Long-term clinical outcomes with nivolumab/ipilimumab with or without <i>Clostridium butyricum</i> MIYAIRI588 in metastatic renal cell carcinoma (mRCC): A randomized phase Ib clinical trial.

4550 Background: In two randomized phase I trials, Clostridium butyricum MIYAIRI588 (CBM588), a live biotherapeutic, demonstrated preliminary activity in modulating the gut microbiome, enhancing systemic immune responses, and improving clinical outcomes in patients receiving first-line nivolumab/ipilimumab and nivolumab/cabozantinib for mRCC (Dizman et al. and Ebrahimi et al. Nature Medicine). Herein, we present the long-term follow-up data for nivolumab/ipilimumab with or without CBM588. Methods: Newly diagnosed patients with mRCC, clear cell and/or sarcomatoid histology, and International mRCC Database Consortium intermediate/high risk were randomized to receive nivolumab/ipilimumab with or without CBM588 in a 2:1 ratio. Response outcomes were assessed using RECIST 1.1. Clinical outcomes were secondary endpoints. Objective response rate (ORR; complete response [CR] or partial response [PR]), disease control rate (DCR; CR, PR, or stable disease [SD] &gt; 6 months), progression-free survival (PFS), and overall survival (OS) outcomes were compared across arms. Results: Twenty-nine patients were included in the final analysis: 19 in the nivolumab/ipilimumab with CBM588 arm and 10 in the nivolumab/ipilimumab arm. The median age was 66.2 years, 72% were male, 83% had IMDC intermediate risk and 93% had clear cell histology. Baseline characteristics were similar across arms. ORR and DCR were 58% and 79% in nivolumab/ipilimumab with CBM588 arm versus 20% and 20% in nivolumab/ipilimumab arm, respectively (p = 0.06 and p = 0.004). At a median follow-up of 60.0 (95% CI 51.9-68.1) months, the median PFS was 38.2 (95% CI 23.6-52.8) months in the nivolumab/ipilimumab and CBM588 arm versus 19.3 (95% CI 0-41.9) months in the nivolumab/ipilimumab arm (Hazard ratio [HR] 0.24, 95% CI 0.09-0.61 p = 0.003). At the time of data cutoff, 9 (47.4%) and two (20%) patients were alive in the nivolumab/ipilimumab with CBM588 and nivolumab/ipilimumab arms, respectively. The median OS with nivolumab/ipilimumab with CBM588 was 55.0 (95% CI 10.5-75.5) months versus 39.0 (95% CI 23.7-54.3) months with nivolumab/ipilimumab (HR 0.438 [95% CI 0.17-1.1] p = 0.09). Conclusions: Although limited by the sample size, the combination of nivolumab/ipilimumab with CBM588 demonstrated superior clinical activity over nivolumab/ipilimumab in our cohort. Additionally, ORR, PFS and OS with nivo/ipi/CBM588 exceeded those observed with nivolumab and ipilimumab in historical datasets (Motzer et al. NEJM). Larger efforts investigating the impact of CBM588 on clinical outcomes are underway. Clinical trial information: NCT03829111 .