259MO - A predictive score of cancer immunotherapy responses based on ecological analysis of gut microbiota

Background

Accumulating evidence points to the clinical relevance of the gut microbiota on outcome of immune checkpoint inhibitors (ICI). Recent work identified a gut oncomicrobiome signature centered by Akkermansia muciniphila (Akk) associated with favorable outcomes to ICI in advanced lung (NSCLC) and kidney (RCC) cancer patients.

Methods

ONCOBIOTICS (NCT04567446) provided shotgun metagenomics sequencing (MGS) of fecal samples from NSCLC and RCC during ICI in France and Canada. We reconstructed topological pearson networks within the microbial ecosystem of patients with overall survival >12 (responders: R) and <12 months (non-responders: NR). Networks of species interacting groups (SIG), notably two highly enriched in harmful (SIG1) or beneficial (SIG2) bacteria, were identified. Then, we computed TOPOSCORE, a monodimensional score based on SIG1/SIG2 ratio combined with Akk relative abundance. Multivariate analysis (MVA) was used to adjust for established prognostic factors.

Results

In two different cohorts with a total of 393 NSCLC, we could classify patients in R or NR using TOPOSCORE. The sensitivity, specificity, positive and negative predictive value were 80%, 47%, 67% and 63%, respectively. The MVA revealed that the TOPOSCORE was an independent prognostic factor (Table). In new cohorts of NSCLC (n=50) and RCC (n=83), TOPOSCORE outperformed PD-L1 and the International Metastatic RCC Database Consortium (IMDC) risk model for RCC in estimating R respectively. Then, we exploited the publicly available datasets of MGS (n=641; NSCLC, RCC and melanoma) to validate TOPOSCORE across different cancer populations. Finally, we developed a friendly user PCR-based score test for SIG bacterial detection allowing the diagnosis of gut dysbiosis within 48 hrs. Table: 259MO

Multivariate analysis for overall survival

Conclusions

TOPOSCORE represents the first easy-to-use and cost-effective tool capable of detecting intestinal dysbiosis associated with longer OS after ICI across cancers on an individual basis. This TOPOSCORE has several implementations, to select donors and recipients of fecal microbial transplantations and follow any microbiota-centered interventions.

Clinical trial identification

NCT04567446.

Editorial acknowledgement

Legal entity responsible for the study

Gustave Roussy.

Funding

LZ and BB were funded by the RHU Torino Lumière (ANR-16-RHUS-0008). LZ and LD were supported by RHU5 “ANR-21-RHUS-0017” IMMUNOLIFE”. LZ was supported by EU-H2020, Project Number: 825410, Project Acronym: ONCOBIOME, Project title: Gut OncoMicrobiome Signatures (GOMS) associated with cancer incidence, prognosis and prediction of treatment response. LZ also received an ANR grant – French-German Ileobiome - 19-CE15-0029-01. LZ and GK received a donation from Seerave Foundation. LZ, LD were supported by the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE). LD AND LZ was supported by SIGN'IT ARC foundation.

Disclosure

C. Alves Costa Silva: Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb. B. Routy: Financial Interests, Personal and Institutional, Research Grant, outside the submitted work: Davoltera, Kaleido, and Vedanta; Financial Interests, Personal and Institutional, Other: patent for G17004-00006-AD (use of castalagin or analogs thereof for anticancer efficacy and to increase the response to immune-checkpoint inhibitors) pending. B. Escudier: Financial Interests, Personal and Institutional, Advisory Role: AVEO; Bristol Myers Squibb; EUSA Pharma; Ipsen; Novartis; Pfizer; Roche/Genentech; Financial Interests, Institutional, Research Grant: BMS France (Inst); Financial Interests, Personal, Sponsor/Funding, Travel, Accommodations, Expenses: Bristol Myers Squibb; Ipsen; MSD; Pfizer; Roche/Genentech; Financial Interests, Personal, Invited Speaker, Honoraria: Bristol Myers Squibb; EUSA Pharma; Ipsen; Novartis; Oncorena; Pfizer; Roche/Genentech. D. Planchard: Financial Interests, Personal, Invited Speaker, Honoraria: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche, Janssen, AbbVie; Financial Interests, Personal, Advisory Role, Consulting, advisory role or lectures: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche, Janssen, AbbVie; Financial Interests, Institutional, Principal Investigator, Clinical trials research as principal or co-investigator (Institutional financial interests): AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo, Janssen, AbbVie; Financial Interests, Personal, Sponsor/Funding, Travel, Accommodations, Expenses: AstraZeneca, Roche, Novartis, prIME Oncology, Pfizer. L. Albiges: Financial Interests, Personal and Institutional, Invited Speaker, consulting fees compensated to the institution, outside the submitted work: Pfizer, Novartis, Bristol Myer Squibb, Ipsen, Roche, MSD, AstraZeneca, Merck, Amgen, Astellas, Exelixis, Corvus Pharmaceuticals, Peloton Therapeutics. L. Zitvogel: Financial Interests, Personal, Invited Speaker: Glaxo Smith Kline, Incyte, Lytix, Kaleido, Innovate Pharma, Daiichi Sankyo, Merus, Pilege, Transgene, Tusk, and Roche. All other authors have declared no conflicts of interest.