Antibiotic treatment prior to immune checkpoint inhibitor therapy as a tumor-agnostic predictive correlate of response in routine clinical practice.

Abstract

147 Background: Antibiotic therapy (ATB) may impair efficacy of immune checkpoint inhibitors (ICPI) through modulation of gut microbiota. Evidence is however limited to trial participants with non-small cell (NSCLC) and renal cell carcinoma (RCC). In this multi-centre study, we validated the impact of ATB in patients (pts) treated with ICPI in routine practice, irrespective of tumour site. Methods: We analysed a prospective dataset of pts treated with ICPI in 2 centres. We documented timing and duration of ATB administered within 1 month prior to ICPI treatment (pATB) or concurrently (cATB) until ICPI cessation. We evaluated response and overall survival (OS) across ATB+/-. Results: We enrolled 196 pts with NSCLC (n=119), Melanoma (n=38) and other histotypes (n=39). Most pts were male (n=137, 70%) with performance status 0-1 (n=159, 84%) and a median number of 2 metastatic sites (range 0-7). Pts received mostly anti-PD-1/PD-L1 ICPI (n=189, 96%) as first-line metastatic therapy (n=120, 62%). Twenty-nine patients (15%) received pATB with penicillins (n=22, 75%) for ≤7 days (n=26, 89%). Sixty-eight pts (35%) received penicillin-based (n=49, 72%) cATB for ≤7 days (n=39, 88%). Respiratory infections were the commonest indication for both pATB (n=16, 55%) and cATB (n=38, 85%). pATB (p<0.001) but not cATB (p=0.76) was associated with worse OS (26 vs. 2 months, Hazard Ratio 7.4, 95% CI 4.2-12.9) and increased likelihood of primary refractoriness to ICPI (44% vs 81%, p<0.001). pATB consistently worsened OS in NSCLC (26 vs. 2.5 months, p<0.001), melanoma (14 vs 3.9 months, p<0.001) and other tumours (11 vs 1.1 months, p<0.001). In multi-variable analyses pATB (p<0.001, HR 3.4, 95% CI 1.9-6.1) and response to ICPI (p<0.001, HR 8.2, 95% CI 4.0-16.9) predicted for OS independent of histotype, tumour burden, PS. Conclusions: This study suggests pATB to exert an independent detrimental effect on response and survival in unselected pts treated with ICPI in routine clinical practice. Mechanistic studies are urgently required to investigate ATB-mediated alterations of gut microbiota as a determinant of poorer outcome following ICPI treatment.