1068P - Phase II trial of fecal microbiota transplantation (FMT) plus immune checkpoint inhibition (ICI) in advanced non-small cell lung cancer and cutaneous melanoma (FMT-LUMINate)

Background

Trials showed that FMT could improve anti-PD-1 activity in melanoma. Safety of FMT in pts treated with dual ICI and role of FMT in NSCLC are unknown. We report results of NCT04951583 combining FMT+ICI in NSCLC and melanoma.

Methods

A total of 40 pts were enrolled across 5 centres in Canada; 20 advanced PD-L1 ≥50% NSCLC amenable to first-line anti-PD-1 and 20 advanced melanoma amenable to dual ICI. FMT from one healthy donor (HD) was administered in oral capsules after bowel preparation 1 week prior to ICI. A total of 11 different HD were used. The primary endpoint was objective response rate (ORR) in NSCLC. Secondary endpoints included immune-related adverse events (irAE), microbiome shift using shotgun metagenomic sequencing, and metabolomic profiling.

Results

Median follow-up was 7 months (IQR 3.2,12.6). In the NSCLC cohort, median age (mAge) was 68 and 55% were male. FMT alone resulted in grade 1 toxicities. Grade 1-2 irAE occurred in 79%. There were no grade ≥3 irAE. ORR in the first 14 pts was 77%. Final ORR for the NSCLC cohort will be available June 2024. In the melanoma cohort, mAge was 56 and 65% were male. Grade 1-2 irAE occurred in 80% and 65% developed grade ≥3 irAE. 3 pts developed ≥grade 3 myocarditis. 6 (30%) completed 4 cycles of dual ICI. 6/13 (46%) that developed ≥grade 3 irAE in the melanoma cohort received FMT from the same HD, including 2/3 of the myocarditis cases. ORR was 75% (4 pts in CR). Gut microbiome profiling post-FMT showed clustering of responders (R) compared to non-responders (NR). The HD associated with most irAE observed in the melanoma cohort clustered separately from other HDs and was of South Asian origin, compared to the other HDs who were Caucasian. We observed increase of ketone bodies, polyamines and bile salts in R post-FMT while NR accumulated plasma carboxylic acids.

Conclusions

We show for the first time that HD FMT can potentiate activity of ICI across two histologies. In anti-PD-1-treated NSCLC, there were less irAE than expected, while in melanoma treated with anti-PD-1/CTLA-4, a significant proportion of irAE occurred earlier, and may be donor-dependent, suggesting that the gut microbiome may mediate irAE differentially according to ICI backbone.

Clinical trial identification

NCT04951583.

Editorial acknowledgement

Legal entity responsible for the study

Centre de Recherche du CHUM.

Funding

Canadian Cancer Society.

Disclosure

All authors have declared no conflicts of interest.