Cabozantinib and nivolumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial
Open accessAbstract
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
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CBM588 supplementation was associated with increased abundance of Ruminococcaceae, which has been linked to ICB response and metabolomic changes.
“Interestingly, CBM588 supplementation was associated with increased abundance of Ruminococcaceae, which has been linked to ICB response and metabolomic changes (Ebrahimi et al., 2024).”
From Microbiota-centered interventions to boost immune checkpoint blockade therapies (2025) · cites this paper as Ebrahimi et al., 2024
Supplementation with CBM588 improved the overall response rate (74% versus 20%) and the 6-month PFS rate (84% versus 60%).
“Ebrahimi et al. (2024) found that supplementation with CBM588 improved the overall response rate (74% versus 20%) and the 6-month PFS rate (84% versus 60%).”
From Microbiota-centered interventions to boost immune checkpoint blockade therapies (2025) · cites this paper as Ebrahimi et al., 2024
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References 42 · Cited by 109
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- Authors
- Ebrahimi, H., Dizman, N., Meza, L., Malhotra, J., Li, X., Dorff, T., Frankel, P., Llamas-Quitiquit, M., Hsu, J., Zengin, Z. B., Alcantara, M., Castro, D., Mercier, B., Chawla, N., Chehrazi-Raffle, A., Barragan-Carrillo, R., Jaime-Casas, S., Govindarajan, A., Gillece, J., Trent, J., Lee, P. P., Parks, T. P., Takahashi, M., Hayashi, A., Kortylewski, M., Caporaso, J. G., Lee, K., Tripathi, A., & Pal, S. K.
- Affiliations
- City Of Hope National Medical Center (US)
- Translational Genomics Research Institute (US)
- Osel (United States) (US)
- Miyarisan Pharmaceutical Co., Ltd. (Japan) (JP)
- Corresponding author
- Tripathi, Abhishek
- Pal, Sumanta K.
- ORCID
- Ebrahimi, Hedyeh
- Meza, Luis
- Malhotra, Jasnoor
- Li, Xiaochen
- Dorff, Tanya
- Frankel, Paul
- Hsu, Joann
- Zengin, Zeynep B.
- Alcantara, Marice
- Castro, Daniela
- Mercier, Benjamin
- Chawla, Neal
- Jaime-Casas, Salvador
- Govindarajan, Ameish
- Gillece, John
- Trent, Jeffrey
- Lee, Peter P.
- Takahashi, Motomichi
- Hayashi, Atsushi
- Kortylewski, Marcin
- Caporaso, J. Gregory
- Lee, Keehoon
- Tripathi, Abhishek
- Pal, Sumanta K.
- Venue
- Nature Medicine
- Published
- 2024-06-28
- Volume
- 30
- Issue
- 9
- Pages
- 2576-2585
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC11405272
- OpenAlex
- W4400126503
- Cited by
- 109
- References
- 42
- Citations by year
- 2026: 50 · 2025: 47 · 2024: 12
- FWCI
- 31.46
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Exelixis
- National Cancer Institute (U24CA248454)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal cell carcinoma treatment
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
- Keywords
- cabozantinib, nivolumab, metastatic renal cell carcinoma, gut microbiota, Bifidobacterium, tyrosine kinase inhibitors, immune checkpoint inhibitors, first-line therapy, objective response rate, progression-free survival, alpha diversity
- MeSH terms
- Gastrointestinal Microbiome, Nivolumab, Progression-Free Survival, Adult, Aged, Anilides, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Renal Cell, Female, Humans, Kidney Neoplasms, Male, Middle Aged, Neoplasm Metastasis, Pyridines
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