4 april 2022: ASCO 2021

Uit een tussenevaluatie van een kleine gerandomiseerde studie (30 patiënten totaal) blijkt dat wanneer patiénten met gevorderde nierkanker naast de immuuntherapie met ipilimumab plus nivolumab tijdens de infusen met nivolumab ook oraal een probioticum genaamd Clostridium butyricum CBM 588 innamen de objectieve respons op de immuuntherapie sterk verbeterde met 38 procent. Ook zagen de onderzoekers in een tussenevaluatie na 12,5 maanden een beduidend langere progressievrije overleving (mediaan 55,0 weken vs 10,7 weken) en een trend naar een betere algehele overleving (mediane overleving was echter nog niet bereikt in beide groepen bij de tussenanalyse)

In onderstaande grafiek de resultaten in een tussenevaluatie 15 april 2021 en 28 februari 2022 gepubliceerd in Nature:

a
,b, Progression-free response (a) and overall survival (b). ce, Best response by treatment arm (c), best change in target lesions from baseline (d), and a swimmers plot showing the response and survival characteristics (e). The data are from n = 29 patients (19 patients in the nivolumab–ipilimumab with CBM588 arm and 10 patients in the nivolumab–ipilimumab arm). The Kaplan–Meier log-rank test was used to compare survival between the two arms.

figure 1




De studie opzet:

Patiënten met ten minste op twee plaatsen uitgezaaide voorbehandelde nierkanker werden willekeurig toegewezen aan vier cycli van nivolumab plus ipilimumab therapie om de 3 weken, gevolgd door maandelijks onderhoud met nivolumab, gegeven met of zonder CBM-588 als een oraal supplement van 80 mg tweemaal daags.

Het primaire einddoel van deze studie was een verandering in verschillende soorten Bifidobacterium.
Na 12 weken behandeling werd geëvalueerd bij 19 patiënten die CBM-588 kregen en bij 10 controles.
Gepaarde ontlastingsmonsters toonden aan dat patiënten die CBM-588 kregen een verandering in hun microbioomsamenstelling hadden, met niet-significante toenames in Bifidobacterium, Bifidobacteriumes en Bifidobacteriaceae.

Daarentegen hadden patiënten die nivolumab plus ipilimumab kregen zonder CBM-588 een afname bij alle drie de bacteriestammen en, in tegenstelling tot hun tegenhangers die CBM-588 kregen, testten ze niet positief op C. butyricum.

Het gebruik van CBM-588 was ook geassocieerd met een hogere objectieve respons (58 vs. 20%), evenals een significant langere progressievrije overleving (mediaan 55,0 vs 10,7 weken) en een trend naar een betere algehele overleving (mediaan niet bereikt in beide armen). ).

De frequenties van graad 3 en ernstigere bijwerkingen waren "vergelijkbaar" in de twee groepen, hoewel Dr. Nazli Dizman de woordvoerder van de studiepresentatie waarschuwde dat één patiënt die CBM-588 kreeg graad 4 neutropenie ontwikkelde.
"Beperkingen van deze studie zijn onder meer de kleine omvang" en dat het op één enkele locatie werd uitgevoerd, zei Meza, eraan toevoegend dat de "resultaten niettemin intrigerend zijn en verder onderzoek rechtvaardigen."

Het volledige studierapprot is gratis in te zien of te downloaden. Klik daarvoor op de titel van het abstract:

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

Abstract

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.

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Acknowledgements

We thank the patients and families for their participation in this study. Funding for the study was provided by a grant from the Gateway for Cancer Research (S.K.P; Grant ID: G-20-100). CBM588 was supplied by Miyarisan Pharmaceuticals Co., Ltd. and OSEL, Inc.

Author information

Affiliations

Contributions

Study conception and design: N.S., P.B., P.F., J.H., S.K.H., S.K.P. Project supervision: N.S., P.B., T.D., J.T., M.T., M.K., S.K.H., S.K.P. Participant recruitment and coordination: N.D., L.M., P.B., V.M., M.L., J.H., Z.Z., N.S., S.S., J.M., N.C., A.C.-R., R.M., S.K.P. Data collection and processing: N.D., L.M., P.B., M.A., V.M., M.L., J.H., J.G., L.R., M.T., K.O., S.H., S.K.H., S.K.P. Clinical data analysis: N.D., P.B., P.F., Y.C., J.H., S.K.P. Microbiome analysis: N.D., P.F., Y.C., J.G., M.T., K.O., S.H., S.K.H., S.K.P. Cytokine analysis: N.D., M.A., P.F., Y.C., M.K., S.K.P. Manuscript preparation: N.D., L.M., P.B., M.A., P.F., Y.C., J.H., M.T., K.O., S.H., M.K., S.K.H., S.K.P. Manuscript review and editing: all co-authors.

Corresponding authors

Correspondence to Sarah K. Highlander or Sumanta K. Pal.


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