Randomized prospective trial assessing Bifidobacterium-containing probiotic supplementation in metastatic renal cell carcinoma (mRCC) patients receiving vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKIs).

Abstract

5078 Background: Studies suggest a link between the gut microbiome and mRCC outcomes, including evidence that mRCC patients (pts) possess a lower abundance of Bifidobacterium spp compared to healthy adults (Pal et al Clin Cancer Res 2015). The aim of this study was to assess if Bifidobacterium-containing probiotics could modulate the gut microbiome and impact rates of clinical benefit (CB) from VEGF-TKIs. Methods: Pts initiating VEGF-TKI therapy for mRCC were randomized to probiotic supplemented (PSu) or probiotic restricted (PRe) treatment arms. Pts in the PSu arm consumed two 4 oz servings of Activia daily. Stool samples were collected prior to therapy and at wks 2, 3, 4 and 12. Gut microbiota composition was assessed using whole genome shotgun metagenomic sequencing (Zhu et al Microbiome 2018). The primary endpoint was change in Bifidobacterium spp with therapy. Microbiome composition was compared across pts with CB (complete/partial response or stable disease) versus no CB (NCB). Results: In total, 20 pts were enrolled. The most frequent VEGF-TKIs were cabozantinib (45%), sunitinib (25%) and lenvatinib (25%). Median progression-free survival (PFS) was 6.5 months (95%CI 0.3-12.9) and CB rate was 75%. Bifidobacterium animalis, the active ingredient of Activia, reached detectable levels in all pts in the PSu arm, but was only detectable in one pt in the PRe arm. CB rate was not significantly different in PSu vs PRe arms (70% vs 80%, p > 0.05), and there was no difference in PFS. LDA effect size (LEfSe) analysis of MetaPhIAn2 data captured 25 enriched species demonstrating an LDA score > 3 in either CB or NCB. Of those with high LDA scores, Barnesiella intesitinihominis and Akkermansia municiphila were the most significant members (p = 7.4 x 10−6 and p = 5.6 10−3, respectively). While 92% of B. intestinihominis positive pts obtained a CB, only 50% of B. intestinihominis negative pts obtained CB (p = 0.036). Conclusions: This is the first prospective randomized study demonstrating modulation of the gut microbiome with probiotics in mRCC. While microbiome modulation by probiotics did not increase CB rates as intended, consecutive stool specimens allowed us to identify an association between B. intesitinihominis, A. municiphila and CB with VEGF-TKIs. In addition to the previously documented association between A. municiphila and immunotherapy outcome (Routy et al. Science 2018), this species may predict activity with VEGF-TKIs. Clinical trial information: NCT02944617 .