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.

Antibiotics impair immune checkpoint inhibitor effectiveness in Hispanic patients with non‐small cell lung cancer (AB‐CLICaP)

“…Compared with the study published by Derosa and colleagues, in the present study we did not observe a difference in PFS. 43 One possible explanation for this difference is the small sample size in our study, which limits the capacity of observing minor differences in PFS between groups.…”

“…This effect on OS was not replicated in patients treated with antibiotics prior to ICI initiation, nor did ATB impact on PFS estimates. 43 In another cohort of 30 patients harboring nonsquamous NSCLC, antibiotic exposure was determined at 30 days prior, or after, the initiation of ICI therapy and a statistically significance of a reduction of around 7.5 months for OS was observed in this subgroup of patients. Contrary to the previous report and the current study, this negative effect also impacted median PFS.…”

“…Furthermore, it is also worth mentioning that this taxon is also diminished in NSCLC compared to healthy controls. 43 Furthermore, the heterogeneous antibiotic administration routes (oral or intravenous), antibacterial spectrum (broad vs. narrow), dosage and duration could be factors that could influence microbiota disruption and are difficult to adjust as confounders in analysis.…”

Cumulative Antibiotic Use Significantly Decreases Efficacy of Checkpoint Inhibitors in Patients with Advanced Cancer

“…In the largest of these, the impact of antibiotic use in patients with RCC and NSCLC was examined across two cancer treatment centers, highlighting an increased risk of progressive disease, with shorter PFS (median 1.9 vs. 7.4 months) and OS (17.3 vs. 30.6 months) in patients who had received antibiotic therapy during their treatment . Other studies have assessed antibiotic therapy more specifically to the month prior of commencing ICI and showed a detrimental effect on response and survival . Preclinical work has demonstrated enhanced efficacy of ICIs in germ‐free or antibiotic‐treated mice receiving FMT from patients who responded to ICI compared with those receiving FMT from patients who did not.…”

Antibiotic use and the efficacy of immune checkpoint inhibitors in cancer patients: a pooled analysis of 2740 cancer patients

“…Finally, 19 studies were included in our quantitative analysis ( Figure 1). 10,[12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] A total of 2,740 patients [mean: 144; median with range: 109 (30-360)] were included in our analysis. The included studies were published between 2017 and 2019 (17/19 studies, 89%, were published in 2018 and 2019) from the United States, the United Kingdom, China, Japan, Canada, Switzerland, Greece, Korea, Austria, and France.…”