Microbiome Impact and Promising Clinical Outcomes for Renal Cell Carcinoma

Hedyeh Ebrahimi, MD, MPH

Evolutions in the science surrounding the human microbiome have been happening rapidly in recent years, and that research extends to the oncology space. Hedyeh Ebrahimi, MD, MPH, and other researchers at City of Hope Comprehensive Cancer Center sought to investigate the potential connection between the gut microbiome and metastatic renal cell carcinoma (mRCC).

In the phase 1 study (NCT05122546), patients with mRCC underwent treatment with a combination of cabozantinib (Cabometyx) and nivolumab (Opdivo) with or without the addition of CBM588, a live bacterial product. The study aimed to understand the impact of CBM588 on clinical outcomes.

Previous studies conducted at City of Hope suggested that the composition of the gut microbiome could influence the effectiveness of immunotherapy, including where the addition of CBM588 to checkpoint inhibitor therapy delivered a higher response rate.

The current trial enrolled 30 patients and randomized them to receive CBM588 in addition to the combination of cabozantinib and nivolumab or cabozantinib/nivolumab. The addition of CBM588 led to better clinical outcomes and a higher response rate.

Although the hypothesis initially focused on changes in the abundance of specific bacterial species, no significant alterations were observed. However, there were observed differences in metabolic pathways related to vitamin K production. Patients who received CBM588 showed an increase in pathways producing menaquinone, a form of vitamin K, while those who did not receive CBM588 had a decline in those pathways.

The study is small, and findings are preliminary yet encouraging, calling for larger trials to validate them. The potential role of CBM588 and vitamin K in enhancing responses to mRCC treatment remains a subject for exploration and could contribute to a better understanding of immunotherapy and the microbiome.

In an interview with Targeted Oncology^TM, Ebrahimi discussed the study and its findings, which were presented at the 2024 Genitourinary Cancers Symposium.

Kidneys, adrenal glands, genitourinary system: © Leo Viktorov - stock.adobe.com

Targeted Oncology: Can you provide an overview of your research on the evolution of microbial communities in metastatic RCC patients who are receiving this cabozantinib/nivolumab combination with or without the CBM588?

Ebrahimi: As you may know, for first-line treatment in the setting of metastatic renal cell carcinoma, most of the time we have 2 options. One is using dual checkpoint inhibitors, and the other is the combination of 1 checkpoint inhibitor plus 1 VEGF targeted therapy, like cabozantinib plus nivolumab.

We have some previous studies that showed that the gut microbiome composition of patients can affect the outcome of immunotherapy. Based on that, in the previous study that we had at City of Hope, we tested whether ipilimumab plus nivolumab, both checkpoint inhibitors, plus CBM588 will increase or decrease or have any kind of effect on the outcome of patients receiving ipilimumab plus nivolumab.

A little bit of background about CBM588: It is a live bacterial product. There was a retrospective study in Japan that showed that people with non–small cell lung cancer who received immunotherapy and took CBM588 had better outcomes. The hypothesis came from that first study in Japan.

In the previous study that we did at City of Hope, we saw that when we add CBM588 to dual checkpoint inhibitor therapy in metastatic renal cell carcinoma, we will see better clinical outcomes in patients. Their response rate was much higher in the arm that received CBM588.

The other regimen that is commonly used in the setting of metastatic RCC is the combination of VEGF-targeted therapy with immunotherapy. In the current study, we designed a phase 1 trial with 30 patients with advanced RCC to get either a cabozantinib plus nivolumab in a standard dosage or cabozantinib plus nivolumab with the addition of CBM588.

What were some of the findings of the study?

In the current study, we again saw that those patients who received CB588 in addition to this standard treatment had better clinical outcomes. The response rate was higher in the patients who received CBM588. We had a first hypothesis that this increased clinical benefit was true, changing the composition of the microbiome in the patient's gut and increasing the Bifidobacterium species. But similar to the previous study, we did not see any significant changes in the abundance of Bifidobacterium species in either arm of the study.

We also checked the diversity of the microbiome composition in our patients and saw no significant changes in the Alpha diversity between baseline and posttreatment in either arm.

We looked further to see if there is a difference between the metabolic pathways that are happening in the gut. To our surprise, we saw that in patients who receive cabozantinib plus nivolumab in standard dose without CBM588, the metabolic pathways that are functional in producing menaquinone, which is a form of vitamin K, had declined. At the same time in patients who receive CBM588, pathways that have function in producing vitamin K had increased.

Our thought in the current study was that there is a chance that CBM588 increases the response in our patients by increasing vitamin K. We have some affirming data from previous studies, clinical and preclinical, that vitamin K has a functional role in the apoptosis of cancer cells.

For instance, there is a study in hepatocellular carcinoma that showed that patients who received vitamin K in addition to sorafenib, a treatment that is used in that setting, have better outcomes. Because of that, we thought CBM588 increased the level of production of menaquinone or vitamin K, and this is how it increased the response in our patients.

Can you describe the methodology of this study?

In this study, we enrolled patients who had metastatic or advanced renal cell carcinoma. It was a first-line treatment, so the patient should not have received any form of systemic treatment for metastatic disease. They should have a confirmed histology report of clear cell, papillary, or sarcomatoid pathology.

In the trial, we had 30 patients. We had 2:1 randomization, which means that 20 patients out of 30 received cabozantinib plus nivolumab plus CBM588, and 10 patients in the control arm received only cabozantinib plus nivolumab in a standard dose alone.

We assessed their outcomes, both the clinical outcome and radiologic outcome. We had imaging every 3 months and assessment by our clinician periodically to assess whether they progressed or not. We also asked our patients to collect their stool at baseline and at week 13 to assess the microbiome composition of their gut.

Did the changes in microbial functionality correlate with any clinical outcomes?

The response rate was much higher in the CBM588 arm, which was an experimental arm. For partial response, we had 74% of patients who had partial response in the CBM588 arm, but in the control arm we only had 20% of patients with partial response, so the response rate was much higher in the experimental arm.

When we checked the functionality of the gut microbiome, we saw that in the CBM588 arm, there was an increase in the pathways that function in producing menaquinone, but in the control arm, we have decreasing rates of those pathways. There is a significant difference between the functionality regarding vitamin K production between the 2 arms. At the same time, we had an increased response in the CBM588 arm, so this is the hypothesis that we have: The benefit was through an increase in the production of menaquinone.

How might these findings contribute to the understanding of immunotherapy and the gut microbiome in metastatic RCC?

I know there is a substantial [amount of] interest among patient communities around the role of CBM588 and, in general, the microbiome. But this study that we had here was a small study. Although it was positive, I should caution that we cannot conclude any clinical intervention at this point. We need a much larger study to suggest or advise our patients to take or not take any form of microbiome therapy.

At this time, we do not see the exact role that would warrant changing our practice. We are hoping that SWOG starts a phase 3 study using CBM588 in patients with metastatic renal cell carcinoma soon. There is an ongoing discussion to start a trial that will be phase 3 with a much larger population. The result of this future trial could be more clarifying regarding our clinical practice. We also are looking for future studies to assess the potential role of vitamin K and increase in the response in our patients.