72 Impact of microbiome modulation on serum cytokine profile in a randomized, phase I trial of cabozantinib/nivolumab (cabo/nivo) with or without CBM588 in pts with metastatic renal cell carcinoma (mRCC)

Abstract Background We have previously demonstrated that the orally administered, live bacterial product CBM588 can augment clinical outcomes with cabo/nivo in pts with mRCC (Ebrahimi et al ASCO 2023). As it is postulated this effect may be mediated through changes in systemic immunity, we sought to characterize changes in serum cytokine profile induced by CBM588. Methods Pts with previously untreated mRCC with clear cell, papillary or sarcomatoid histology were enrolled. Key eligibility criteria included Karnofsky performance status ≥ 70% and measurable disease. Pts were randomized to receive cabo/nivo on a standard schedule alone or the same regimen with CBM588 at 80 mg bid. Pts had blood collection performed at baseline and at weeks 9, 13, 17 and 25. Samples underwent processing within 4-6 hrs of collection, and a total of 30 cytokines and growth factors were assessed using the Luminex Flexmap 3D system (Biotechne). Changes in circulating cytokine levels between baseline and week 13 (± 7 days) were examined across the treatment arms to investigate the impact of CBM588 on the immune system. The Wilcoxon matched-pairs test was used to compare the levels of cytokines at the two timepoints. Results A total of 30 pts were enrolled; the majority were male (67%) and had intermediate- or poor-risk disease (60%). Most pts had clear cell histology (87%); 5 pts (17%) had sarcomatoid features. As previously reported, pts receiving cabo/nivo/CBM588 had a significantly higher response rate as compared to pts receiving cabo/nivo alone (74% vs 20%; P=0.01). Across baseline and week 13, a total of 53 samples were available for assessment. In pts receiving cabo/nivo/CBM588, there was a significant change in the level of IL-12, IL-13, eotaxin, interferon-γ, and granulocyte-macrophage colony stimulating factor (GM-CSF); this was not observed in the cabo/nivo alone arm. Additional flow cytometric analyses characterizing relevant CD4- and CD8-positive subsets will be presented. Conclusions Taken together with our previous study evaluating nivolumab/ipilimumab with CBM588 (Dizman et al Nat Med 2022), these results suggest that the augmented clinical outcome seen with the addition of CBM588 to cabo/nivo may be related to systemic immunomodulation. Combined analyses of the cohorts across studies are planned.