1172O - Akkermansia muciniphila-based multi-omic profiling in advanced non-small cell lung cancer

Background

Besides PD-L1 expression, biomarkers of response to immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC) are critically needed. Previous studies have demonstrated that the relative abundance (rel abu) of fecal Akkermansia muciniphila (Akk) is associated with clinical benefit, defined by response rate and survival.

Methods

Patients (pts) with advanced NSCLC amenable to upfront ICI, +/- chemotherapy (CT), were prospectively enrolled between June 2021 and March 2024 at Gustave Roussy (NCT04567446). Stool (n=182) and blood (n=202) samples were collected at two different time points: before starting ICI (T0) and after 2 cycles of ICI (T1). Metagenomics (MGS) analyses were used to determine the prevalence and rel abu of Akk in stool samples. Anti-Akk IgG and IgA antibodies were assessed by flow cytometry and ELISA/VIDAS assays were performed on fresh blood to characterize memory T_H17 (IL17) and T_H1 (IFNg; after 22h stimulation by pasteurised Akk) responses. Objective Response Rate (ORR) and Progression-Free Survival (PFS) were assessed.

Results

Among 104 pts with advanced NSCLC, 72% were treated with ICI+CT and 28% with ICI alone. The median follow-up and PFS were 14.5 months (mo) and 9.11 mo, respectively. MGS analyses on 59 pts showed that Akk+ pts (36%) tended to have longer PFS than Akk- pts (64%). After categorizing pts by rel abu - Akk ^hi (>4.799), Akk ^lo (≤4.799), or Akk⁰ (absence of Akk) -, we found both Akk ^hi and Akk ⁰ pts demonstrated a significantly higher proportion of progressive disease (PD) compared with Akk ^lo (p=0.001). Furthermore, Akk ^hi pts had a significantly shorter PFS (p=0.020). Among pts with longitudinal MGS data in the ICI+CT subgroup, 59% showed no change in Akk group, while 41% presented a shift from Akk ⁰ to Akk ^lo between T0 and T1. Among 37 pts, high levels of IgG anti-Akk were correlated with higher rates of PD (p=0.068) and shorter PFS (p<0.0001). Pts who lacked T_H1 and T_H17 memory T cell responses against Akk also had significantly better PFS (p=0.02 / p=0.033, respectively).

Conclusions

These findings suggest that immune responses targeting a clinically relevant and immunogenic commensal (such as Akk) can be deleterious, prompting the use of Akk products to increase response rates, especially in Akk-negative patients.

Clinical trial identification

NCT04567446.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

RHU5 “ANR-21-RHUS-0017” Immunolife Rhu Lumiere: ANR-16-RHUS-0008 SIGN'IT ARC Foundation 2020 and 2023.

Disclosure

L. Zitvogel: Financial Interests, Institutional, Project Lead: EverImmune, EverImmune SAB. All other authors have declared no conflicts of interest.