1452MO - Longitudinal analysis reveals gut microbiota shift during standard therapies in metastatic renal cell carcinoma (mRCC)

Background

Baseline GM composition is associated with pts outcomes in immune-checkpoint blockade (ICB)-treated mRCC. GM shift during mRCC therapies has never been described. We report IMDC risk and tyrosine kinase inhibitors (TKI)’s GM signatures and changes during ICB and TKI treatment.

Methods

We prospectively collected fecal samples of all comers mRCC pts who started a 1^st or >2^nd line (ICB or TKI or combinations) in the NCT04567446 trial at Gustave Roussy. Fecal samples were collected before and during treatment (within 1, 3, 6 and 12 months of treatment start). Shot gun metagenomic sequencing (MGS) data were analyzed by multivariate and pair-wise/fold ratio. Patients under TKI were classified as either responders (R) (CR+PR+SD and OS>12 months) or non-responders (NR) (PD and OS<12 months). Patients under ICB were classified as elite if CR+PR with PFS>12 months and OS>24 months by RECIST1.1.

Results

From February 2016 to July 2021, 160 mRCC pts were screened for enrollment and 127 met inclusion criteria. TKI-ORR was 48%, more than a half experienced related diarrhea and ICB-ORR was 31%. Overall, we observed significant differences in alpha and beta diversity of GM between IMDC risk groups, intermediate IMDC harboring immunogenic commensals (Faecalibacterium, Akkermansia spp, Ruminococcaceae), and between TKI R versus NR, NR harboring pro-TH17 bacteria such as Veillonella parvula. Interestingly, both ICB and TKI induced significant and opposite GM shifts during treatment. While TKI induced pro-Treg tolerogenic bacteria (belonging to Enterocloster genus or diarrhea-associated B. intestinalis and Klebsiella), at the expense of health-related Eubacteriaceae and Bifidobacteria in R patients, ICB promoted the loss of tolerogenic Enterocloster gen. in elite and the loss of health-relatred bacteria in NR.

Conclusions

In this largest longitudinal MGS study, we conclude that in contrast to ICB, TKI favor the over-representation of harmful commensals despite treatment success. TKI increased bacteria related to carcinogenesis, weight loss, sarcopenia and inflammation as a possible consequence of gastrointestinal toxicity. Our data provide new rationale for decision making in first line and treatment sequencing in mRCC.

Clinical trial identification

NCT04567446.

Editorial acknowledgement

Legal entity responsible for the study

Laurence Zitvogel and Lisa Derosa (Gustave Roussy).

Funding

RHU Lumière and Gustave Roussy Foundation.

Disclosure

B. Escudier: Financial Interests, Personal, Other: Bristol Myers Squibb (BMS), Aveo Pharmaceuticals, Eisai, Ipsen, Oncorena, Pfizer. L. Zitvogel: Financial Interests, Other: Bristol Myers Squibb (BMS), Sanofi, Kaleiodo, Roche, Glaxo-SmithKline, Daiichi Sankyo, Transgene; Non-Financial Interests, Member: Everimmune. L. Albiges: Financial Interests, Institutional, Other, Consulting: Astellas, AstraZeneca, BMS, Eisai, Ipsen, Janssen, MSD, Merck, Novartis, Pfizer; Non-Financial Interests, Principal Investigator: Pfizer, BMS, Ipsen, AVEO, AstraZeneca, MSD; Non-Financial Interests, Other, Clinical Trial Steering Committee: Roche, Exelixis; Non-Financial Interests, Member: ASCO; Non-Financial Interests, Other, Medical Steering Committee: Kidney Cancer Association; Non-Financial Interests, Other, Member of the Renal Cell Carcinoma Guidelines Panel: European Association of Urology (EAU); Non-Financial Interests, Other, Member of the Kidney Cancer Research Summit Scientific Committee 2021: Kidney Can; Other, Scientific Committee: BMS France. L. Derosa: Financial Interests, Personal, Other: Bristol Myers Squibb (BMS), Sanofi. All other authors have declared no conflicts of interest.