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

Chicago, IL ( 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

[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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