Cabozantinib (cabo) and nivolumab (nivo) with or without CBM588 in patients with metastatic renal cell carcinoma: Updated clinical outcomes of a phase I study.
Authors: Ebrahimi Hedyeh , Meza Luis A , Dizman Nazli , Barragan-Carrillo Regina , Li Xiaochen , Llamas-Quitiquit Marian , Hsu Joann , Zengin Zeynep Busra , Castro Daniela V. , Mercier Benjamin , Zugman Miguel , Jaime-Casas Salvador , Chehrazi-Raffle Alex , Trent Jeffrey M. , Lee Peter P. , Takahashi Motomichi , Dorff Tanya B. , Caporaso Gregory , Lee Keehoon , Pal Sumanta Kumar 
Published: February 2025

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Background:
We previously reported that combining CBM588 (
Clostridium butyricum
MIYAIRI588), a live bacterial product, with cabozantinib (cabo) and nivolumab (nivo) enhanced clinical benefit in treatment-naïve patients with mRCC (Ebrahimi
et al
;
Nature Medicine
2024). The current study provides updated clinical data to further evaluate the potential benefits of CBM588 in combination with cabo/nivo.
Methods:
This open-label, randomized trial enrolled patients aged ≥18 years old with a Karnofsky performance status ≥70% and histologically verified (clear-cell, papillary or sarcomatoid component) advanced or mRCC with no prior systemic therapy for metastatic disease. Patients were randomized in a 1:2 ratio to receive either cabo/nivo (40mg PO QD and 480mg IV monthly, respectively) alone or with CBM588 (80mg PO BID). This analysis provides updated secondary clinical endpoints with extended follow-up, including overall response rates (ORR), progression-free survival (PFS), and toxicity. Clinical benefit was defined as complete response, partial response, or stable disease, per RECIST 1.1. The association between treatment arm and ORR was evaluated using Fisher’s exact test, and PFS was estimated using the Kaplan-Meier method.
Results:
A total of 30 patients (20:10 M:F) were recruited, with a median age of 65 years (range, 36-84). Five patients (17%) had sarcomatoid features, and two (7%) had predominant papillary histology. As of June 1, 2024, the median follow-up was 25.8 months (interquartile range, 19.2-28.1) in the overall cohort. The ORR was significantly higher in the CBM588-containing arm compared to cabo/nivo alone arm (79% versus 20%,
P
=0.004). In the CBM588 arm, 17 (89%) patients, and in the control arm, 8 (80%) patients had a reduction in target lesion size, with median decreases of 51% (range, 17-94%) and 22% (range, 13-100%), respectively. Clinical benefit for at least 6 months was achieved in 80% of patients treated in experimental arm and 60% patients in the control arm. The median PFS was not reached in patients receiving CBM588, compared to 13.4 months in the control arm. The median OS was not reached in either of the arms at the time of data cutoff. Grade 3 or higher treatment-related adverse events (TRAEs) were observed in 45% of the CBM588 arm compared to 40% in the control arm. The most common TRAEs in the overall cohort were transaminitis (10%), hypertension (7%), and diarrhea (7%), with no significant differences between treatment arms. No new safety signals were detected.
Conclusions:
The addition of CBM588 to cabo/nivo continues to show promising efficacy in mRCC, with an improved PFS and ORR. The safety profile remains consistent with previous findings, supporting further exploration in larger trials. Further translational efforts are underway to characterize the mechanism through which CBM588 augments clinical activity. Clinical trial information:
NCT05122546
.