Impact of gut microbiota (GM) and antibiotic (ATB) use on immunotherapy efficacy in patients with lung cancer (LC): Preliminary results from a prospective trial.

Abstract

e20610 Background: LC is the leading cause of cancer death globally. Immune checkpoint inhibitors (ICI) have changed cancer treatment, but surpass resistance is still a challenge. The GM impact cancer immune-surveillance, and it can be modulated through diet/lifestyle and comedications (such as ATB). Microbiota-based biomarkers and interventions are promising strategies to overcome ICI resistance. We conducted a prospective trial (NCT04965129) to evaluate the impact of GM and ATB in non-small cell LC (NSCLC) patients (pts) treated with ICI. Methods: Pts with NSCLC eligible for ICI were assessed by monthly pharmaceutical visits and weekly telemonitoring to record the use of comedications up to 3 months before ICI start (T0) and from T0 to 4 months post-ICI start (T4), interaction assessment and pharmacotherapeutic follow-up. GM was analyzed at T0 and T4 by 16S rRNA sequencing. Alpha diversity was assessed using Shannon, Simpson, and InvSimpson indices; beta diversity by Bray-Curtis dissimilarity and differential relative frequency analysis using the Mann-Whitney test. Treatment response was evaluated according to RECIST v1.0, considering disease control (DC) if complete response, partial response, or stable disease. Results: We included 27 pts from February 2022 to February 2024: mean age of 70,6 years ± 7,5 [SD], mostly male (59%), with two or more comorbidities (63%), and polypharmacy (74%). Overall, 37% required pharmaceutical interventions and 47% used ATB. Progressive disease (PD) occurred in 88% of ATB users versus 12% of ATB non-users. ATB users and non-users did not differ in alpha or beta diversity. Clostridium difficile was detected in 75% of ATB users versus 0% non-ATB users. The relative frequency analysis brought up 8 species that significantly changed (p<0.05) between T0 and T4 among ATB users, including the pro- inflammatory Bacteroides clarus and Prevotella spp. Inversely, ATB non-users lost oral taxa Streptococcus spp. and gained the health-related Alistipes finegoldii . 81 species differed significantly between PD and DC (p<0.05) pts. All DC pts were positive for Akkermansia muciniphila versus 33% in PD pts, and they were enriched with health-related Lachnospiraceae (Roseburia spp., Blautia spp.) and Alistipes spp. Bacteroides caccae (p=0.035) and Prevotella copri (p=0.045) were present at TO and T4 in all patients. Conclusions: ATB use is associated to PD and pro-inflammatory taxa. Our study is a pioneer in the evaluation of Brazilian pts with LC treated with ICI. We contribute to equity and diversity in GM research towards more robust biomarkers for precision medicine. Clinical trial information: NCT04965129 .