observe that perhaps that we can.
We see from other sections in the biopsy from pretreatment to post-treatment that we see for FOXP3, CD4, and DAPI on the left-hand side, a marked reduction in those markers going to the post-treatment biopsy suggestive of that mechanism of depleting Tregs, so FOXP3 + CD4 cells. This is quite encouraging to suggest both mechanisms of action as have been described for TRX518 could be in play with agonism or feed forward around interferon gamma with granzyme B activity and influx of CD8 cells, and now here to see depletion of Tregs in addition. In contrast to this, I would note that another patient who had urothelial cancer on the study had a pre to post-treatment biopsy while not demonstrating a benefit. Here we observe, in fact, that the biomarkers also hold up in predicting a patient who would not respond.
Whereas in the previous responding patient, we saw from a pre to post-treatment biopsy an increase in CD8 granzyme B PD-1, here, in the patient who did not benefit, we essentially see no change. Which is what we would expect, in that there's no upregulation of the interferon gamma-associated response. Another patient that's worth noting was the patient with ocular or uveal melanoma. This patient, the clinical vignette includes a 45-year-old man diagnosed in 2016. Patient was diagnosed initially with a left choroidal eye melanoma and quickly went on to develop multiple liver metastases. Patient was treated for the primary with brachytherapy and laser thermal ablation as is standard of care. At the time of metastases, however, went on to treatment on the protocol.
Here I would note that perhaps for those that are less familiar with this disease, advanced uveal or ocular melanoma is a very different disease than cutaneous melanoma. Whereas cutaneous melanoma demonstrates high staining for PD-L1 and high tumor mutational burden, uveal melanomas are exactly the opposite. They're not UV light driven, they tend not to demonstrate a TIL response or PD-L1, and they have low TMB on the order of 10 to 40 mutations total in the genome. Previous retrospective multi-center efforts to describe the response rate of anti-PD-1 in this relatively rare subset of melanomas have described a response rate of about 5%. You can see the reference there, and I would suggest to all who are interested in this data to follow that up.
As a physician who treats these patients, I can tell you that it's, generally speaking, considered that there is no standard of care for these patients and that anti-PD-1 as a monotherapy, is actually a weak option to treat them. In this patient then, who went on to have treatment with pembrolizumab plus TRX518, in fact, we see at the end of two cycles, patient is demonstrating 23% reduction in tumor volume and is now in cycle nine going out on therapy. On the subsequent slide, we see, again, translational data to support the activity of this kind of an approach. Again, pre to post-treatment biopsy. The post-treatment biopsy now in cycle three. Again, an increase in granzyme B as well as infiltration of CD8 T cells suggestive of potential treatment effect.
While I would note that this patient is PD-1 naive, again, this is a disease where there's a, I would actually hazard a greater than 95% for no clinical benefit. Here we see the tumor actually shrinking, and we see biomarkers suggestive of an improved anti-tumor immune response in the context of this combination therapy. Those data have informed the development of TRX518 in combination with anti-PD-1 as standard of care. This program is moving forward, I think, in a very interesting way, which is with a subsequent study that combines TRX518 or anti-GITR in combination with the PD-L1 antibody avelumab, as well as the chemotherapy drug cyclophosphamide. I think it's notable that cyclophosphamide is a good choice here as pre-clinical modeling has suggested enhancement of GITR expression in proliferating immune cells.
Cyclophosphamide is one of those chemotherapies that's been described as immunogenic, thus increasing antigen release, and therefore seems to be a good partner to synergize with GITR agonism. The TRX518 + avelumab is intended to enhance antigen-specific anti-tumor immune response, and I think this triplet combination has a lot of potential interest for high-need populations that perhaps have not benefited as much to date with immunotherapy, notably including triple-negative breast cancer or even hormone-positive breast cancer, prostate cancer, as well as ovarian cancer. In conclusion, I would note that TRX518 is a very interesting immuno-oncology agent that hits GITR. Again, a novel target. TRX518 has unique antibody engineering to be aglycosylated, and we think that may enhance the immune activity of the drug.
