# Antibiotic Exposure Does Not Impact Anti-BRAF/Anti-MEK Targeted Therapy Outcome in Patients with Advanced Melanoma

## TL;DR

Antibiotics do not harm outcomes in melanoma patients treated with BRAF/MEK inhibitors, unlike their negative effect on immunotherapy.

## Contribution

This study is the first to show that antibiotics do not impact BRAF/MEK therapy outcomes in melanoma patients.

## Key findings

- Antibiotic use did not worsen objective response rate, progression-free survival, or overall survival in BRAF/MEK inhibitor-treated patients.
- Antibiotics appear uniquely harmful in immunotherapy contexts, not in BRAF/MEK targeted therapy.
- Microbiome effects on treatment outcomes may be context-specific, depending on therapy type.

## Abstract

Although immunotherapy has greatly improved outcomes in advanced melanoma, antibiotics can negatively alter the gut microbiome composition, thereby reducing the effectiveness of immunotherapy. In parallel, BRAF/MEK inhibitors are another key therapeutic option for BRAF-mutated melanoma. However, the impact of antibiotics on outcomes in BRAF/MEK targeted therapy is unknown. In our cohort of 49 melanoma patients treated with BRAF/MEK inhibitors, antibiotic use did not worsen outcomes (objective response rate, progression-free survival, and overall survival). Our findings suggest that antibiotics are uniquely deleterious in immunogenic contexts such as immunotherapy, as opposed to a general effect related to patient fragility. We are currently working to confirm these results in larger, independent patient groups.

The gut microbiome is an established predictor of response to immune checkpoint inhibitors (ICI) in melanoma, and antibiotic exposure prior to ICI initiation is a validated negative prognostic factor. About half of melanoma patients harbor BRAF mutations and are treated with BRAF/MEK inhibitors (BRAFi/MEKi). While the detrimental impact of antibiotics is well described in the ICI setting, their effect on BRAFi/MEKi efficacy remains unknown. We retrospectively analyzed 49 advanced BRAF-mutant melanoma patients treated with BRAFi/MEKi. Antibiotic-exposed patients were compared with non-exposed patients across three time windows: within 30, 60, or 90 days before and after therapy initiation. Outcomes included progression-free survival (PFS), overall survival (OS), and overall response rate (ORR). Among the cohort, 41% had antibiotic exposure within ±30 days, 53% within ±60 days, and 57% within ±90 days. Baseline characteristics were comparable between groups, except for worse ECOG scores in antibiotic-exposed patients. Across all windows, ORR, PFS, and OS were comparable between groups. Unlike what was observed in the ICI setting, antibiotic use did not negatively affect outcomes with BRAFi/MEKi. Despite small sample size, these findings suggest that the detrimental prognostic impact of antibiotics is specific to immunotherapy, highlighting the importance of evaluating the microbiome as a predictive biomarker across treatment contexts.