Supplementation with CBM588, a bifidogenic live bacterial product, has been associated with improved clinical outcomes in persons with metastatic renal cell carcinoma (mRCC) receiving nivolumab and ipilimumab. However, its effect on those receiving tyrosine kinase inhibitor-based combinations is unknown. In this open-label, randomized, investigator-initiated, phase 1 study, 30 participants with locally advanced or mRCC with histological confirmation of clear cell, papillary or sarcomatoid component were randomized in a 2:1 fashion to receive cabozantinib (an inhibitor of vascular endothelial growth factor receptor, MET and AXL) and nivolumab (anti-programmed cell death protein 1) with or without CBM588 as first-line treatment. Metagenomic sequencing was performed on stool samples to characterize their gut microbiome at baseline and 13 weeks into treatment. The primary endpoint was a change in the relative abundance of Bifidobacterium spp.; secondary endpoints included objective response rate (ORR), progression-free survival (PFS) and toxicity profile. The primary endpoint of the study was not met and the addition of CBM588 to cabozantinib and nivolumab did not result in a difference in the relative abundance of Bifidobacterium spp. or alpha diversity (as measured by the Shannon index). However, ORR was significantly higher in participants treated with CBM588 compared to those in the control arm (14 of 19, 74% versus 2 of 10, 20%; P = 0.01). PFS at 6 months was 84% (16 of 19) and 60% (6 of 10) in the experimental and control arms, respectively. No significant difference in toxicity profile was seen between the study arms. Our results provide a preliminary signal of improved clinical activity with CBM588 in treatment-naive participants with mRCC receiving cabozantinib and nivolumab. Further investigation is needed to confirm these findings and better characterize the underlying mechanism driving this effect.

ClinicalTrials.gov identifier: NCT05122546

补充 CBM588（一种双歧活细菌产品）可改善接受纳武单抗和伊匹单抗治疗的转移性肾细胞癌 (mRCC) 患者的临床结果。然而，它对接受基于酪氨酸激酶抑制剂的组合治疗的患者的影响尚不清楚。在这项开放标签、随机、研究者发起的 1 期研究中，30 名局部晚期或 mRCC 且组织学证实有透明细胞、乳头状或肉瘤样成分的参与者以 2:1 的方式随机接受卡博替尼（一种血管抑制剂）内皮生长因子受体（MET 和 AXL）和纳武单抗（抗程序性细胞死亡蛋白 1）联合或不联合 CBM588 作为一线治疗。对粪便样本进行宏基因组测序，以表征基线和治疗 13 周时的肠道微生物组。主要终点是双歧杆菌属相对丰度的变化；次要终点包括客观缓解率（ORR）、无进展生存期（PFS）和毒性特征。该研究的主要终点并未达到，并且在卡博替尼和纳武单抗中添加 CBM588 并没有导致双歧杆菌属相对丰度的差异。或阿尔法多样性（通过香农指数衡量）。然而，与对照组相比，接受 CBM588 治疗的参与者的 ORR 显着更高（19 名参与者中的 14 名，74% vs 10 名中的 2 名，20%；P = 0.01）。实验组和对照组在 6 个月时的 PFS 分别为 84%（19 例中的 16 例）和 60%（10 例中的​​ 6 例）。研究组之间的毒性特征没有显着差异。 我们的结果提供了一个初步信号，表明 CBM588 在接受卡博替尼和纳武单抗治疗的 mRCC 初治参与者中改善了临床活性。需要进一步的研究来证实这些发现并更好地描述驱动这种效应的潜在机制。

ClinicalTrials.gov 标识符：NCT05122546