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

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. Participants were randomized 2:1 to the CBM588-containing regimen or cabozantinib plus nivolumab alone; the active intervention arm included 20 participants.

CBM588, a live bacterial product (Clostridium butyricum), was given at 80 mg by mouth twice daily and continued indefinitely while participants remained on protocol. It was added to cabozantinib 40 mg by mouth daily plus nivolumab 480 mg IV every 4 weeks, compared with cabozantinib plus nivolumab alone.

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 and grade 4 events in 0% versus 10%.

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. Follow-up was relatively short, overall survival and progression-free survival were not reached, and the microbiome endpoints were exploratory and did not show the expected change. Generalizability is limited, and the findings require confirmation in larger trials.