Faecal microbiota transplantation increases activity of immunotherapy in mRCC

Dr Chiara Ciccarese - Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy

We have strong data about the role of the composition of the microbiota in influencing the response to immunotherapy in diverse cancer types, including RCC. We have data about the possibility of modifying the composition of the gut microbiota through dietary interventions in RCC but they are, as of today, only single arm phase I or II trials. We didn’t have yet a randomised study about transplantation of the microbiota in patients undergoing immunotherapy in RCC. We have some trials with faecal microbiota transplantation in melanoma cancer patients where there are preliminary signals of the possibility of restoring the response to immunotherapy. The key innovation of our trial is that it’s the first to randomise with FMT, so with the transplantation of faecal microbiota, in kidney cancer patients.

What was the study design?

We enrolled 50 patients, metastatic RCC, treatment naïve, that were eligible for standard first line therapy with axitinib plus pembrolizumab. They were randomised 1:1 to FMT from a donor, which was an immune responder RCC patient, or placebo. FMT were performed at three different timepoints and with different approaches, this is another novelty. The first one by colonoscopy at the beginning of the treatment, so at baseline, within eight weeks. The second and the third by frozen oral capsules, so orally, after three and six months. The patient donor was an almost 60 years old man that started nivolumab plus ipilimumab, so an immunotherapy, for more than 60 lung metastases, achieving a complete response that is long-lasting, more than five years as of today. The characterisation of his microbiota is currently ongoing.

What were the results you were presenting?

Our study was designed to detect at least a 20% absolute increase in the one year PFS. These are preliminary results because we have data as of today of 44 patients with a minimum follow-up of one year. They are quite impressive because the PFS rate at one year is more than 66% compared to 35%, so an improvement of more than 30%. Even more, we found almost double the overall response rate and a quite huge drop in the rate of patient primary progressors because they are 8% in the experimental arm compared to 28%. The overall survival data are still immature as of today but the curves are pretty nicely diverged so we are hoping to confirm this data with a longer follow-up.

What is the safety of the procedure?

The procedure was really safe. We had no adverse events related to the transplantation procedures in the experimental arm. Furthermore, we have the same rate of severe adverse events in both groups so it means related to axitinib plus pembrolizumab, so it means that the transplantation procedures were not responsible for an increase in the rate of toxicity. This is great data for us.

What are the next steps?

First of all we have to absolutely characterise the microbiota of the patient. We collected the faeces and blood samples of the patients at baseline and after the FMT. So our goal is to try to identify the way the microbiota changed and how it is correlated with the outcomes, with the clinical outcomes for sure. I’m not pretty sure that only one component, akkermansia rather than bifidobacterium, only one being responsible for the increase of immunotherapy activity. But probably the answer will be the analysis of the metagenomic composition and try to design a new study based on this characteristic as at least the stratifying factors.

What do you hope the long-term impacts of this study might be?

I do really believe that microbiota is a crucial factor in influencing the response to treatment. I do really believe that somehow the use of antibiotics should be strictly evaluated. I do think that the diet should be another factor to take into account, to reduce the consumption of alcohol, stop smoking, a Mediterranean diet, because they are all factors that nicely influence, positively influence the composition of the microbiota. I guess that in the future we should be able to discriminate those patients with a good microbiota from those with a bad one that probably need support. I don’t know if it will be with a transplantation or with live bacteria supplementation but I think that the microbiota composition is a key factor in influencing the response to immunotherapy.