Pedro Barata: Hi, I'm Pedro Barata. I'm a GU medical oncologist at Tulane Medical School in New Orleans, Louisiana. I have today joining us, Dr. Ricardo Fernandes. He's a colleague and friend, medical oncologist at London Regional Cancer Center and assistant professor in the department of oncology at Western University in London, Ontario, Canada. He's also the director of the medical oncology fellowship there. So Ricardo, welcome. Thank you for joining us.

Ricardo Fernandes: Thank you for very much for the kind introduction Dr. Barata. It's a pleasure to be here. Thank you for having me here.

Pedro Barata: Absolutely. And first I'll start by congratulating you by very, very provocative interesting results from your phase one study called PERFORM. So PERFORM study is a study conducted in patients with advanced renal cell carcinoma, who basically were offered fecal microbiota transplantation. And Dr. Fernandez presented the results, the initial results of that phase one study. And I think Ricardo, you define the primary endpoint as feasibility and also safety of that fecal microbiota transplantation, FMT. I'm wondering, see, this is such a hot topic right now. We have seen a little bit of data on that, very provocative data, with checkpoint inhibitors. But perhaps I should, maybe I'll start by asking you, what is your thought process, you and your team, to put this together? How did you think about it and how do you actually implemented it?

Ricardo Fernandes: Yeah, thanks for the question. That's a very important question because that goes back to few years ago, when we were seeing that the treatment landscape of metastatic renal cell carcinoma was rapidly, it has rapidly changed it over the past few years with the advent of immunotherapy based combinations. The role of immunotherapy as a first line systemic therapy for these patients has become quite clear with the either doublet immunotherapy with CTLA-4 inhibitor, NP double inhibitor, or the combination of a PDL1 inhibitor plus a VGF TKI. So these patients initially with intermediate to poor risk disease, they did have a better overall survival with ipilimumab and nivolumab. So that was the initial rationale to include those patients.

The problem, the concern was that these combination therapies can be quite toxic. They're associated with a lot of side effects, namely immuno-related adverse events requiring often multidisciplinary management, discontinuation of treatment.

And the main toxins associated with these immunotherapy combinations, they occur either during the first four cycles of ipilimumab and nivolumab or with the PDL1 inhibitor plus VGF, in the long run.

We also know that gut microbiota plays a central role in the development of local and systemic immunity. The influence of gut microbiota controlling anti-tumor immunoresponse in cancer patients treated with immunotherapy has been established a few years ago. We know that the gut microbiota control various aspects of adapted immune system through the production of metabolites, and most importantly, through the direct activation of antigen presenting cells.

So few years ago, again, when we were thinking about doing this type of trial, a remarkable study was published in a couple of patients with genitourinary malignancies, prostate and bladder. These patients were treated with immunotherapy and they develop refractory colitis, a refractory immuno-related colitis.

These patients at that point were treated with FMT, with fecal microbiota transplantation, and the colitis did improve. So based on that, so we learned that this study reviewed the capacity of the gut microbiota to exert rapid immune homeostasis in patients affected with the severe immuno-related adverse events.

So all these things led to the design and conduct of PERFORM, of this phase one trial. So our hypothesis was that adding FMT or fecal microbiota combination transplantation in combination with immunotherapy to treat renal cell carcinoma patients in a phase one study would establish a gut microbiome similar to that from a healthy person.

Pedro Barata: Got it. Thank you so much. That's very, very, very helpful, and it makes a lot of sense to conduct such study. So knowing that obviously the gut microbiota as you said, played a central role in, also in efficacy, but also safety of these therapies. What was your experience? I believe you present this data for the first 10 patients enroll in this study. Can you briefly summarize for us what are the the key highlights?

Ricardo Fernandes: Absolutely. Thank you again, for the question. Perform was a phase, well, is a phase one study evaluating the safety of FMT, or fecal microbiota transplantation. And initially for the first 10 patients, they were treated with dual immunotherapy. They were treated with ipilimumab and nivolumab in patients with first line metastatic renal cell carcinoma.

And we also tried to assess whether FMT would prevent or mitigate the immuno-related side effects. So the eligible patients were patients, again, untreated with metastatic RCC or renal cell carcinoma. They received three FMT procedures prior to the first three immunotherapy based combinations. So the first FMT, it's a full FMT we call, because it had 80 to a hundred grams of fresh stools given by capsules, about 40 capsules, followed by two subsequent FMT procedures that had 50 to 60 grams of fresh stool, again, via capsules containing this intestinal bacteria from health donors.