TRX518 in combination with anti-PD-1 has showed complete and partial responses in patients who otherwise would not particularly be expected to respond or who are anti-PD-1 refractory prior to therapy. We see in translational biomarkers an increased intratumoral infiltration of CD8 T cells and a reduction in Tregs and biopsies consistent with the mechanism of action for an anti-GITR antibody. This really sets the stage for TRX518 in combination with the triplet regimen of avelumab and cyclophosphamide, potentially to bring this molecule forward into other settings where immuno-oncology agents have not quite had the activity we have desired to- date. Thank you very much, and I'll pass the program over to my colleague, Dr. Bauer.
Hello, everybody. This is Todd Bauer, Associate Director of Drug Development with Sarah Cannon Research Institute in Nashville, Tennessee. I appreciate the chance to speak today about TRX518, the clinical development we followed, and some patient perspective on how this drug and the combinations are tolerated. I've had the chance to work with TRX518 since the first-in-human dosing almost two years ago, and this drug has been developed as most typical phase I agents are with a single dose monotherapy dose escalation study. Then expanding out to explore the alternative dosing schedules. Each time trying to determine what's going to be the optimal dose and schedule for not just efficacy, but also tolerance. One thing I want to point out is that all the patients that are enrolling on our phase I studies have been through standard therapies, oftentimes a number of those.
Finding a therapy that offers them a reasonable chance of benefit and even more importantly to me, a good quality of life, is a very important thing. That's how we think about patients as they enroll in these studies. After we defined multiple dose schedules, we then started to combine TRX518 with multiple agents, one being gemcitabine and then two PD-1 inhibitors, nivolumab and pembrolizumab. Those expansion cohorts are ongoing at this time, and we'll talk about some patients from these, mainly from the gemcitabine cohorts today. The first patient I'd like to share with you is a patient treated here in Nashville. This is a gentleman in his 70s with hepatocellular carcinoma. He's currently in cycle 28, which means he's been on this combination for 19 months with this durable stable disease with a 15% reduction in target lesion.
I share with all my patients that are on these trials that stable is good, smaller is better. Anytime we can have reduction in tumor volume, that's a good thing. We often talk about curing cancer and eradicating it, and there's not a single patient who I treat who I don't truly believe hopes that we get that, and obviously I hope that too. I try to remind them that we don't cure diabetes, and we don't cure hypertension, but these are diseases that we have good drugs for that can last a long time. That's really what sets cancer therapy apart from any hypertensive therapy is the tolerability and the duration of benefit.
When we see a patient who has a disease that can be aggressive as hepatocellular carcinoma can be, and we see them 19 months out with a 15% reduction in target lesion, that's not just a solid base hit. That's an absolute home run for this patient. You'll note that this patient also was treated with CTLA-PD-1 combination therapy and did stay stable on that for 14 months, which is also a pretty great response. I know that most of you listening today will be fairly comfortable with the toxicities that we see with CTLA-4 in combination with PD-1 and know that if you can get through the first four doses, it can be an incredibly beneficial therapy. That not everybody can. This patient, in particular, has just been on single agent TRX518 with very good tolerability.
In fact, really the major side effects that he complains of are mild fatigue. With any phase I patient, it's often difficult to decide if that's really related to the drug or to the disease. Why we see that associated, in my mind, with so many different drugs because most people at this stage of their disease will have some fatigue. It was interesting in the pharmacodynamic analysis of this patient that paired tumor biopsy did demonstrate a reduction in T regulatory cells, an increase in the CD8 to T regulatory cell ratio, which is what we would expect to see with on-target efficacy of TRX518. I mentioned previously that we have to find a drug that a patient can tolerate.
