Study illustrates changes to gut microbiome with CBM588 in kidney cancer
“These findings provide a plausible mechanism for the enhanced clinical outcome with CBM588 now seen across 2 small, randomized trials,” write the authors.
Live bacterial supplementation with CBM588 led to a notable correction in gut microbial dysbiosis and prevented the depletion of species previously associated with immune checkpoint inhibitor (ICI) response among patients with metastatic renal cell carcinoma (mRCC) receiving frontline ICI combinations, according to data presented at the 2024 Kidney Cancer Research Summit in Boston, Massachusetts.1
The investigators noted a marked difference in the ratio offirmicutes to bacteroidetes among the 2 cohorts.
The data were collected from 2 previous randomized phase 1 trials of CBM588 in which the clostridium butyricum-based live biotherapeutic was shown to enhance clinical outcomes with ICI-based regimens in patients with RCC. The first trial (NCT03829111) enrolled patients to either standard of care (SOC) with nivolumab (Opdivo) and ipilimumab (Yervoy) or to SOC plus CBM588. The second study (NCT05122546) enrolled patients to either cabozantinib (Cabometyx) and nivolumab (SOC) with or without CBM588.
The current analysis focused on the impact of CBM588 on gut microbiome composition, which may illustrate potential mechanisms behind the enhanced clinical efficacy observed in the 2 prior studies. Overall, data showed no statistically significant difference in alpha and beta diversity from baseline to week 12 between the SOC arms and the CBM588 arms.
Among individual species, no significant differences were noted regarding change in bifidobacterium spp between the SOC arms and the CBM588 arms from baseline to week 12, consistent with what was reported in the results from each individual study. However, a decrease in eubacterium siraeum was observed only in the SOC cohort (log fold change, -1.75; P = .0049).
According to presenting author Nazli Dizman, MD, a hemotology/oncology fellow at MD Anderson Cancer Center, “This species is one of the species that has been repeatedly shown to be associated with better response to immune checkpoint inhibitors, mostly in melanoma.”
The investigators also noted a marked difference in the ratio of firmicutes to bacteroidetes among the 2 cohorts. In the CBM588 arms, this ratio decreased from 100.0% at baseline to 75.7% at 12 weeks. In the SOC arm, the ratio remained stable, with an increase from 89.0% at baseline to 96.4% at 12 weeks. According to Dizman, this finding may suggest “a shift towards a more [ubiquitous] microbiome signature with the addition of CBM588 in first-line setting with immune checkpoint blockade.”
With these results taken altogether, the authors write, “These findings provide a plausible mechanism for the enhanced clinical outcome with CBM588 now seen across 2 small, randomized trials.”1
In total, the study included 58 patients with RCC, of whom 38 received SOC with CBM588. The median age of participants was 60 years (range, 36-90). The majority of patients were male (71%), had clear cell mRCC (88%), and had intermediate/poor-risk disease (79%). Stool samples were collected from all patients at baseline and week 12.
In both trials included in the analysis, the primary endpoint was the effect of CBM588 on the relative abundance of bifidobacterium spp. The primary end point was not met in either study. Secondary outcome measures included progression-free survival, objective response rate, and safety. On these measures, the addition of CBM588 was associated with improvements in clinical outcomes.
According to the authors, plans for additional evaluation of CBM588 are underway. They write, “A phase 3 study is planned within the cooperative groups to evaluate the clinical activity and gut microbiome modulation capacity of CBM588 in combination with ICIs in mRCC.”
References
1. Dizman N, Ebrahimi H, Barragan-Carrillo R, et al. Impact of CBM588 on gut microbiome composition and dysbiosis in patients receiving frontline immune checkpoint inhibitor (ICI) combinations for metastatic renal cell carcinoma (mRCC). Presented at: 2024 Kidney Cancer Research Summit. July 11-12, 2024. Boston, Massachusetts. Abstract 77. Accessed July 15, 2024. https://kcrs.kidneycan.org/wp-content/uploads/2024/06/KCRS24-Abstract-Book-6.27.24.pdf
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