So what we, the primary endpoint of the trial was safety of combining FMT using this intestinal bacteria from health donors with immunotherapy. And in terms of secondary endpoint, we also look at the instance of immuno-related adverse events, overall response rates, and changes in the microbiome or microbiota, and also changes in the immune profile post FMT.

Pedro Barata: Okay. And so what did you see in terms of efficacy and safety, anything on the, I know most patients were clear cell, correct? I think 90% or so. A small number, but did you identify any new signals? Anything you can share with us?

Ricardo Fernandes: Yeah. So most patients, as you said, had clear renal, clear cell renal cell carcinoma. I think the medium age was 60 years old. These first 10 patients, these preliminary analysis of the first 10 patients, all of them were treated with ipilimumab and nivolumab. So therefore all of them had intermediate or poor risk disease based on the IMDC, the hand criteria. We had about, I believe, one or two patients had sarcomatoid differentiation as well.

So in terms of clinical outcomes, almost 94% of the patients did receive FMT, the planned FMT. There was no safety concerns. So we did not observe any dose-limiting toxicities with FMT. Most FMT-related adverse events with grade one or grade two, including diarrhea, flatulence, nausea, abdominal discomfort. So it is safe to be giving with immunotherapy based on that.

In terms of other outcomes, I think, it's a very small sample size, but the disease control rate was 40%. So four out of this 10 patients had disease control rate with one patient having partial response. In terms of colitis, we saw that three patients had grade three colitis. Again, it's a small sample size to conclude that this could be effective, but we do think, we do believe this is safe to be giving, FMT's safe to be giving with immunotherapy, to treat these patients.

Pedro Barata: Got it. So it sounds like a longer follow up in more patients going to help identify if there's an effect, not on the short term that maybe we can assess that with response rate efficacy wise, but also longer term. Right? See if how many stay, have progression and look at how that PFS going to look like, et cetera. That's awesome.

So I guess, I mean, this is great and I'm sure a lot of who are listening to this today are thinking, "Okay, how can I conduct such a study in my cancer center?" Right? And so I guess the question I have for you Ricardo, is just, can you tell us a little bit about, can you share with us a few tips, a few key points that you learn, or you basically recommend us if you were to launch such a study with fecal microbiota transplantation? What the things we need to know? And also how often do you do each treatment?

Ricardo Fernandes: So that's a great question. Obviously I'm a clinician, a medical oncologist. We need a team to be able to work in such a trial. So we have, I'm lucky here in London because we have a Microbiome Research Institute led by Dr. Michael Steverman. I also have a immunologist and my microbiologist, Dr. Malaki and Dr. Burton. So I cannot do that without their help and their expertise. So I think the first thing to be able to conduct such a trial is to have a good collaborative team with experts in the field, people who can actually produce these capsules.

It's also important to mention that because we are doing this stools from health donors, these FMT collected by stools from health donors. So we have a good pool of health donors at our academic center. Our group has great experience with the screening process for donors too, because of course there is always the, we have to decrease or mitigate the risks of transmissible diseases. So it's a very strict criteria to identify these health donors, to collect these stools from. So that's important to have as well.

The other piece of the puzzle is that you have to have, of course, Dr. Barata a group of physicians with experience in phase one studies. We collect a lot of stools, blood work. We do PKs and microbiome and immuno changes. So it's important to have a laboratory group to collect those samples as well. So I think at the end of the day, it's a matter of having a good group with different disciplines. Like I said, medical oncology with phase one experience and also the immunologists, microbiologists, and the microbiome experts in the field.

Pedro Barata: Yeah. I mean, this is so, so helpful, right? And clearly this is, you're not playing alone and you have a fantastic team around you and you guys pull these together as a group. So I'm actually looking forward to extended follow up data and analysis that I'm sure you're going to present whenever you have that data available. So with that, I mean, I have to, congratulations for the great job, and very, very interesting and provocative study. Congrats for that design. And yeah, I mean, we're probably going to sit down once we have more data about that study. We definitely want to keep an eye on that. So congratulations.

Ricardo Fernandes: Thank you. Thank you so much for the kind invitation. I hope that has been helpful to highlight some of our data from our Perform trial. And I want to thank for, of course the patients, the families, and my colleagues who, without whom I wouldn't be able to do such a trial.

Pedro Barata: Right. Thank you so much for joining us today.

Ricardo Fernandes: Thank you, Pedro. Have a good day. Bye bye.

Pedro Barata: Bye.