Microbial dysbiosis may predict response to CBM588 in mRCC

In the following video, Rahul Winayak, MD, discusses a study evaluating whether baseline microbial dysbiosis influences the benefit of the Clostridium butyricum-based live biotherapeutic CBM588 when added to first-line immune checkpoint inhibitor (ICB)-based regimens for metastatic renal cell carcinoma (mRCC).¹ These results were presented at the 2026 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois.

Winayak is a postdoctoral fellow in genitourinary oncology at City of Hope in Duarte, California.

CBM588 is a live bacterial product containing Clostridium butyricum that has shown the ability in preclinical studies to enhance antitumor immune responses. The agent also demonstrated signals of enhanced clinical activity when combined with first-line ICB-based combinations in 2 phase 1 trials for mRCC. The current analysis sought to understand the mechanism behind this benefit by assessing the prognostic and predictive value of microbial dysbiosis.

The phase 1 studies included 59 treatment-naïve patients with mRCC who received nivolumab (Opdivo)/ipilimumab (Yervoy) (NCT03829111) or nivolumab/cabozantinib (Cabometyx) (NCT05122546) with or without CBM588. Overall, the addition of CBM588 was associated with improved clinical outcomes, with an objective response rate of 66.7% with the standard of care (SOC) + CBM588 arm compared with 20.0% for SOC alone (P = .001). The median progression-free survival (PFS) was 32.1 months with SOC + CMB588 vs 3.7 months, respectively (HR, 0.36; 95% CI, 0.19 to 0.67; P = .001).

To investigate the mechanism underlying these benefits, investigators analyzed baseline stool samples using TOPOSCORE, a metagenomic dysbiosis index linked to ICB outcomes, which categorizes patients into dysbiotic (SIG1+) and non-dysbiotic (SIG2+) phenotypes. The findings suggested that patients with a dysbiotic microbiome derived the greatest benefit from CBM588. Among patients with the SIG1+ phenotype, median PFS was 24.9 months with CBM588 plus standard therapy vs 2.8 months with standard therapy alone (HR, 0.19; 95% CI, 0.07 to 0.53; P < .001), whereas differences in the SIG2+ cohort were not statistically significant (32.0 vs 10.9 months; HR, 0.49; 95% CI, 0.19 to 1.3; P = .149). Investigators also observed that higher baseline S scores, a quantitative component of TOPOSCORE, were associated with response among patients treated with the nivolumab/ipilimumab backbone but not among those receiving nivolumab/cabozantinib. According to the investigators, these findings support the potential utility of TOPOSCORE as a predictive biomarker for microbiome-directed therapy and will be further evaluated in the phase 3 BIOFRONT trial.

REFERENCE

1. Winayak R, Qi X, Moradi A, et al. Microbial dysbiosis as predictor of benefit from CBM588 as an adjunct to immune checkpoint blockade (ICB)–based first line therapies in metastatic renal cell carcinoma (mRCC). J Clin Oncol. 44, 2026 (suppl 16; abstr 4519). doi:10.1200/JCO.2026.44.16_suppl.4519