KEY TAKEAWAYS
- The phase 1 trial aimed to investigate the correlation between gut microbial functionality and clinical outcomes in mRCC patients undergoing cabo/nivo therapy, ± CBM588.
- Researchers noticed distinct metabolic changes and improved clinical outcomes in mRCC patients treated with cabo/nivo.
The previous prospective studies revealed CBM588’s potential to enhance clinical outcomes in patients with metastatic renal cell carcinoma (mRCC). Hedyeh Ebrahimi and her team aimed to investigate the association between gut microbial functionality and clinical outcomes in mRCC patients undergoing cabo/nivo therapy, with or without CBM588.
They performed an inclusive analysis enrolling patients aged ≥18 yrs old with histologically verified mRCC, including (clear-cell, papillary, or sarcomatoid components) and without prior systemic therapy for metastatic disease. The study employed a 1:2 randomization, with patients receiving either standard-dose cabo/nivo alone or combined with CBM588 dosed at 80mg PO BID. Stool specimens collected at baseline and week 12 underwent whole metagenome sequencing. Taxonomic profiling utilized MetaPhlAn 4, while functional profiling employed HUMAnN 3, offering accurate information on metabolic pathways and molecular functions. Open reading frames were annotated to provide insights into metagenomic or metatranscriptomic sequencing data. The ANCOM-BC method detected taxonomic/genetic features with differential abundance within the same treatment arm.
About 30 patients (20:10 M:F) were enrolled in the study, with a median age of 65 (36-84). Of these, 5 patients (17%) exhibited sarcomatoid features, and 2 (7%) presented with predominant papillary histology. In the cabo/nivo arm, 20% of patients achieved an objective response, while in the cabo/nivo/CBM588 arm, this rate increased significantly to 65%.
The analysis identified noteworthy changes in metabolic pathways between the two arms. In the control arm, cabo/nivo treatment resulted in significant alterations in 9 metabolic pathways (1 upregulation, 8 downregulation), and 7 metabolic pathways (2 upregulation, 5 with downregulation) in the experimental arm were identified.
Notably, the super pathways associated with the biosynthesis of various forms of menaquinole, a reversible redox component in the electron transfer chain, were depleted in the cabo/nivo arm. In contrast, the cabo/nivo/CBM588 arm exhibited upregulation in the biosynthesis of menaquinol-8 and 1,4 dihydroxy-6-naphthoate—an intermediate in the menaquinone pathway. These findings shed light on the impact of CBM588 on the metabolic dynamics of mRCC patients undergoing cabo/nivo therapy, potentially influencing treatment outcomes.
The study concluded that observed differences in menaquinone biosynthesis pathways between control and experimental arms suggest a potential mechanism for the impact of CBM588 on gut microbiome function. Drawing on previous reports linking menaquinones (vitamin K2 derivatives) to apoptosis induction and enhanced response rates to sorafenib in hepatocellular carcinoma, our findings provide mechanistic evidence for CBM588’s addition to cabo/nivo therapy in mRCC. This potential enhancement of enteric production of vitamin K2 offers insights into the observed improvement in clinical outcomes, suggesting a promising avenue for therapeutic strategies in mRCC.
The study is sponsored by City of Hope Medical Center
Source: https://meetings.asco.org/abstracts-presentations/229978
Clinical Trial: https://clinicaltrials.gov/study/NCT05122546
Ebrahimi H, Meza L A, Lee K, et al (2024). “Evolution of the functionality of microbial communities in patients with metastatic renal cell carcinoma (mRCC) receiving cabozantinib (cabo)/nivolumab (nivo) with or without CBM588: A randomized clinical trial.” Presented at ASCO-GU 2024 (Abstract 460).
