ASCO 2018: Gut Microbiome Composition to Predict Resistance in Renal Cell Carcinoma Patients on Nivolumab

Chicago, IL (UroToday.com) One of the important goals of physicians treating RCC patients is to discover mechanisms underlying the resistance to immune checkpoint inhibitors (ICI). Recently it has been published that there is a negative association of antibiotics on clinical activity of ICI in patients with advanced RCC. [1] In this study, the authors evaluated the impact of microbiome in RCC.

Using a large cohort of RCC patients (n = 85) treated in the NIVOREN study with nivolumab at the Gustave Roussy institute in France, the authors prospectively collected fecal samples from the patients (n = 69). Of note, the minority of them received antibiotics before starting ICI (n = 11).

Patients were classified as either primary resistant (PD) or non-PD based on RECIST criteria (outcome, 6 months progression free survival [PFS]). Metagenomic data from whole genome sequencing (WGS) were analyzed by multivariate and pair-wise/fold ratio (FR). Subsequently, the authors took ICI-resistant RENCA mice and transplanted them with fecal microbiota (FMT) from non-PD patients or with commensals identified by WGS-MG to restore responsiveness to ICI to establish cause-effect relationship between dysbiosis and resistance.

The median follow-up in this study was 14 months. A total of 27 (39%) patients were PD and 42 (61%) patients were non-PD, based on best response. When specifically assessing patients who received antibiotics, 8 (73%) were PD and 3 (27%) were non-PD (p = 0.01). The microbiome alfa (intra-sample) and beta (inter-sample) diversity were not significantly different among PD and non-PD RCC patients. However, specific gut MG-fingerprints were related to best responses and/or PFS6. When the authors excluded the patients, who were treated with antibiotics, Akkermansia muciniphila and Bacteroides salyersiae bacteria were more abundant in non-PD patients with a FR of 2.65 (p = 0.01) and 27.09 (p = 0.05), respectively. Lastly, the authors demonstrated that Bacteroides (B. salyersiae but not B. xylanisolvens) or A. muciniphila could restore the efficacy of ICI in "unfavorable/dysbiotic" FMT-recipient tumor bearers, improving by a 43% the prevalence of non-PD.

According to the authors, this is the largest prospective analysis to demonstrate that the composition of gut microbiome may predict resistance to anti-PD-1 in RCC patients. This could potentially suggest that various interventions in an attempt to modulate the gut microbiome, may represent strategies to improve clinical outcomes with ICI therapy.

Presented by: Lisa Derosa, Paris Saclay University, Villejuif, France

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, Twitter:@GoldbergHanan at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA

References:
[1] Derosa L, et al. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small cell lung cancer. Ann Oncol. 2018
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