Cabozantinib and nivolumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial

作者：Hedyeh Ebrahimi, Nazlı Dizman, Luís Meza, Jasnoor Malhotra, Xiaochen Li, Tanya B. Dorff, Paul Frankel, Marian Llamas-Quitiquit, Joann Hsu, Zeynep Büşra Zengin, Marice Alcantara, Daniela V. Castro, Benjamin Mercier, Neal Shiv Chawla, Alex Chehrazi‐Raffle, Regina Barragán-Carrillo, Salvador Jaime‐Casas, Ameish Govindarajan, John D. Gillece, Jeffrey M. Trent, Peter P. Lee, Thomas P. Parks, Motomichi Takahashi, Atsushi Hayashi, Marcin Kortylewski, J. Gregory Caporaso, Keehoon Lee, Abhishek Tripathi, Sumanta K. Pal · 发表于：Nature Medicine · 年份：2024 · DOI：10.1038/s41591-024-03086-4 · 被引用次数：93 · 研究领域：Pancreatic and Hepatic Oncology Research、Renal cell carcinoma treatment、Cancer Research and Treatments

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) ...