Cabozantinib and nivolumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial
- H. Ebrahimi
- N. Dizman
- Luis Meza
- J. Malhotra
- Xiaochen Li
- T. Dorff
- P. Frankel
- Marian Llamas-Quitiquit
- J. Hsu
- Z. Zengin
- Marice Alcantara
- Daniela V. Castro
- Benjamin D. Mercier
- N. Chawla
- A. Chehrazi-Raffle
- R. Barragán-Carrillo
- S. Jaime-Casas
- Ameish Govindarajan
- J. Gillece
- Jeffery M. Trent
- Peter P. Lee
- Thomas Parks
- Motomichi Takahashi
- Atsushi Hayashi
- Marcin Kortylewski
- J. Caporaso
- Keehoon Lee
- A. Tripathi
- S. Pal
What this study found
Adding CBM588 to cabozantinib plus nivolumab showed a signal of clinical benefit, but it did not alter gut Bifidobacterium abundance or alpha diversity. Objective response rate was higher with CBM588 than control: 74% (14 of 19) versus 20% (2 of 10), P = 0.01. Six-month progression-free survival was also higher in the CBM588 group: 84% (16 of 19) versus 60% (6 of 10), and clinical benefit occurred in 80% (16 of 20) versus 60% (6 of 10). The regimen did not show excess toxicity overall, although grade greater than or equal to 3 adverse events were reported in 40% versus 30% of participants…
- Study & population
- Randomized phase 1, single-center trial in treatment-naive adults with locally advanced or metastatic renal cell carcinoma, including clear cell, papillary, or sarcomatoid components and adequate performance status.
- Intervention
- CBM588, a live bacterial product (Clostridium butyricum), was given at 80 mg by mouth twice daily and continued indefinitely while participants remained on protocol.
- Key limitation
- This was a small phase 1, single-center study with only 20 participants in the active arm and limited power to assess efficacy or safety.
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Open PDFOriginal abstract
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 In a randomized phase 1 trial, the addition of a live Clostridium species-containing product to a tyrosine kinase inhibitor and anti-programmed cell death protein 1 treatment combination did not increase bacterial abundance of Bifidobacterium spp. but enhanced clinical responses in participants with metastatic renal cell carcinoma.