Zach Klaassen: Hi, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined today by Dr. Chiara Ciccarese, who is a medical oncologist from Rome, Italy. Chiara, thanks so much for joining us today on UroToday.

Chiara Ciccarese: Thank you, too. It's a pleasure for me to be here.

Zach Klaassen: So we're going to discuss the exciting results from the TACITO-II trial, which looked at fecal microbiota transplantation versus placebo in patients receiving pembrolizumab plus axitinib in patients with metastatic renal cell carcinoma. So just to start off, why don't you tell us how the history of fecal microbiota transplantation came to be about?

Chiara Ciccarese: Yeah. As you know, first-line treatment for metastatic RCC is based on immunotherapy. And the composition of fecal microbiota is a crucial regulator in influencing the response to immunotherapy. The first data came from Lisa De Rosa and the role of antibiotics that can compromise the efficacy of immunotherapy. Then they discovered that different microbiota footprints between responders and non-responders and how this could affect the response to immunotherapy.

There are early-phase trials investigating the possibility of modifying the composition of intestinal, so gut microbiota, through dietary interventions.

Zach Klaassen: Right.

Chiara Ciccarese: There are trials of Natalie Disman that identify how you can exactly modify the composition of the gut microbiota. And these can be associated with preliminary signals of improved clinical activities. Regarding FMT, so fecal microbiota transplantation, there are no randomized or prospective data on RCC, so on kidney cancer. But as of today, just phase one trials in melanoma patients where they saw that with fecal microbiota transplantation, you can restore the response to immunotherapy. And we start from these preliminary results.

Zach Klaassen: Excellent. That's a great explanation. So just from a logistical standpoint for our listeners, how is this actually performed? How is the FMT performed?

Chiara Ciccarese: There are different ways. We do a combination of the two most important ways/procedures. So colonoscopy, so by direct infusion in the bowel of the patient of stools from a donor, and the second one by frozen oral capsules.

Zach Klaassen: I see.

Chiara Ciccarese: And there are two different possibilities about the donors because in melanoma studies, there are studies with healthy donors, but also with responder patients to immunotherapy. And we use the latter one.

Zach Klaassen: Okay.

Chiara Ciccarese: So a patient with kidney cancer and an exceptional response to immunotherapy, it was our donor.

Zach Klaassen: I see. Wonderful. So I'd love for you to walk us through the TACITO trial design and some of your exciting results.

Chiara Ciccarese: Our study is a phase two prospective randomized trial that included patients with metastatic RCC eligible to first-line pembrolizumab plus axitinib, but were randomized one-to-one to FMT or placebo during standard treatment with axitinib plus pembrolizumab. FMT was performed at three different time points. The first, by colonoscopy, as I previously said, within eight weeks from the start of systemic treatment. The second and the third, by frozen oral capsules after three and six months from the first FMT.

The primary endpoints were, so our study was designed to detect a 20% absolute increase in the rate of patients with no disease progression after one year. So it was one-year PFS rate.

Zach Klaassen: Okay.

Chiara Ciccarese: We randomized 50 patients, 25 in each arm. Here, I show you the main characteristics of the patients. All of them received at least the first FMT procedure. And as you can see on my right, despite many technical difficulties related to the FMT procedures, almost 90% of the patients received all three FMTs. So we achieved a quite high dose intensity. And I think this is a big piece of evidence.

Zach Klaassen: Yeah.

Chiara Ciccarese: About our primary endpoint, so one-year PFS rate, these are preliminary data of 44 patients that had a minimum follow-up of 12 months. And as you can see, FMT was able to increase the activity of pembrolizumab plus axitinib with one-year PFS rate of 66.7% compared to 35% and an absolute increase of more than 30%. As I said before, our goal was 20%. So the primary endpoint was met. About the PFS in the overall population, 14.2 months compared to 9.2 months, and about overall survival, data are still immature, but the median overall survival was not reached in the FMT group compared to 25.3 months in the placebo group. And as you can see, the curves, even though immature, are pretty well separated. In terms of activity, FMT almost doubled the overall response rate of pembrolizumab plus axitinib. Unfortunately, we saw no complete responses, but only 8% of primary refractory patients.

And in terms of safety, FMT was pretty well tolerated with no adverse events related to the transplantation procedures. And even more, as you can see below, FMT was not responsible for an increase in the rate of severe adverse events related to pembrolizumab plus axitinib.

So I think this trial is a real novelty in terms of proof of concept because it demonstrates for the first time the possibility to transfer the immune response from one patient to another through a microbiota transplantation. This procedure is safe, feasible, 90% of dose intensity achieved, and probably for me for sure, it deserves further investigation.

Zach Klaassen: Chiara, thanks very much for those results. That's really exciting work. And as you said, there seems to be a signal here both in the ability to do the procedure, but also, objective response rate and certainly in the one-year PFS. So what's next for the TACITO phase II trial?

Chiara Ciccarese: As you can imagine, the analysis of the microbiota of our patient donor is currently ongoing as well as the analysis of the microbiota composition and how it changed in the patients because we collected the stool of the patients at the baseline and after the FMT procedures. And this, I think, is the most interesting analysis that we are going to do. And for sure, waiting for a longer follow-up and seeing if these data will be confirmed.

Zach Klaassen: Excellent. And I guess just from, as we look towards the future with these results and influencing potential clinical trial design, maybe assessing different combinations of therapy, how do you see the FMT incorporated into future, maybe even phase III clinical trials?

Chiara Ciccarese: Yeah, so as of today, obviously the gut microbiota is not a key factor in influencing the choice of first-line treatment.

Zach Klaassen: Okay.

Chiara Ciccarese: But probably in the future, the identification of those patients with a good microbiome, so more likely to respond to immunotherapy, from those who have a bad microbiome, and allow us to select the latter more suitable for FMT.

Zach Klaassen: Yeah.

Chiara Ciccarese: And obviously, the characterization of the ideal microbiome composition of the donor will help us design a prospective phase III trial.

Zach Klaassen: Excellent. It's been a great discussion. Thank you so much in advance for your time. Can you just leave our listeners with maybe two to three take-home messages from the TACITO trial?

Chiara Ciccarese: Yeah. For today's clinical practice, I will say, I will suggest, use antibiotics only when necessary, pay attention to the diet of the patient, and think that probably in the future, also the microbiome, microbiota composition and all the conditions that lead to a dysbiosis can be the key to select patients to increase the response to immunotherapy.

Zach Klaassen: Excellent. Congratulations on the excellent work and thank you again for joining us on UroToday.

Chiara Ciccarese: Thanks so much. Thank you.

Zach Klaassen: Thank you.