TY - JOUR
T1 - Cabozantinib and nivolumab with or without live bacterial supplementation in metastatic renal cell carcinoma
T2 - a randomized phase 1 trial
AU - Ebrahimi, Hedyeh
AU - Dizman, Nazli
AU - Meza, Luis
AU - Malhotra, Jasnoor
AU - Li, Xiaochen
AU - Dorff, Tanya
AU - Frankel, Paul
AU - Llamas-Quitiquit, Marian
AU - Hsu, Joann
AU - Zengin, Zeynep B.
AU - Alcantara, Marice
AU - Castro, Daniela
AU - Mercier, Benjamin
AU - Chawla, Neal
AU - Chehrazi-Raffle, Alex
AU - Barragan-Carrillo, Regina
AU - Jaime-Casas, Salvador
AU - Govindarajan, Ameish
AU - Gillece, John
AU - Trent, Jeffrey
AU - Lee, Peter P.
AU - Parks, Thomas P.
AU - Takahashi, Motomichi
AU - Hayashi, Atsushi
AU - Kortylewski, Marcin
AU - Caporaso, J. Gregory
AU - Lee, Keehoon
AU - Tripathi, Abhishek
AU - Pal, Sumanta K.
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/9
Y1 - 2024/9
N2 - 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
AB - 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
UR - http://www.scopus.com/inward/record.url?scp=85197924685&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85197924685&partnerID=8YFLogxK
U2 - 10.1038/s41591-024-03086-4
DO - 10.1038/s41591-024-03086-4
M3 - Article
C2 - 38942995
AN - SCOPUS:85197924685
SN - 1078-8956
VL - 30
SP - 2576
EP - 2585
JO - Nature Medicine
JF - Nature Medicine
IS - 9
ER -