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Recent years have seen rapid evolutions in the science surrounding the human microbiome, and that research extends into the oncology space. Hedyeh Ebrahimi, MD, MPH, and other researchers at City of Hope Comprehensive Cancer Center sought to investigate the possible 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, even though the addition of CBM588 to checkpoint inhibitor therapy produced 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 produced 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, differences were seen in metabolic pathways related to vitamin K production. Patients who received CBM588 showed an increase in pathways that produce menaquinone, a form of vitamin K, while those who did not receive CBM588 had a decrease in those roads.
The study is small and the findings are preliminary but encouraging, so larger trials are required to validate them. The potential role of CBM588 and vitamin K in improving mCRC treatment responses remains a topic of exploration and could contribute to a better understanding of immunotherapy and the microbiome.
In an interview with Targeted OncologyM.T.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 give us an overview of your research on the evolution of microbial communities in patients with metastatic CRC receiving this cabozantinib/nivolumab combination with or without CBM588?
Ebrahimi: As you may know, for first-line treatment in the setting of metastatic renal cell carcinoma, most of the time we have two options. One uses dual checkpoint inhibitors and the other is the combination of a checkpoint inhibitor plus a VEGF-targeted therapy, such as cabozantinib plus nivolumab.
We have some previous studies that showed that the composition of patients’ gut microbiome 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 who receive ipilimumab plus nivolumab.
A little background on 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 arose from that first study in Japan.
In the previous study 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 commonly used in the setting of metastatic CRC is the combination of VEGF-targeted therapy with immunotherapy. In the current study, we designed a phase 1 trial with 30 patients with advanced CRC to receive either cabozantinib plus nivolumab at a standard dose 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 patients who received CBM588. We had a first hypothesis that this greater clinical benefit was true, since it changed the composition of the microbiome in the patient’s intestine and increased Bifidobacterium species. But as in the previous study, we did not see any significant change in the abundance of Bifidobacterium species in any of the study branches.
We also checked the diversity of microbiome composition in our patients and saw no significant changes in Alpha diversity between baseline and post-treatment in either arm.
We looked further to see if there is a difference between the metabolic pathways that occur in the gut. To our surprise, we saw that in patients who received cabozantinib plus nivolumab at standard doses without CBM588, the metabolic pathways that are functional in the production of menaquinone, which is a form of vitamin K, were decreased. At the same time, in patients who received CBM588, pathways that function in vitamin K production increased.
Our thinking in the current study was that there is a possibility that CBM588 increases the response in our patients by increasing vitamin K. We have some data that states from previous studies, clinical and preclinical, that vitamin K has a functional role in apoptosis of cancer. cells.
For example, there is a study in hepatocellular carcinoma that showed that patients who received vitamin K in addition to sorafenib, a treatment used in that setting, have better outcomes. So we thought that CBM588 increased the level of menaquinone or vitamin K production, and that’s how it increased the response in our patients.
Can you describe the methodology of this study?
In this study, we enrolled patients who had advanced or metastatic renal cell carcinoma. It was a first-line treatment, so the patient should not have received any type of systemic treatment for the metastatic disease. They must have a confirmed histology report of clear cell, papillary, or sarcomatoid pathology.
In the trial, we had 30 patients. We had a 2:1 randomization, meaning 20 patients out of 30 received cabozantinib plus nivolumab plus CBM588, and 10 patients in the control group received only cabozantinib plus nivolumab at a standard dose alone.
We evaluate their results, both the clinical result and the radiological result. We had imaging every 3 months and our doctor evaluated them periodically to assess whether they were progressing or not. We also asked our patients to collect their stool at baseline and at week 13 to assess the composition of their gut microbiome.
Were changes in microbial functionality correlated with any clinical outcomes?
The response rate was much higher in the CBM588 group, which was an experimental group. For partial response, we had 74% patients who had a partial response in the CBM588 group, but in the control group we only had 20% patients who had a partial response, so the response rate was much higher in the experimental group.
When we checked the functionality of the gut microbiome, we saw that in the CBM588 arm, there was an increase in pathways that function in menaquinone production, but in the control arm, we have decreasing rates of those pathways. There is a significant difference in functionality with respect to vitamin K production between the 2 arms. At the same time, we had a greater response in the CBM588 group, so this is the hypothesis we have: the benefit came through an increase in menaquinone production.
How might these findings contribute to the understanding of immunotherapy and the gut microbiome in metastatic CRC?
I know there is a substantial [amount of] interest among patient communities around the role of CBM588 and, more generally, the microbiome. But this study that we had here was a small study. Although it was positive, I must warn that we cannot conclude any clinical intervention at this time. 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 justify changing our practice. We expect SWOG to soon begin a Phase 3 study using CBM588 in patients with metastatic renal cell carcinoma. 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 enlightening regarding our clinical practice. We are also looking at future studies to evaluate the potential role of vitamin K in increasing response in our patients.