Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
MD Anderson Cancer Center, Houston, TX, USA.
Nat Med. 2024 Sep;30(9):2576-2585. doi: 10.1038/s41591-024-03086-4. Epub 2024 Jun 28.
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 CBM588，一种双歧杆菌活菌产品，与接受纳武利尤单抗和伊匹单抗治疗的转移性肾细胞癌（mRCC）患者的临床结局改善相关。然而，其对接受酪氨酸激酶抑制剂联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 患者（组织学证实为透明细胞、乳头状或肉瘤样成分）以 2:1 的比例随机接受卡博替尼（血管内皮生长因子受体、MET 和 AXL 的抑制剂）和纳武利尤单抗（程序性细胞死亡蛋白 1 抑制剂）联合或不联合 CBM588 作为一线治疗。在基线和治疗 13 周时，对粪便样本进行宏基因组测序以表征其肠道微生物组。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。研究的主要终点未达到，CBM588 联合卡博替尼和纳武利尤单抗治疗并未导致双歧杆菌属相对丰度或 alpha 多样性（以 Shannon 指数衡量）的差异。然而，与对照组相比，接受 CBM588 治疗的患者的 ORR 显著更高（19 例中有 14 例，74%，而 10 例中有 2 例，20%；P=0.01）。实验组和对照组 6 个月时的 PFS 分别为 84%（19 例中有 16 例）和 60%（10 例中有 6 例）。两组之间的毒性特征没有显著差异。我们的结果初步表明，在接受卡博替尼和纳武利尤单抗治疗的初治 mRCC 患者中，CBM588 具有改善的临床活性。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。临床试验.gov 标识符：NCT05122546。
