Long-term clinical outcomes with <i>Clostridium butyricum</i> MIYAIRI 588 (CBM588) and TOPOSCORE assessment in patients receiving immune checkpoint inhibitor (ICI)-based combinations for metastatic renal cell carcinoma (mRCC).

507 Background: Two randomized phase I trials demonstrated that CBM588, a live biotherapeutic, may enhance the antitumor efficacy of frontline ICI-based regimens in mRCC (Dizman et al Nat Med 2022; Ebrahimi et al Nat Med 2024). For the first time, we present an updated, pooled analysis of long-term clinical outcomes from a combined cohort of these two studies. Methods: Data from two open-label, randomized phase I clinical trials were analyzed. Eligible patients were adults with advanced or metastatic RCC, Karnofsky performance status ≥70%, no prior systemic therapy, and measurable disease per RECIST 1.1. Participants were randomized to receive nivolumab/ipilimumab or nivolumab/cabozantinib alone (standard of care [SOC]) or with CBM588 (SOC + CBM588). The pooled clinical outcomes including objective response rate (ORR; complete response [CR] or partial response [PR]), disease control rate (DCR; CR, PR, or stable disease [SD] ≥ 6 months), progression-free survival (PFS), and overall survival (OS), were compared between treatment groups, using Fisher’s Exact test and Kaplan Meier log rank test, respectively. The TOPOSCORE, a measure of microbial dysbiosis associated with poor prognosis with ICIs, was derived for all stool samples collected across both studies, using previously published bioinformatic methods (Derosa et al Cell 2024). Results: Fifty-nine patients were included: 20 received SOC and 39 received SOC + CBM588. The median age was 65 years (range 36-90); 69.5% were male, 88.1% had clear-cell mRCC, and 67.8% had intermediate/poor IMDC risk. Baseline characteristics were similar in both arms. Pooled ORR and DCR were 66.7% and 82% with SOC + CBM588 versus 20% and 55% with SOC alone (p = 0.001 and p = 0.019, respectively). Median follow-up was 43.9 months (95% CI 42.5-73) for SOC+CBM and 44.1 months (95% CI 35.4-NE) for SOC. Median PFS was 35 months (95% CI 25.3-NE) with SOC + CBM588 and 19.3 months (95% CI 6.5-NE) with SOC, with a hazard ratio (HR) of 0.44 (95% CI 0.22-0.88; p = 0.02). Median OS was 52.7 months (95% CI 37.3-NE) with SOC+CBM588 and 45.7 months (95% CI 29.2-NE) with SOC (HR 0.69, 95% CI 0.32-1.47, p = 0.33). Exploratory analysis using the TOPOSCORE microbiome metric showed that baseline microbiota profiles were similar between SOC and SOC + CBM588 in both trials. Notably, however, baseline gut microbiota composition was associated with treatment response in the dual ICI subgroup, but not in the ICI + VEGFR-TKI subgroup. Conclusions: In this pooled analysis of two randomized phase I trials, the addition of CBM588 to frontline ICI-based therapy was associated with higher ORR and prolonged PFS compared with SOC alone, supporting the design of the upcoming phase III SWOG BIOFRONT study. We also identify baseline TOPOSCORE as a potential predictor of benefit with dual ICI regimens. Clinical trial information: NCT05122546 , NCT03829111 .