The criteria to enroll in a phase I trial do require good performance status, usually ECOG 0 to 1, which means that they're up and about most of the day. They might take a nap or two in the afternoon, but really pretty functional. We want to keep that. What we don't want to do is put a patient on a drug, no matter how well it may work, but rob them of good quality time. As we look at the safety of TRX518, you'll note Part C is in combination with gemcitabine, where Part D and E are in combination with nivolumab and pembrolizumab, respectively. As we go through these adverse events, what is a great sign in a combination study is when you don't see increased evidence of expected toxicities related to either drug. You understand that you might see an additive percentage of toxicities.
You don't expect cytopenias from an immunotherapy, and you don't expect necessarily autoimmune toxicities from gemcitabine. What you really don't want to see is an increase in either of those, almost a synergistic adverse event profile. TRX518 did demonstrate a good, clean profile when combined with gemcitabine, really with common rates of Grade 2 and 3 toxicities associated with chemotherapy alone and/or with immunotherapy alone, but no synergistic effect. Similarly, when we look at Parts D and E with nivolumab and pembrolizumab, we don't see a dramatic increase in autoimmune side effects as would be a concern. We do know that when you combine CTLA-4 and PD-1, overall, those combinations are really poorly tolerated compared to either one alone.
Being able to combine TRX518 with pembrolizumab and nivolumab and not see dramatic increase rates really gives you hope that these can be combined for a long durable benefit. When we skip to the efficacy in combination with gemcitabine, there have been 25 patients evaluable at the data cut for this data set. 13 of those patients had stable disease, which represents tumor shrinkage down to 30% up to tumor growth of 20%, and 12 patients with progressive disease or a growth of greater than 20% on therapy. We did see clinical benefit observed mainly in the higher dose cohort of TRX518 as patients were given standard gem dosing. 19 of the patients had pancreatic or biliary tract cancer, and 15 were evaluable and nine remain on study.
It's notable that we subsetted these out because these are diseases where gemcitabine can be used either in combination or alone, and we're going to come back to that shortly. In those pancreatic cancer patients, half of them had stable disease with tumor reductions in two of those patients. Four of them remain on study. For those who don't treat pancreas cancer on a daily basis, this is promising. Gemcitabine can work well in some patients, but tumor reductions of 9% and 21% are very happy days in my clinic, if I can see that with single-agent gemcitabine. Biliary tract cancer, similarly, a very difficult to treat cancer with limited options. 80% with stable disease, four out of five, and one of them with tumor reduction of -3%. Again, stable is good. Smaller is better, but stable is a home run in these types of cancers.
What about other tumor types where maybe gemcitabine isn't a standard therapy? We did have three patients, or four patients rather, with non-typical tumor types for that, including appendiceal, mesothelioma, and a couple of ovarian cancer patients, where we may see a little bit of gemcitabine used. These patients did well. All of them were stable but trending towards smaller, which is great in these diseases that have limited treatment options after their standard therapy in ovarian, and really with appendiceal and mesothelioma, very few standard options to begin with. What we're seeing for these patients with progressive advanced disease that have exhausted their standard options or may not have any standard options at all, we're seeing disease control with a good side effect profile. Which is what we're going for in phase I trials currently.
I'd like to talk about one of the ovarian cancer patients that we've treated here in Nashville. This is a delightful patient who was 65 years old when she was diagnosed in February of 2018. She had an aggressive debulking surgery and unfortunately did have extensive residual disease, is often a problem. She was treated with standard carboplatin and Taxol and then recurred. This was a BRCA- negative tumor, and so she did not meet criteria for a PARP inhibitor. She was started on TRX518 and gemcitabine. At the time of baseline scans, as is typical in a phase I trial, she was showing progressive disease. After two cycles, we showed a 3% reduction. At the end of cycle four, she continues to have tumor shrinkage.
