Intestinal Akkermansia muciniphila predicts overall survival in advanced non-small cell lung cancer patients treated with anti-PD-1 antibodies: Results a phase II study.
Authors: Derosa Lisa , Routy Bertrand , Zitvogel Laurence , Thomas Andrew M. , Zalcman Gerard , Friard Sylvie , Mazieres Julien , Audigier-Valette Clarisse , Moro-Sibilot Denis , Goldwasser Francois , Richard Corentin , Ghiringhelli François , Barlesi Fabrice , Elkrief Arielle , Alves Costa Silva Carolina , Planchard David , Segata Nicola , Martinez Stéphanie , Soria Jean-Charles , Besse Benjamin 
Published: June 2021

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Background: The gut microbiome, most specifically centered on one of the most prevalent anaerobic bacterium Akkermansia muciniphila (Akk), has emerged as a potential hallmark of clinical benefit to ICI. The goal of this study was to validate the prognostic significance of Akk in advanced NSCLC patients amenable to ICI. Methods: The multicentric prospective observational study enrolled patients with advanced NSCLC amenable to single agent ICI in first and second line. Stool sample was collected at study entry. Primary end-point was investigator-assessed objective response rate (ORR). We considered that a meaningful clinical difference would correlate to a 10% ORR increase in the Akk-Pos group compared to the Akk-Neg group. At least 292 patients equally divided each in each group would be required for a power at 80% and a two-sided alpha level of 5%. Results: From Dec 2015 to Nov 2019, a total of 409 patients were screened and 311 patients enrolled across 12 academic centers in France and Canada. Median age was 64yr, 32% were female, 77% had non-squamous NSCLC and PD-L1 was ≥1% in 70% of the 213 assessable samples. Akk was detectable in 158 (51%) and absent in 153 (49%) patients. Baseline characteristics were well balanced between the two groups. When considering Akk-Pos vs Akk-Neg groups the primary endpoint ORR was 27% and 17% respectively ( p = 0.04). Rates of partial response, stable disease and progressive disease (PD) were 62%, 50% and 46% respectively in the Akk-Pos group compared to 38%, 50% and 54% in the Akk-Neg group ( p = 0.04). Moreover, 57% of patients were still alive after 12 months in the Akk-Pos group vs 43% in the Akk-Neg group ( p = 0.04). Microbiome profiling demonstrated that Akk-Pos group was associated with increase bacterial diversity and enrichment of Ruminococcus, Alistipes and Eubacterium. When considering the variations of the relative abundance of Akk within the Akk-Pos group, we obtained a large interval ranging from 0.0022% up to 64.78% with a 75th percentile at 4.42%. The relative abundance of Akk within > 0% to < 4.42% range in stools at diagnosis was associated with increased ORR, overall survival (OS) in multivariate analysis, independent of PD-L1 expression and ECOG. This sub-group was associated with more inflamed tumors with upregulation of CD3e, IfngTH1 and Vcam-1. Conversely, patients with overrepresentation of Akk > 4.42% experienced more PD and shorter OS. Antibiotic use was associated with a shift in favor of Gammaproteobacteria, enrichment of Akk ( > 4.42%) and shorter OS. Conclusions: We validated the prognostic role of Akk in patients with NSCLC. Stratification based on Akk relative abundance represents a more accurate independent predictor than the binary modality. Our study provides the rationale to develop microbiome-based approach to study gut dysbiosis in routine clinical oncology care. Clinical trial information: NCT04567446.