The Impact of Antibiotics on Prognosis of Metastatic Renal Cell Carcinoma in Japanese Patients Treated With Immune Checkpoint Inhibitors

Abstract

Background/Aim: The present study aimed to examine the influence of antibiotics (AB) on the clinical outcomes of Japanese patients treated with immune check point inhibitors (ICIs) for metastatic renal cell carcinoma (RCC) patients. Patients and Methods: A total of 31 patients with metastatic RCC treated with ICIs from November 2016 to April 2019 were retrospectively reviewed and analyzed. Results: Five patients were treated with AB prior to ICIs treatment. Median progression free survival (PFS) of patients treated with AB vs. patients not treated with AB was 2.8 months and 18.4 months, respectively. The difference between PFS was statistically significant (p=0.0004). In multivariate analyses, AB use (p=0.0377) and presence of immune related adverse events (p=0.0042) were independent prognostic factors for PFS in association with ICIs therapy. Conclusion: The use of AB before ICIs treatment was a predictor of poor ICIs response in metastatic RCC.Immune checkpoint inhibitors (ICIs) that target programmed cell death-1 (PD-1) protein, programmed cell death-ligand 1 protein, and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), have changed the therapeutic landscape and are currently standard treatment options in patients with advanced and metastatic renal cell carcinoma (RCC) (1, 2). Despite the remarkable success of clinical applications, the efficacy of ICIs in RCC varies greatly across individual patients. Some researchers have reported biomarkers for predicting prognosis in patients treated with ICIs, such as PD-L1 and PD-L2 positivity, tumor mutation burden, and profile of immune-related genes (3). Furthermore, the association of immune related adverse events (irAEs) with prognosis in metastatic RCC has been recently reported (4, 5). Thus, it is critical to explore reliable predictors to improve prognosis of RCC patients treated with ICIs.Recently, several studies have demonstrated the crucial impact of human gut microbiota on ICIs therapies (6-9). It is well recognized that antibiotics (AB) alter the diversity and composition of gut microbiota and consequently shift their metabolic capacity (10). The hypothesis was that modulation of gut microbiota by AB may be associated with poor response to ICIs. However, the data on the association between AB use and clinical outcomes with ICIs are limited, especially in Japanese patients with genitourinary cancer.In the present study, we performed a retrospective analysis to examine the influence of AB on the clinical outcomes of Japanese patients treated with ICIs therapy for metastatic RCC patients. Patients and MethodsStudy design and patients. We retrospectively examined clinical information collected from 31 RCC patients treated with ICIs at Kurume University Hospital from November 2016 to April 2019. All patients received nivolumab or the combination of nivolumab and ipilimumab. Nivolumab was intravenously administered at 3 mg/kg or 240 mg/body every 2 weeks. Nivolumab and ipilimumab were administered intravenously at a dose of 240 mg/body and 1 mg/kg, respectiv...

Impact of the corticosteroid indication and administration route on overall survival and the tumor response after immune checkpoint inhibitor initiation

“…25,26 Finally, our results showed that OS was similar in patients treated with inhaled corticosteroids and in those not treated with these drugs, as already described by Li et al 18 Thus, the use of this corticosteroid administration route does not appear to influence the effectiveness of ICIs. 23,[29][30][31][32] ATBs appear to have an indirect negative impact on the ICIs' effectiveness by modifying the composition of gut microbiota. 29,33 However, these results could also be explained by the indication bias -that is, the infection for which the ATB is used -and not the ATB itself.…”

Presence of constipation predicts the therapeutic efficacy of pembrolizumab in metastatic urothelial cancer patients

“…8,9,19 Other reports have shown that antibiotic use reduces the clinical efficacy of immunotherapy in patients with metastatic renal cell and non-small-cell lung cancer. 20,21 It has been widely known that human gut microbiota consists of nearly 1000 bacterial species, and metagenome analyses are improving to acquire the functional information regarding these species. 22 Recently, it was reported that gut microbiota richness is strongly associated with defecation patterns, including stool consistency and frequency.…”

“…Compared with non‐responders to the immunotherapy, responders had more abundance of bacteria of the Ruminococcaceae family, and Bifidobacterium and Faecalibacterium genera, whereas the microbiota of non‐responding patients was enriched with bacteria of the Bacteroides genus 8,9,19 . Other reports have shown that antibiotic use reduces the clinical efficacy of immunotherapy in patients with metastatic renal cell and non‐small‐cell lung cancer 20,21 …”

Die Rolle des Mikrobioms bei urologischen Erkrankungen

“…Das heißt, Patienten, die vor oder während einer Immuntherapie mit Checkpoint-Inhibitoren eine Antibiotikatherapie erhielten, zeigten einen insgesamt ungünstigeren Krankheitsverlauf in Bezug auf progressionsfreies Überleben und Gesamtüberleben. Dieser Zusammenhang wurde in weiteren Studien und Meta-Analysen untersucht und bestätigt [18][19][20][21]. Durch die Antibiotikagabe kam es unter anderem zu einem vermehrten Auftreten von Clostridium hathewayi, was insgesamt zu einem schlechteren Outcome führte [22].…”