I tell patients all the time that I would overwhelmingly like to see a slow reducing trend in their tumor, rather than a dramatic drop at front, because it always gives me a little bit more confidence that they can have a prolonged benefit as it is a more measured response. Now, this patient continues to dose at this time in cycle five. She also has tolerated this combination very well, with most of the side effects that we've seen being cytopenias related to the gemcitabine. She's living a pretty normal life, which is incredibly important for a patient with metastatic cancer. I mentioned earlier we'd come back to patients treated with gemcitabine who've gone on to the combination on TRX518 + gemcitabine. Gemcitabine is a standard drug used for biliary tract cancer and pancreas cancer. It doesn't always work.
What we see in this, 12 of our patients have been treated previously with gemcitabine alone. What we see is a really pleasantly surprising trend towards benefit in patients who'd already failed gemcitabine. Whenever we give drugs in combinations, it's always tough to parse out what's working. Had these patients not been treated with gemcitabine previously, we could say, maybe all the benefit's coming from gemcitabine. In this case, when they've had it and progressed on it, with the exception of two patients noted with a red asterisk, these patients responded or had stable disease. Let me be clear, they had stable disease, not a technical partial response, but better than a clear progression in eight of the 12 patients, which is, again, a pleasantly unexpected response to patients previously treated with the chemotherapeutic.
Going on to another patient now, a 48-year-old patient diagnosed one year prior to starting study. She was heavily pre-treated with appropriate regimens, including FOLFIRINOX, which, if you haven't seen any patients treated with that, I refer to it as kitchen sink chemotherapy because it is everything plus the kitchen sink. She also had second-line gem, nab-paclitaxel, and then third-line capecitabine. At that point, patients with pancreas cancer really have no further options. We can throw chemotherapy at them, but typically it is not going to benefit with an expected benefit probably in the low single digits. This 48-year-old woman wanted to continue to try therapy, so she enrolled in TRX plus gemcitabine, again noting she was previously treated with gem. Her initial post-therapy scans after two cycles did show a little bit of growth. Again, 5% growth is stable disease, and that's a win in pancreas cancer.
We went ahead and continued her on therapy. As you can see, she went from growth to tumor shrinkage. Now why do patients respond this way? Is that an immune flare? It's hard to say with 5% growth in target lesions, but reassuringly, the next set of scans, she had dropped down to about minus 7% or 8%, if memory serves, and currently is down 21%. Again, this trend makes me very happy because I feel like I'm giving the patient great benefit, and she also is doing very well on this combination with a good quality of life and very limited side effects. What about biliary tract disease? Again, a similar cancer type to pancreas cancer, that they have limited options, and when they progress through their standard therapies, they're really oftentimes referred straight to hospice.
This is a 64-year-old patient who was diagnosed about a 1.5 year ago. She was treated with the standard first-line agent, gemcitabine and cisplatin, and then had paclitaxel added for another four months. She progressed, and so was switched to FOLFOX, which is a reasonable second-line option for this patient. Again, we're talking about clinical benefit rates probably in the teens with FOLFOX as second-line treatment for biliary tract cancer. She also, after progressing on FOLFOX, was held. She then had scans again done at baseline that showed during the time off of therapy, her washout period for the study, that she did have notable growth in lungs, liver, lymph nodes, and in the spleen. She was started on TRX518 and gemcitabine.
Again, she had a similar response curve to what the previous pancreas cancer patient had with a 6% increase in target lesion, but then with second set of restaging scans dropped down to 3% reduction. Is there really a huge difference between 6% larger and 3% smaller when you're talking in terms of maybe a sum in the target lesions of 50 mm, 60 mm. I think to you and I, there's probably not. Those are kind of the same thing, whether it's three millimeters bigger or 2 mm smaller. I will tell you, for a patient to see a smaller number on a set of scans, it is a world of difference. I know that I can tell them all day long that stable is good. Smaller is better. Stable is good.
