Dr. Pal continued and presented the clinical conundrum that the microbiome raises (figure 1) and has attempted to answer some of the questions represented in this conundrum in this presentation.
Figure 1 – The clinical conundrum raised by the microbiome in RCC:
The first question debated was whether antibiotics have an impact in patients receiving VEGF-directed therapies. Dr. Pal presented a study with a 147 metastatic RCC patients with intermediate and poor risk disease who received 1st line VEGF-TKIs. 17 patients received antibiotics with Bacteroides spp coverage, 32 patients received antibiotics with no bacteroides spp coverage, and 96 patients did not receive any antibiotic coverage (1). The study showed that patients with bacteroides coverage did the best regarding progression free survival. It is not clear whether this is associated with increased tolerance of therapy (for example – less diarrhea).
Next, the same question was debated in patients receiving immunotherapy. Another study was presented with 121 patients with RCC, of whom 105 were not given antibiotics, and 16 patients were given antibiotics (2). The results demonstrated again, that patients treated with antibiotics had a much higher complete response rate than those who weren’t (75% vs. 22%).
The next topic discussed was whether the microbiome profile has an impact on clinical outcomes in patients receiving VEGF directed therapies. In a study including 20 patients with metastatic RCC, who were treated with any VEGF-TKI, stool samples were collected after at least 2 weeks of therapy. 16s ribosome RNA sequencing was performed, and bacteria analyzed (3). The patients were divided based on the development of diarrhea or lack of it. The results demonstrated that microbial diversity was not linked to age, presence or absence of diarrhea, line of therapy and type of VEGF-TKI. Additionally, high risk disease was associated with high bacteroides spp and low Prevotella spp, while low risk disease was exactly the opposite.
Lastly, Dr. Pal debated the same question but for patients receiving immunotherapy. In a study with 40 RCC patients, stool collection was performed at baseline and at several following time points after initiation of immunotherapy (4). The results demonstrated that specific bacterial species were associated with response and progression free survival (PFS). Furthermore, the response to immunotherapy in murine models was enhanced following the transplant of stool from responders.
Dr. Pal summarized his elegant talk stating that all 4 question that were raised in the clinical conundrum have been answered, and we are now at a stage where we need clinical prospective randomized studies, comparing microbiomes in these therapeutic settings. Dr. Pal concluded his talk presenting a current ongoing randomized prospective study of intermediate/poor risk metastatic RCC patients with no prior systemic therapy, with clear cell histology, and measurable disease who are randomized in a 2:1 ratio to receive either nivolumab/ipilimumab + Clostridium butyricum MIYAIRI 588(®) (CBM 588(®) or receive ipilimumab + nivolumab alone. The primary endpoint will be change in the Bifidobacteria spp. Hopefully this, and other similar trials will give us the required data we seek.
Presented By: Sumanta K. Pal, City of Hope, Duarte, CA
References:
Hahn A et al. Clin Genitourinary Cancers 2018
Derosa L et al Ann Pcol 2018
Pak SK et al. Clin Cancer Res 2016
Routy B et al. Science 2017
Written by: Hanan Goldberg, MD, Urologic Oncology Fellow, SUO, University of Toronto, Princess Margaret Cancer Centre, @GoldbergHanan, at the 19th Annual Meeting of the Society of Urologic Oncology (SUO), November 28-30, 2018 – Phoenix, Arizona