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Nivolumab plus ipilimumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial

  • Nazli Dizman,
  • Luis Meza,
  • Paulo Bergerot,
  • Marice Alcantara,
  • Tanya Dorff,
  • Yung Lyou,
  • Paul Frankel,
  • Yujie Cui,
  • Valerie Mira,
  • Marian Llamas,
  • Joann Hsu,
  • Zeynep Zengin,
  • Nicholas Salgia,
  • Sabrina Salgia,
  • Jasnoor Malhotra,
  • Neal Chawla,
  • Alex Chehrazi-Raffle,
  • Ramya Muddasani,
  • John Gillece,
  • Lauren Reining,
  • Jeff Trent,
  • Motomichi Takahashi,
  • Kentaro Oka,
  • Seiya Higashi,
  • Marcin Kortylewski,
  • Sarah K. Highlander,
  • Sumanta K. Pal

Publication: Nature Medicine, February 2022

Previous studies have suggested that the gut microbiome influences the response to checkpoint inhibitors (CPIs) in patients with cancer. CBM588 is a bifidogenic live bacterial product that we postulated could augment CPI response through modulation of the gut microbiome. In this open-label, single-center study (NCT03829111), 30 treatment-naive patients with metastatic renal cell carcinoma with clear cell and/or sarcomatoid histology and intermediate- or poor-risk disease were randomized 2:1 to receive nivolumab and ipilimumab with or without daily oral CBM588, respectively. Stool metagenomic sequencing was performed at multiple timepoints. The primary endpoint to compare the relative abundance of Bifidobacterium spp. at baseline and at 12 weeks was not met, and no significant differences in Bifidobacterium spp. or Shannon index associated with the addition of CBM588 to nivolumab–ipilimumab were detected. Secondary endpoints included response rate, progression-free survival (PFS) and toxicity. PFS was significantly longer in patients receiving nivolumab–ipilimumab with CBM588 than without (12.7 months versus 2.5 months, hazard ratio 0.15, 95% confidence interval 0.05–0.47, P = 0.001). Although not statistically significant, the response rate was also higher in patients receiving CBM588 (58% versus 20%, P = 0.06). No significant difference in toxicity was observed between the study arms. The data suggest that CBM588 appears to enhance the clinical outcome in patients with metastatic renal cell carcinoma treated with nivolumab–ipilimumab. Larger studies are warranted to confirm this clinical observation and elucidate the mechanism of action and the effects on microbiome and immune compartments.

Dr. Maria Carmen Mir

The current publication (Dizman et al) belongs to a prospective, randomised phase 1 trial on the effect of oral administration of CBM588 (live bacteria) in patients with metastatic renal cell carcinoma (mRCC) receiving ipililumab+nivolumab. A total of 29 patients were included and randomised to receive or not receive the supplements. The primary endpoint was to characterise the effect of CBM588 on the relative abundance of gut microbial populations and specifically Bifidobacterium. The study included mostly patients with synchronic metastatic disease and without cytoreductive nephrectomy. In summary, the results demonstrate that the supplemental bacteria may augment the activity of immunotherapy in this population. In fact, median PFS was prolonged on the supplement group to 12.7 mo vs 2.5 mo on the no-supplement group. Moreover, 75% of patients experienced a reduction on targeted lesions when receiving CBM588.

This is a pioneer trial , the first of its kind in the genitourinary sphere and brings to the table some thought-provoking concepts that require some background description. The stool composition is a new concept for urology. Previous studies had described the relevance of stool diversity on mRCC patients. Abundance of species such as Bifidobacterium adolescentis, Barnesiella intestinihominis, Odoribacter splanch-nicus and Bacteroides eggerthii bring the greatest clinical significance among patients with mRCC (PMID: 32828600). CMB588 is a probiotic containing a specific strain of the anaerobic, butyric acid-forming Gram-positive bacterium Clostridium butyricum with potential immunomodulatory, anti-inflammatory and antineoplastic activities. Upon oral administration of C. butyricum CBM 588 probiotic strain, C. butyricum modulates the composition of the normal gastrointestinal microflora, by increasing the beneficial bacteria and decreasing the harmful bacteria. By restoring gut microbiota, these bacteria may restore or enhance intestinal immune responses. Patients experiencing clinical benefit have greater alpha diversity according to the Shannon index (Shannon diversity Index tells you how diverse the species in a given community are. It rises with the number of species and the evenness of their abundance).

Initial studies on manipulating intestinal microbiota in order to enhance immunotherapy response go back to 2015 (PMID: 26541606), on melanoma cells. The association between probiotic administration and response to immunotherapy use was recently described last year on patients with lung cancer with similar outcomes as described by Dizman et al, however in a retrospective fashion and hypothesizing that Clostridium butyricum probiotic therapy would increase the response rates while on immunotherapy (Tomita, Y. et al. ‘Association of probiotic Clostridium butyricum therapy with survival and response to immune checkpoint blockade in patients with lung cancer.’ Cancer Immunol. Res. 8, 1236–1242 (2020).

Several questions remain unanswered at this point that require further evaluation though phase II and III trials. Antibiotics usage has shown to be detrimental while patients are receiving immunotherapy, would those alter the current results? Similarly for probiotic intake concomitant to therapy. Interestingly, in the current analysis one of the patients on placebo reported to have taken over-the-counter high-dose probiotic with a spectacular response, would that also enhance the current results? Moreover, dosing and frequency of administration and in-depth mechanism of action are still to be determined. Even though preliminary with live bacteria, the concurrent administration of components enhancing host immunity is not new, concepts such as cancer vaccination have been previously postulated to facilitate responses.