I know that seeing a smaller number on a scan on a medicine that they tolerate well is a world of good to a patient. This is a great response for this patient. She also continues dosing in cycle five without any major side effects to speak of. This is a 73-year-old patient actually treated at another site, but I've had a chance to learn about her case. She was diagnosed about a year and a half ago over two years ago with gallbladder cancer, which in a 73-year-old is a very poor prognosis. Expected survival of less than a year is very reasonable for those patients. She interestingly was treated with Leap's agent DKN-01, which I've also had the chance to use in other patients. This patient was treated with gemcitabine and cisplatin, had a great response, 43% reduction.
Probably a little bit more than what you would expect to see with gem and cis alone, she remained on therapy for 11 months. This patient, unfortunately, did progress and went on to be treated with both standard agents, including capecitabine and also some other clinical trials, ultimately progressing with disease in the lungs, lymph nodes, gallbladder, adrenal gland, and the mesentery. I think this particular patient was trying to get her picture up on the walls of Leap's headquarters, enrolling in a second clinical trial with one of their agents, TRX518. Adding that to gemcitabine, again, an agent she had experienced previously. She continued on therapy for six months with stable disease. I'll tell you that in a 73-year-old, now 75-year-old by the time she starts this therapy, getting an extra six months of disease control doesn't just give her six more months.
It gives her six more months of good quality of life. The clock ticking on her time on hospice is pushed out by six months, that really does help the patient and their family to explore other options and get to go on trips. Really, six months is tremendous for patients in this situation. We'll go on to a patient of mine, I know that just like parents don't have favorite children, physicians don't have favorite patients, but she's probably one of my favorite patients of all time. She's 86 years old and was diagnosed by one of my partners with an esophageal squamous cell cancer last year. If I look half as good at 66 as she looks at 86, I'll feel like I've been blessed. She truly looks about as young as her daughter, who accompanies her to every visit.
She lives independently, is always dressed to the nines, usually with pearls on when she comes into clinic. She knew that she was recurring because she started having dysphagia again. My partner called me and said, "Hey, do you have anything beyond just single-agent immunotherapy? She's PD-L1 positive. I can put her on a PD-1 inhibitor, but do you have anything that might make it better, might get more interesting?" I said, "Absolutely. Let me have her come over and visit with me in my phase I unit." We did get her on TRX518 and pembrolizumab, she's a fiery 86-year-old.
We were waiting to get the slot and waiting to get all of her screening procedures done, she's like, "I just don't understand why I'm wasting my days," literally it was a matter of days, "when I could be over with your partner and getting treated on this." I said, "Just be patient with me, I think this could be better than what we'd expect otherwise." After two cycles, really after one cycle, she came in and said, "I think it's getting better because my swallowing is better. I'm not having trouble swallowing anymore. I'm not coughing, I'm able to eat more full foods," which she was delighted about. Their highlight of coming to see me is she gets to pick lunch, her daughter has to take her wherever she wants to go for lunch.
Yes, I've asked multiple times, and no, I've not been invited to any of those lunches as of yet. However, I think there's still a window for that down the road. Her response continued at the end of cycle four with a 77% reduction in tumor volume. This generated certainly a lot of excitement for her, for I, and the folks at Leap because this is a really good response. I've treated a lot of patients with single-agent immunotherapy. That's seeing almost an 80% reduction after four cycles is not an expected response. When she came in at the end of cycle six and had her third set of her staging scans, she was known to have a complete response with no evidence of the esophageal tumor. These are her cycle seven, day one scans shown here.
You can see the pre-treatment slide showing a fairly obstructive mass, almost an olive shape sitting there in the middle of the esophagus to resolution at the end of cycle seven with no clear disease. I know that these pictures are always impressive to see, but what I think is incredible is more so the patient to sit across the room from them and just tell you that, "My life is back to normal now." She has no other ongoing side effects from her therapies. She is now in cycle 11, seven months out, with a confirmed complete response. As I share with her, in a little bit of a kidding way every time, I think those days that she spent waiting for me to get her started were probably worth the wait. Also looking a little at pharmacodynamic results.
