First results of a randomized phase IB study comparing nivolumab/ipilimumab with or without CBM-588 in patients with metastatic renal cell carcinoma.

Abstract

4513 Background: Recent evidence suggests that the gut microbiome is a potent mediator of immune checkpoint inhibitor (ICI) activity in metastatic renal cell carcinoma (mRCC), with both specific bacterial species and cumulative microbial diversity driving response (Routy et al Science 2018; Salgia et al Eur Urol 2020). We examined whether the butyrate-producing bacterium Clostridium butyricum, the key constituent of CBM-588, could modulate the gut microbiome in patients (pts) with mRCC receiving nivolumab/ipilimumab (N/I) and secondarily improve clinical outcome. Methods: An open-label, randomized study was conducted, with key eligibility criteria including confirmed clear cell and/or sarcomatoid mRCC, intermediate/poor risk by IMDC criteria and no systemic therapy for metastatic disease. Patients were randomized 2:1 to receive either N/I+CBM-588 or N/I alone. N/I was dosed at 3 mg/kg and 1 mg/kg IV every 3 weeks for 12 weeks, followed by N at 480 mg IV every 4 weeks. CBM-588 was dosed orally at 80 mg bid. Stool was collected for bacteriomic profiling at baseline and 12 weeks. Metagenomic sequencing was employed using previously published methods (Dizman et al Cancer Med 2020). The primary endpoint of the study was change in Bifidobacterium spp. from baseline to week 12. Secondary endpoints included change in microbial diversity and clinical outcomes including response rate (RR) and progression-free survival (PFS). Results: 30 pts were randomized between April 2019 and Nov 2020; 1 pt was excluded after genomic sequencing clarified a diagnosis of sarcoma. Among 29 evaluable patients (21:8 M:F), median age was 66, 10 pts (34%) had sarcomatoid features and 24 pts (83%) were intermediate risk. Metagenomic sequencing of paired stool specimens showed an 8-fold increase in B. bifidum and a 6-fold increase in B. adolescentis in pts receiving N/I+CBM-588 from baseline to week 12. C. butyricum was detected only in pts receiving CBM-588. Pathogenic species (e.g., Escherichia. coli and Klebsiella spp.) were more prevalent in pts not receiving CBM-588. RR was significantly higher among pts receiving N/I+CBM-588 vs N/I alone (59% vs 11%; P = 0.024). Median PFS was also prolonged with the addition of CBM-588 to N/I (NR vs 11 weeks; P < 0.001). No significant difference in grade 3/4 toxicities were observed between study arms. Conclusions: This is the first randomized, prospective study to suggest enhancement of ICI response with a live bacterial product. The observed clinical impact is corroborated by biologic findings supporting gut modulation by CBM-588. Clinical trial information: NCT03829111.

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“…67 There have been promising early results looking at immunotherapy in combination with probiotic treatment in renal cell carcinoma, and there is currently a trial in metastatic CRPC studying fecal transplants from pembrolizumab responders to nonresponders (NCT04116775). 68 Although these findings are not specific to MMRd, it is possible that they may also play a role in influencing tumor response in this population.…”

“…Antibiotics, which alter commensal bacteria in the gut, have also been shown to reduce response to checkpoint inhibitors, supporting the role of specific gut flora composition in immunotherapy response 67 . There have been promising early results looking at immunotherapy in combination with probiotic treatment in renal cell carcinoma, and there is currently a trial in metastatic CRPC studying fecal transplants from pembrolizumab responders to nonresponders (NCT04116775) 68 . Although these findings are not specific to MMRd, it is possible that they may also play a role in influencing tumor response in this population.…”

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“…Expression or upregulation of target molecules such as CTLA-4 or PD-1/PD-L1 in normal tissues has also been associated with risk of IRAEs targeting the respective cells[ 69 , 70 ]. The composition of gut microbiota is implicated in the risk for IRAEs development[ 71 ]; the former is known to be associated with response to ICIs[ 72 ] and active modification through probiotic supplementation has been shown to enhance ICI activity and responses[ 73 ]. Systemic administration of antibiotics is known to affect gut microbiota composition[ 74 ] and has been associated with worse responses to ICIs[ 75 , 76 ].…”

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“…were detected more frequently in patients not receiving the investigational agent. Clinical response to ICI-based therapy was improved among patients receiving CBM-588, with higher ORR (59% vs. 11%, p = 0.024) and longer mPFS (NR vs. 11 weeks, p < 0.001) [ 89 ]. The gut microbiome has also been associated with toxicity to ICI-based therapy.…”