Can we do a biopsy and see an early indicator of clinical outcome? Well, in this patient, there was an influx of CD8-positive T-cells and increased granzyme B, suggesting an anti-active tumor immune response at cycle one, day 21. Similarly, decreased FOXP3 staining suggestive of reduced tumor immunosuppression, which is what we're hoping to get out of TRX518. In summary, TRX518 is safe and well-tolerated as monotherapy. When we combine it with either chemotherapy or other immune checkpoint inhibitors, we did not demonstrate any dose-limiting toxicities. Similarly, no additive or synergistic toxicities. There were no new safety signals seen when adding two new agents beyond what we saw with the monotherapy. This does give promise for continued combinations down the road. We see pharmacodynamic activity with the decreased FOXP3 in the combination that would not necessarily be expected to see with standard immune checkpoint therapy.
When we combine it with gemcitabine, we see meaningful clinical benefit in patients heavily pretreated, oftentimes with gemcitabine either alone or even in combination previously. 90% or 89.5% of those patients did have some prior gemcitabine. 47% have received more than four cycles of therapy indicating a least stable disease, and 37% of the patients treated with the combination of 518 and gemcitabine remain on active study. Also, patients with other immunoresistant tumors have had durable clinical benefit with reduction in tumor volume. Again, they aren't just immunoresistant tumors. Mesothelioma, appendiceal, and platinum-resistant ovarian cancers are often chemo-resistant as well. They're getting a chance to have benefit where truly benefit can't be counted on with FDA-approved agents. One of my pride and joy, my patient with esophageal squamous cell carcinoma, has generated a durable, complete response. She's just doing great.
We often talk in cancer world that it's the nicest people that bad cancers happen to. I'm happy to break that trend with this patient. She is one of the nicest people in the world. Through treatment with TRX518 and pembrolizumab, she is having some really, really good stuff happen for her. Guys, I hope that my talk through these slides hasn't gone on too long. I appreciate your attention and wish you a good afternoon. Thanks.
Ladies and gentlemen, if you have a question at this time, please press star and then the one key on your touchtone telephone. If your question has been answered or you wish to remove yourself from the queue, please press the pound key. Again, if you have a question at this time, please press star one. Our first question comes from Robert Benjamin of Raymond James. Your line is now open.
Hi. Good morning, everyone, thanks for taking the questions. Maybe just starting off for Dr. Luke, can you talk a little bit about those patients that responded, whether it was SD, PR, or CR, how many were truly refractory versus predicted to be refractory? Do you have any thoughts regarding
The mechanisms of progression and how you might be able to take such learnings to potentially get more patients to respond going forward.
Yeah, Dr. Luke was unable to join us this morning. I will attempt to address your question. Can I just clarify? I think you were asking of Dr. Bauer's patients as it relates to the CR and the PR with the combination with the PD-1, is that correct?
Yep. Sorry.
Okay. I think the patient with the CR, the esophageal squamous cell patient, had had one prior therapy, which was a combination chemotherapeutics and radiotherapy, and then subsequently recurred and was known to be PD-L1 positive upon coming onto study. That said, it is not an approved indication for pembrolizumab nor nivolumab at this point in time. The PD-1 inhibitors are approved for adenocarcinomas of the esophagus. That subject was not known to be resistant to PD-1 therapy, however, has had a nice response that perhaps is even expanded upon what would be expected with a PD-1 antagonist alone. It relates to the urothelial patient who had the confirmed partial response, that patient, in fact, had had prior anti-PD-1 therapy and had had a short response duration.
The patient had about nine months of therapy on a PD-1, didn't develop their first response until about five months in. Subsequently, was a responder for approximately four months before ultimately progressing. That patient progressed immediately preceding study entry and came on study at that point in time with now, obviously, had a nice confirmed partial response to the TRX518 and PD-1 antagonist as well. It relates to resistance mechanism, I can't really speak to that at this point in time. I think it's unclear. We don't have particular biopsies for prior to anti-PD-1 therapy, prior to joining study to speak to the resistance mechanism of that particular patient.
Okay. Then I've probably got the physicians' names mixed up here, but the physician who's treating the patients with in combination with gemcitabine, what was the longest responses that they've seen to date? What has been the shortest? Just to give us a good sense as to how long these responses are lasting. I guess when we take a look at stable disease, I think the quote was, "Stable is great, but smaller is better," or something along those lines. How long does a stable disease need to be maintained before it's materially important to the physician? For the patient, of course, every month is beneficial, but to where a physician will sit up and take notice and say, "Hey, there's something major going on here.
Yeah, that's a great question. I think to your point about the duration of some of these patients, this particular cohort began enrolling in the early part of 2018. Regarding bearing in mind these patients in combination with gemcitabine are stable disease patients, you want to speak to the durability of the stable disease. The one pancreatic cancer patient that Dr. Bauer described, the 48-year-old female who had had three prior therapies, has been on study therapy now for about seven months and is continuing to dose with deepening reductions over time, and now in cycle nine. The durability of the stable disease, I think you have to really think about the individual cancer types to answer that question.
I think, three to four months for a patient with pancreatic biliary tract cancer who have been treated with a number of prior therapies, it exceeds what would be expected with traditional therapies. I think anything beyond three or four months for those particular indications is very impressive, especially as it relates to later lines therapy. As Dr. Bauer mentioned, to continue a therapy without significant adverse events is very beneficial to those patients.
Okay, then just one final one for me. What are the next steps? I know with the PD-1s, you guys are going to avelumab, in terms of the gemcitabine study, what are the next steps for moving this combination or a combination like it going forward?
Our plan at the present time is to wait for this study to read out in its entirety because we do still have some patients on study, then to look at the survival outcomes of those patients, then determine the next steps, and if there is a particular indication or two that we should continue developing in combination with chemotherapeutics.
Great. Thank you for taking the questions, congratulations on the results.
Thanks.
Thank you. Our next question comes to the line of Wangzhi Li of Ladenburg Thalmann. Your line is now open.
Hey, this is [Ken] Lee calling for Wangzhi. Thank you very much for taking my questions, congrats on the new data. I just have a couple. One is started with an ocular melanoma patient. Now the patient is on the study for that for one nine months, if I remember correctly. Do you see any signs of a continuously tumor reduction at this point?
This patient began on study therapy in June, did have tumor reductions over the course of six cycles. At the end of cycle eight, has unfortunately begun to develop some growing disease but remains on study with clinical benefit at this time.
Okay. Thank you. That's helpful. The second question, can you clarify the time intervals between this is for patients TRX-519 with nivo with a partial response. What is the time interval between the TRX 518 given and the previous KEYTRUDA?
Yes. It was very short. That was the patient with urothelial carcinoma who came on and treated with TRX518 and OPDIVO. That patient had had KEYTRUDA previously.
Yeah.
That KEYTRUDA therapy, again, as mentioned, he was on for roughly nine months. He had his initial response to KEYTRUDA after about five months on therapy and then progressed after four additional months. It was approximately one month from the last dose of KEYTRUDA to the start of the combination with TRX518 and OPDIVO, that was required per entry criteria to get them through the screening period. It would've been roughly one month with the progressive disease with KEYTRUDA, immediately following, the patient came on combination therapy.
Okay. Thank you. Oh, for that one, for the pre-treatment, the biopsy tumor, when did that take place for the biopsy sample?
It would've taken place during the screening period, the immediate 28 days preceding study therapy. Then the on-treatment biopsies are required roughly about three weeks into therapy. Right as they near the end of cycle one.
Okay. All right. Thank you. That's helpful. With that, we can exclude the delayed factor from the previous KEYTRUDA effect?
I think it's likely that you can, because the patient's tumor volume was growing immediately preceding. You see the stark change in their pharmacodynamic profile as you treat with the new combination.
Perfect. All right. Thank you. My last question is mainly for the development on this PD-1 treatments going forward for the pembro and the nivo. In terms of the selection of patient of solid tumors, I saw a couple of overlaps between these. In terms of the future developments, how does that work out in each cohort with pembro and nivo?
I just want to make sure that I understand the question. You're asking about specific tumor types that are coming on to pembro and nivo?
Yes. Correct. These.
Yeah. On the current study, the way this study has been designed is that the patients are to come on to pembro and nivolumab with the studies, they have to be indications in which those agents would be routinely used. One thing they can do, they can come on either naive to that particular agent, or they can come on with a disease stability for a period of time on the single agent of the PD-1 antagonist and then add the TRX plus the PD-1 to see if there's an increase. At this point in time, the indications are vast as you've seen across, what we've been able to use because the agents are used across a number of indications. We're not specifically limiting the indications on this provided the subjects would be eligible to receive the antagonist.
That will change as we go into the next development in combination with Cytoxan or cyclophosphamide and avelumab, where we are specifically identifying four groups that include triple negative breast cancer, hormone sensitive refractory breast cancer, prostate cancer, as well as ovarian cancer, as separate subgroups moving forward with the subsequent study.
Okay. Thank you very much. That's all the question. Congrats again.
Thanks.
Thank you. Our next question comes to the line of Swayampakula Ramakanth of HC Wainwright. Your line is now open.
Thank you. Thank you for taking my questions. Great couple of presentations. One specific question is, the picture that has been painted this morning is that TRX518 works with either chemo or checkpoint inhibitors. It seems to work well in certain set of patients, obviously. What are the common biomarkers or initial indications that you are noticing in these patients so that you can look out for them early on, to understand that these patients would have a positive effect eventually?
That's a great question. I think we're building upon our prior experience from the single-dose study in which we reported out with Memorial Sloan Kettering Group, a reduction in peripheral blood as well as tumor T regulatory cells and FOXP3. We've once again been able to demonstrate that, at least in combination with the PD-1 antagonist at this point in time. Not all of the pharmacodynamic work has been completed in the gemcitabine combination to date. We're continuing to monitor the patients for peripheral blood flow. That includes the Tregs as well as the CD8 cells. Then, as well, we're also looking at those immune markers in the biopsies.
As has been depicted in the slides today, I think what you've seen is an increase in the CD8 cells, the infiltrate in both in the tumor as well as a reduction in the CD4 FOXP3 + cells as well.
Thank you. One last question from me is, probably you answered this question, but I'm not sure. We certainly have seen interesting data both in uveal melanoma and also in the urothelial cancer. How representative are these two patients for these diseases? When you're thinking about expansion cohorts, would these indications qualify for that? What sort of patient numbers do you need to be enrolling if these indications become the ones of choice?
Yeah, no. We are very interested in enrolling additional patients with uveal melanoma onto the study and the combination of the PD-1 antagonist because of the activity that we've seen in the first patient enrolled with that disease. I think that is a rare indication, and as Dr. Luke mentioned, there are very few diseases in which the therapeutic options are very limited. That would be one. I think you could get a subset of 10, 20 patients that could give you a clear signal to continue to develop in that particular disease space. As it relates to the urothelial, there are some approved PD-1 antagonists for urothelial malignancies. I think that that is one that's a little more challenging.
However, I do think that once they've failed the prior PD-1, to be able to come back in and rerespond with the combination of a Tregs and a PD-1 antagonist, I think is very encouraging and something that needs to be further explored.
Thank you. Thank you for taking my questions, congratulations on the data.
Thanks.
Thank you. Ladies and gentlemen, I'm showing no questions. This concludes today's event. Have a great day.